Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[NH:12][C:13]3[C:18]([N:19]=2)=[C:17]([O:20][C@H:21]2[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22]2)[N:16]=[CH:15][N:14]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[S:29]([NH2:32])(=[O:31])=[O:30]>CC(N(C)C)=O.CC#N>[S:29](=[O:31])(=[O:30])([O:27][CH2:26][C@H:23]1[CH2:24][CH2:25][C@H:21]([O:20][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[C:18]=2[N:19]=[C:11]([C:1]2[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=2)[NH:12]3)[CH2:22]1)[NH2:32]
Reactant: NS(=O)(=O)Cl
Reactant: OC[C@H]1CC[C@H](Oc2ncnc3[nH]c(-c4cccc5ccccc45)nc23)C1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: NS(=O)(=O)OC[C@H]1CC[C@H](Oc2ncnc3[nH]c(-c4cccc5ccccc45)nc23)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of ((1S,3S)-3-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)-methanol (66.1 mg, 0.000183 mol) in DMA (8.12 mL) at 0° C. was added chlorosulfonamide (106 mg, 0.00091.7 mol) in CH3CN (2.0 mL). The reaction was stirred at 0° C. for 10 mins, then 23° C. for 3 hours. The reaction was quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (2×), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (0 to 6% MeOH/CH2Cl2) to obtain 56.3 mg (70%) of the title compound as a white solid. 1H NMR (CD3OD, 400 MHz) δ: 8.52-8.48 (m, 2H), 8.10-8.07 (m, 111, 8.01-7.98 (m, 1H), 7.90-7.87 (m, 1H), 7.65-7.57 (m, 3H), 5.89-5.85 (m, 1H), 4.12-4.07 (m, 2H), 2.75-2.66 (m, 1H), 2.30-2.21 (m, 2H), 2.16-2.01 (m, 2H), 1.93-1.85 (m, 1H), 1.62-1.53 (m, 1H) ppm. LC/MS: Rt=1.38 min, ES+ 442 (FA standard).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:10][CH2:9][N:8]([O:11][CH2:12][CH3:13])[CH2:7][CH2:6]1)=O.C[O-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:12]([O:11][N:8]1[CH2:9][CH2:10][C:5]2([NH:14][C:15](=[O:26])[C:16]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])=[C:3]2[OH:2])[CH2:6][CH2:7]1)[CH3:13]
Reactant: CCON1CCC(NC(=O)Cc2c(C)cc(C)cc2C)(C(=O)OC)CC1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCON1CCC2(CC1)NC(=O)C(c1c(C)cc(C)cc1C)=C2O
Temperature: 65 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
To a solution of 2.3 g of 1-ethoxy-4-[2-(2,4,6-trimethyl-phenyl)-acetylamino]-piperidine-4-carboxylic acid methyl ester in 26 ml of dimethylformamide was added 3 g of sodium methoxide. The reaction mixture was heated to 65° C. and stirred for 5 hours. The reaction mixture was poured into brine, neutralized and extracted with ethyl acetate. The organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography (heptane/ethyl acetate 2:1) to yield 510 mg of 8-ethoxy-4-hydroxy-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (compound C8) as a solid, mp: >250° C.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8](NC(=O)C1C=CC=CC=1C(F)(F)F)([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[CH3:9].C(O)(=O)C.CCOC(C)=O>C1COCC1.CCOC(C)=O.C1CCCCC1.O>[C:8]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:20])([F:21])[F:19])([CH3:9])=[CH2:7]
Reactant: CC(C)(NC(=O)c1ccccc1C(F)(F)F)NC(=O)c1ccccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C=C(C)NC(=O)c1ccccc1C(F)(F)F
Temperature: 0 °C
Yield: 53.8 %

