Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:34])=[C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([C:21]4[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH:26]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9]([CH3:34])=[C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)[CH:11]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4=CCN(C(=O)OC(C)(C)C)CC4)n[nH]c3c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4=CCNCC4)n[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A solution of 1,1-dimethylethyl 4-(6-{5-[(ethylamino)carbonyl]-2-methylphenyl}-1H-indazol-3-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (Intermediate 14, 550 mg) in dichloromethane (10 ml) under nitrogen was treated dropwise with trifluoroacetic acid (0.89 ml) then stirred at room temperature for 2 h. More trifluoroacetic acid (0.89 ml) was added and stirring was continued for a further 1 h. The solvent was evaporated and the residue was dissolved in methanol and applied to an SCX ion exchange cartridge. Elution with a solution of aqueous ammonia (0.88) in methanol (10%) gave the title compound as a white solid (432 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([CH:18]=O)[CH2:14][CH2:15][CH:16]=O)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@:9]21[CH2:18][N:27]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=1)[CH2:16][CH2:15][CH2:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@]1(C=O)CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@]12CCCN(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A solution of [(1R,2S)-2-formyl-2-(3-oxo-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (4.73 g, 16.7 mmol) and 4-fluorobenzylamine (2.3 g, 18 mmol) in dichloromethane (50 mL) was cooled in an ice bath and treated with sodium triacetoxyborohydride (10.1 g, 48 mmol). The resulting mixture was then stirred at room temperature overnight. The mixture was treated with 1.0 N aqueous sodium hydroxide (25 mL) and stirred at room temperature for 1 hour. The organic phase was removed and washed with water and saturated aqueous sodium chloride. The solvent was removed under vacuum to give a residue. The residue was purified by chromatography on silica gel, eluting with 60% ethyl acetate/hexane, to give an oil (6.3 g). 1H NMR (300 MHz, CDCl3) δ7.31-7.24 (m, 2H), 6.97-6.94 (m, 2H), 4.82 (bm, 1H), 3.62 (m, 1H), 3.37 (bs, 2H), 2.42 (m, 1H), 2.20 (m, 3H), 1.69-1.21 (m, 12H), 1.45 (s, 9H). Mass spec (ES+) m+/z 377.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Solvent: CC#N
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(Br)cn1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
To a mixture of 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 42, 0.146 g, 0.48 mmol) in acetonitrile (3 mL), 2-bromo-1-phenylethanone (0.105 g, 0.53 mmol) was added and the reaction mixture was heated to 80° for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting solids were filtered and washed with acetonitrile to yield 164 mg of the title compound as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[N:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:23]([O:27][C:28](=[O:38])[NH:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28](=[O:38])[NH:29][CH2:30][CH2:31][CH:32]1[CH2:33][CH2:34][N:35]([C:11]([C:10]2[CH:14]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[N:16]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][CH:21]=3)[CH:9]=2)=[O:13])[CH2:36][CH2:37]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: CC(C)Oc1cc(C(=O)O)cc(Oc2ccc(C#N)cc2)n1
Product: CC(C)Oc1cc(C(=O)N2CCC(CCNC(=O)OC(C)(C)C)CC2)cc(Oc2ccc(C#N)cc2)n1
Yield: 35.2 %

Procedure:
2-(4-cyano phenoxy)-6-isopropoxy isonicotinic acid (0.20 g, 0.67 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.16 g, 0.7 mmol) were coupled using the procedure of Example 5(c) to afford 0.12 g of the required product. 1H NMR (DMSO-d6): δ 1.12 (2H, m), 1.15 (6H, d), 1.4 (9H, s), 1.6 (2H, m), 1.75 (1H, m), 2.7 (1H, m), 2.98 (3H, m), 3.5 (1H, m), 4.45 (1H, m), 4.8 (1H, m), 6.48 (1H, s), 6.58 (1H, s), 6.8 (1H, brs), 7.38 (2H, d), 7.9 (2H, d).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[N+]1([O-:18])C=CC=CC=1.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[NH4+].[NH4+]>C1(C)C=CC=CC=1.O>[CH3:10][C:4]([CH3:11])([CH2:3][CH:2]=[O:18])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(C)(C)CCBr
Reactant: [O-][n+]1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CC(C)(C)CC=O
Yield: 63 %