Procedure:
A solution of KOtBu in THF (1 M, 4.4 ml, 4.39 mmol) was added to a solution of N-[1-methyl-1-[[2-(trifluoromethyl)benzoyl]amino]ethyl]-2-(trifluoromethyl)benzamide (1.53 g, 3.66 mmol) in THF (10 ml). After 16 hours at room temperature the mixture was cooled to 0° C. and acetic acid (0.5 ml) added, and the mixture shaken between EtOAc and water, washed with NaHCO3 (1 M), brine, dried with MgSO4 and evaporated to yield 1.48 g of crude product which contained ca 20% starting material. Chromatography with EtOAc/cyclohexane yielded 451 mg (54%) N-isopropenyl-2-(trifluoromethyl)benzamide. M.p. 95-98° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(O)[C:11]([NH2:16])(CO)CO.Cl.C1N=C(N)C2N=CN([C@@H]3[O:32][C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OP(O)(O)=O)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O.[Mg+2].[Cl-].[Cl-].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].C1S/C(=C2/N=C3C(S/2)=CC(=O)C=C3)/N[C@H]1C(O)=O.N[C@@H](C(O)=O)CS>CS(C)=O>[OH:32][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[C:2]([C:11]#[N:16])[S:1][C:5]=2[CH:6]=1.[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: NC(CO)(CO)CO
Agent: Cl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: N[C@H](CS)C(=O)O
Solvent: CS(C)=O
Product: N#Cc1nc2ccc(O)cc2s1
Reaction time: 0.5 h

Procedure:
Stock solutions of the benzothiazole compounds 3016, 3019, 3026, 3806, 3814, 3820, 3821, 3833, 3835, 3866, and 3868 were made at 50 mM in DMSO. One picomole of each P450 enzyme (Supersomes™, BD Bioscience) was incubated with 50 mM of each of the compounds in a 50 μl, reaction in KPO4 buffer pH 7.4 (25 mM KPO4 for CYP2C9, 50 mM KPO4 for CYP2B6, -2C8, -2C19, -4F2, -4F3A and -4F3B, 100 mM KPO4 for CYP1A1, -1A2, -1B1, -2D6, -2E1, -3A5, -3A7, -2J2, -4F12, -19 and minus P450 control, 200 mM KPO4 for CYP3A4) or 100 mM Tris-HCl, pH 7.5 (for CYP2A6, -2C18 and -4A11). Reactions were initiated by adding an NADPH regenerating system (final concentrations of the regenerating system components in the assay were: 1.3 mM NADP+, 3.3 mM glucose-6-phosphate, 3.3 mM MgCl2, 0.4 U/mL glucose-6-phosphate dehydrogenase and 0.05 mM sodium citrate). Reactions were incubated for 30 minutes at 37° C. After incubation, 50 μl, of P450-Glo™ luciferin detection reagent (available from Promega Corp.) supplemented with 6.6 mM D-cysteine was added to each reaction, allowed to incubate at room temperature for 20 minutes, and luminescence was detected on a Veritas luminometer. FIGS. 14-25 demonstrate that the benzothiazole compounds can also be used to detect CYP450 enzyme activity as light output in this assay scheme. Each compound was active with one or more P450 enzymes and the profile of P450 activity varied across the panel of enzymes depending on the compound structure. The light output specific to a given P450 enzyme can be due to oxidation of the benzothiazole compound by the P450 enzyme to yield 6-hydroxybenzo[d]thiazole-2-carbonitrile (a benzothiazole derivative). The 6-hydroxybenzo-[d]thiazole-2-carbonitrile can then react with D-cysteine to form a D-luciferin derivative that in turns reacts with luciferase in the luciferin detection reagent to generate light in proportion to the amount of D-luciferin present.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH:16]=1)=[NH:5])C.[NH2:27][NH:28][C:29](=O)[CH2:30][N:31]([CH3:33])[CH3:32].C[O-].[Na+]>CO>[CH3:26][O:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:9]1[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]4[N:5]=[C:29]([CH2:30][N:31]([CH3:33])[CH3:32])[NH:28][N:27]=4)[CH:7]=3)[NH:11][N:10]=1)[CH:24]=[CH:23]2
Reactant: CN(C)CC(=O)NN
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc4cc(OC)ccc4c3)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(-c3n[nH]c4ccc(-c5n[nH]c(CN(C)C)n5)cc34)ccc2c1
Temperature: 95 °C
Yield: 5.6 %

Procedure:
To a suspension of ethoxy[3-(6-methoxy(2-naphthyl))(1H-indazol-5-yl)]methanimine (0.430 g, 1.13 mmol) in methanol (5 mL) was added N-amino-2-(dimethylamino)acetamide (0.396 g, 3.38 mmol) and 4.3 M sodium methoxide (0.578 mL, 2.49 mmol). The mixture was heated in a sealed tube at 95° C. for 16 h. The solvent was removed using a rotary evaporator and gave a solid residue. Purification of the residue by preparative HPLC (10-80%, acetonitrile/water) gave the title compound (0.025 g, 5% yield): 1H NMR (DMSO-d6) δ 13.95 (br s, 1H), 13.40 (br s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.09 (t, 2H), 8.00 (t, 2H), 7.68 (d, 1H), 7.39 (d, 1H), 7.21 (dd, 1H), 3.90 (s, 3H), 3.60 (s, 2H), 2.22 (s, 6H); ES-MS (m/z) 399 [M+1]+.
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>C(O)C>[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:5][CH:4]=1
Reactant: OCCCCCCCl
Reactant: Nc1ccc(S)cc1
Agent: [Na]
Solvent: CCO
Product: Nc1ccc(SCCCCCCO)cc1
Reaction time: 1 h

Procedure:
Sodium metal (24 g, 1.05 mol) was added cautiously, in small portions, to 1 liter of stirred absolute ethanol under nitrogen. When the sodium has dissolved, 125 g (1.0 mol) of 4-aminothiophenol was added slowly. 6-Chlorohexanol (143 g, 1.05 mol) was added in small portions, and the resulting mixture was heated at reflux with stirring for one hour. The reaction mixture was cooled, filtered, and the ethanol was evaporated at reduced pressure. The residue was taken up in dichloromethane, and the solution was washed with water, with 5% NaHCO3 and again with water. The organic layer was dried (Na2SO4), concentrated, and the solid residue was recrystallized from ethanol. A pale yellow solid was obtained, mass 156 g.
Reaction SMILES: CO/C=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[C:15](/[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=[N:16]/[O:17][CH3:18])/[C:5]([O:7][CH3:8])=[O:6].[Mn]([O-])(=O)(=O)=[O:30].[K+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl.O.S([O-])(O)(=O)=O.C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC>[CH3:18][O:17]/[N:16]=[C:15](\[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=1)/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:4](=[O:30])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1/C(=N/OC)c1cccc(C(F)(F)F)c1
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: O=S(=O)([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CO/N=C(\c1cccc(C(F)(F)F)c1)c1ccccc1C(=O)C(=O)OC
Reaction time: 2 h
Yield: 54.4 %

Procedure:
A solution of (E,E)-methyl 3-methoxy-2-[2-(methyl(3-trifluoromethyl-phenyl)oximinomethyl)phenyl]propenoate (2.0 g as prepared in EP-A-0370629) in dichloromethane (20 ml) was added to potassium permanganate (0.93g) in water (20 ml) containing tetra-n-hexyl-ammonium hydrogensulphate (0.1 g). After stirring for 2 hours, the reaction mixture was poured into sodium metabisulphite solution (40 mls of a 10% aqueous solution) and extracted with dichloromethane. The combined organic extracts were dried, concentrated and chromatographed using a mixture of ether and hexane (1:1) as the eluant to give (E)-methyl 2-[methyl(3-trifluoromethylphenyl)oximinomethyl]phenylglyoxalate (1.01 g, 54% yield) as a clear oil; 1H NMR : δ2.31(3H,s), 3.92(3H,s), 5.60(2H,s), 7.4-7.9(8H,m) ppm; IR maxima (film): 1740, 1686 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[CH:15][P:16]([O:25][CH3:26])([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])=[C:12]([CH:27]([CH3:29])[CH3:28])[CH:11]=[C:10]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:9]=2)=[CH:4][CH:3]=1.CC(O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](/[CH:14]=[CH:15]/[P@@:16]([O:25][CH3:26])([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])=[C:12]([CH:27]([CH3:28])[CH3:29])[CH:11]=[C:10]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCCP(=O)(C=Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)CCC[P@@](=O)(/C=C/c1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
A solution of (S,E)-3-[[1,1-Dimethylethyl)diphenylsilyl]oxy]-4-[[2-[2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoic acid, methyl ester (241 mg, 0.321 mmol) in THF (7 ml) was treated with HOAc (92 ul, 96 mg, 1.61 mmol) and tetra-n-butylammonium fluoride (1.0M in THF, 963 ul, 0.963 mmol). After stirring at room temperature for 18 hours, the solution was poured into saturated NaHCO3 and extracted with EtOAc. The EtOAc extract was washed with brine, dried, (Na2SO4), filtered, and stripped to give an oil which was subsequently chromatographed (flash, Merck SiO2, 1:1 acetone:hexane followed 100% acetone). (S,E)-4-[[2-[2-(4-Fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinyl]ethenyl]methoxyphosphinyl]butanoic acid, methyl ester (124 mg, 76%) was obtained as a colorless oil.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:40])[CH2:11][C@H:12]([C:17](=[O:39])[NH:18][C@H:19]1[CH2:36][C:35]2=[CH:37][N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=32)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:38])[CH2:13][CH:14]([CH3:16])[CH3:15])C1C=CC=CC=1.C1COCC1>C(O)C.[Pd]>[OH:8][NH:9][C:10](=[O:40])[CH2:11][C@H:12]([C:17](=[O:39])[NH:18][C@H:19]1[CH2:36][C:35]2=[CH:37][N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=32)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:38])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C[C@H](CC(=O)NO)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 4 h
Yield: 91.9 %

Procedure:
Alternatively, (3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6. 1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide (1.0 g, 1.83 mmol) was taken up in a solution of 20% THF in ethanol (500 mL) and then Pd on activated charcoal (200 mg) was added portionwise. The resulting slurry was stirred as H2 gas was gently bubbled through the solution. After 4 hours, the reaction mixture was suction filtered through a bed of celite (1.5 cm), and the filtrate was concentrated and then taken up in methanol (30 mL) and filtered through a plug of cotton. Recrystallization from methanol/ethyl acetate/ether/petroleum ether gave (3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-yl-carbamoyl)hexanamide (768 mg, 92%), MS: 455 (M-H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])[CH2:16][CH2:15][C:14]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])(O)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.N12CCCN=C1CCCCC2>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[F:30])[CH2:16][CH2:15][C:14](=[CH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CC1(O)CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)C=C1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The alcohol from the foregoing step (420 mg, 0.88 mmol) in dichloromethane (20 mL) was cooled to 0° C. under nitrogen and triethylamine (0.25 mL, 1.7 mmol) and methane sulfonyl chloride (0.1 mL, 1.3 mmol) were added. The reaction was stirred for 1 hour at 0° C. then further triethylamine (0.5 mL, 3.4 mmol) and methane sulfonyl chloride (0.21 mL, 2.7 mmol) added. After a further 30 minutes, the solution was washed with 2N aqueous hydrochloric acid (2×10 mL) and brine (10 mL), dried (MgSO4), evaporated and the residue taken up in tetrahydrofuran (20 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL, 1.7 mmol) was added and the mixture stirred for 5 minutes. Ethyl acetate (30 mL) was added, the solution washed with 1N aqueous sodium hydroxide (20 mL), and the aqueous layer extracted with further ethyl acetate (10 mL). The combined organic layers were washed with 2N aqueous hydrochloric acid (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by flash column chromatography on silica eluting with ethyl acetate:iso-hexane 1:1, to afford the desired product (196 mg).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Br:24])[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:25](=[O:27])[CH3:26])[CH2:9][CH2:8]1)(=O)=O.[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>C(#N)C.O1CCOCC1>[C:25]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][C@H:10]1[CH2:11][CH2:12][C@H:7]([CH2:6][N:31]3[CH2:32][CH2:33][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:30]3)[CH2:8][CH2:9]1)=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 70 °C

Procedure:
To a solution of ((trans-4-((3-acetyl-6-bromoquinolin-4-yl)amino)cyclohexyl)methyl methanesulfonate (300 mg, 0.66 mmol) and tert-butyl piperazine-1-carboxylate (566 mg, 3.0 mmol) in acetonitrile (5 mL) and dioxane (5 mL) was added KI (500 mg, 3.0 mmol) and N,N-diisopropylethylamine (0.60 mL, 3.44 mmol) and the reaction mixture was heated at 70° C. for 16 h. The solution was cooled to room temperature, diluted with satd. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica, 0-20% methanol/dichloromethane) to afford the desired product (248 mg, 69%) as an off-white solid. ESI MS m/z 545 [C27H37BrN4O3+H]+
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.Cl[C:18]1[N:23]=[C:22]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1.C(O)CCC>CO>[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:18]2[N:23]=[C:22]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH:21]=[CH:20][N:19]=2)=[CH:8][CH:7]=1
Reactant: Clc1nccc(N2CCc3ccccc32)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Solvent: CO
Solvent: CCCCO
Product: CN(C)CC(O)COc1ccc(Nc2nccc(N3CCc4ccccc43)n2)cc1
Temperature: 100 °C
Yield: 64.4 %

Procedure:
A hot solution of 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 1, 219 mg, 0.77 mmol) in methanol (2 ml) was added to a solution of 2-chloro-4-(indolin-1-yl)pyrimidine (Method 3, 200 mg, 0.86 mmol) in ii-butanol (20 ml). The mixture was heated at 100° C. for 18 hours and silica (1 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-5% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (201 mg, 61%). NMR: 2.19 (s, 6H), 2.21-2.3 (m, 1H), 2.3-2.4 (m, 1H), 3.1-3.25 (m, 2H), 3.8-4.1 (m, 5H), 5.75 (m, 1H), 6.2 (m, 2H), 6.8-6.9 (m, 3H), 7.0-7.1 (m, 1H), 7.15-7.25 (m, 1H), 7.5-7.6 (m, 2H), 8.05-8.1 (m, 1H), 8.3-8.4 (m, 1H), 8.95 (s, 1H); MS (MH+): 406.5.
Reaction SMILES: NC1N=C(N)C2C(=NC=C([CH2:13][N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)N=2)N=1.C1C2NC3C(=CC=CC=3)C=2C=CC=1.[H-].[Na+].Br.[NH2:43][C:44]1[N:49]=[C:48]([NH2:50])[C:47](CBr)=[CH:46][N:45]=1>>[NH2:43][C:44]1[N:49]=[C:48]([NH2:50])[CH:47]=[C:46]([CH2:13][N:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:22]3[C:21]2=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:45]=1
Reactant: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Nc1cc(Cn2c3ccccc3c3ccccc32)nc(N)n1

Procedure:
N-[(2,4-Diaminopyrimidin-6-yl)methyl]carbazole (Formula I: Ar=2,4-diaminopyrimidin-5-yl; W=CH2; X=N; Z=chemical bond; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using carbazole (129 mg, 0.77 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-5-bromomethylpyrimidine hydrobromide (86 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([O:18]C(=O)C)[CH2:16]3)[CH:13]=[N:14][C:7]=12.N1C=CC=CC=1.C(N(C(C)C)CC)(C)C.P(N)(OCl)[O:42]N(C(C)C)C(CCC#N)(C)C>C(OCC)(=O)C.CO.C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:15]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([OH:18])[C@H:16]3[OH:42])[CH:13]=[N:14][C:7]=12
Reactant: CC(C)N(OP(N)OCl)C(C)(C)CCC#N
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(-c4cccs4)ccnc32)O[C@@H]1CO
Solvent: CO
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: OC[C@H]1O[C@@H](n2cnc3c(-c4cccs4)ccnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 220.2 %

Procedure:
Compound 9 (290 mg, 0.47 mmol) was azeotroped with pyridine, followed by addition of THF (2.4 ml) and diisopropylethylamine (123 μl, 0.7 mmol). To this solution, 2-cyanoethyl-N,N-diisopropylamino chloro phosphoroamidite (115 μl, 0.52 mmol) was added and stirred at room temperature for 1 hour. After addition of methanol (50 μl), the reaction mixture was diluted with ethyl acetate:triethylaime (20:1, v/v) and partitioned with 5% aqueous NaHCO3. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and then purified on a silica gel column to give Compound 11 (345 mg, 90%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][N:31]([C:41](=[O:43])[CH3:42])[CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCNCC2)ns1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n2)CC1
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (29.52 g, 61.81 mmol) and triethylamine (21.54 ml, 154.5 mmol) were dissolved in THF (300 mL). Acetic anhydride (6.310 g, 61.81 mmol) was added and the reaction was stirred for 90 minutes. Saturated sodium bicarbonate (200 mL) and water (400 mL) were added and the reaction mixture was extracted with dichloromethane and 10% methanol in dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in MeOH (˜75 mL) and let stand. The resultant solids were filtered and washed with cold methanol to give a first crop (22.3 g). The filtrate was concentrated and solids were redissolved in methanol (30 mL) and allowed to stand. The precipitated solids were filtered and washed to afford a second crop (4.3 g). The 2 crops were combined to afford 1-(4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (26.7 g, 51.38 mmol, 83.13% yield).