Procedure:
A mixture of methyl 5-bromo-3,3-dimethylpentanoate (5.0 g), pyridine-N-oxide (4.49 g), sodium bicarbonate (3.77 g) and toluene (30 cm3) was heated at the reflux temperature with vigorous agitation for a period of 14 hours. After cooling the mixture to the ambient temperature, water (20 cm3), saturated ammonium carbonate solution (20 cm3) and toluene (50 cm3) were added and the aqueous phase separated and extracted with toluene (3×75 cm3). The toluene extracts were added to the main organic phase and the whole dried over anhydrous magnesium sulphate concentrated by evaporation of the more volatile components under reduced pressure. The residual liquid was purified by Kugelrohr distillation (130° C./water pump pressure) to give methyl 3,3-dimethyl-5-oxopentanoate in 63% yield.
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([C:9](=[O:22])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:4](=[O:23])[O:3]1>CCO>[O:22]=[C:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:23]
Reactant: CC1(C)OC(=O)C(C(=O)CCc2ccc(C(F)(F)F)cc2)C(=O)O1
Solvent: CCO
Product: CCOC(=O)CC(=O)CCc1ccc(C(F)(F)F)cc1
Yield: 99.5 %

Procedure:
2,2-Dimethyl-5-{3-[4-(trifluoromethyl)phenyl]propanoyl}-1,3-dioxane-4,6-dione (200 mmol) was dissolved in 500 mL absolute EtOH and refluxed for 3 h. Concentration provided the title compound as a pale yellow oil (57.35 g, 199 mmol, 99.5%, two steps): 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.0 Hz, 2H), 4.15 (m, 2H), 3.42 (s, 2H), 2.96 (m, 2H), 2.90 (m, 2H), 1.24 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.OS(O)(=O)=O.[OH-].[Na+].[CH3:22][CH2:23]O>>[CH2:22]([O:13][C:12]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14])[CH3:23]
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Yield: 82 %

Procedure:
5-Methoxy-1H-indole-2-carboxylic acid (10 g, 52.3 mmol) in EtOH (400 ml) containing 36% H2SO4 (7 ml) was heated under reflux for 18 hr. After cooling the mixture was neutralised with 2N NaOH (to pH 7) and extracted with EtOAc (3×150ml), the combined extracts were washed with 10% NaHCO3 (2×25 ml), dried (MgSO4), filtered and evaporated to afford 5-methoxy-1H-indole-2-carboxylic acid ethyl ester as a brown solid (9.52 g, 43.3 mmol, 82%) Mp. 154-155° C., MS: m/e=219.1 (M+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Brc1ccc(NCc2ncc[nH]2)cc1
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ncc[nH]2)c2ccc(Br)cc2)[C@H]1O
Yield: 60 %

Procedure:
The title compound (570 mg, 60%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (500 mg, 1.78 mmol) and 4-bromophenyl-1H-imidazol-2-ylmethylamine (450 mg, 1.78 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([NH:36][CH2:35][CH2:34][N:31]5[CH2:32][CH2:33][O:28][CH2:29][CH2:30]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: NCCN1CCOCC1
Product: O=C(NCCN1CCOCC1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2-morpholinoethanamine via General Procedure B. The product was purified via reverse phase HPLC to give 22 mg of 255. MS (Q1) 493.8 (M)+.
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[C:5]([C:14]([NH:16][CH2:17][C@@H:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C@H:19]2[OH:31])=[O:15])[C:6]2[O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]=2[CH:13]=1>Cl.CC(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:14]([NH:16][CH2:17][C@@H:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]2[OH:31])=[O:15])[C:6]2[O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)c2cc(Cl)cc3c2OCCCO3)[C@H](O)C1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: O=C(NC[C@@H]1CCNC[C@H]1O)c1cc(Cl)cc2c1OCCCO2
Yield: 5.6 %

Procedure:
A mixture of intermediate (12) (0.095 mol) in a mixture of HCl in 2-propanol (100 ml) and HCl (500 ml) was stirred and refluxed for one hour. The reaction mixture was cooled. The solvent was evaporated. The residue was taken up into DCM and washed with NH3/H2O. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent CH2Cl2/(CH3OH/NH3) 90/10). The product fractions were collected and the solvent was evaporated. A sample (2 g) of this fraction was crystallized from DIPE with a small amount of ACN, filtered off, washed and dried, yielding 1.8 g of (3S-trans)-8-chloro-3,4-dihydro-N-[(3-hydroxy4-piperidinyl)methyl]-2H-1,5-benzodioxepin-6-carboxamide (intermediate 3-t) (mp: 114 ° C.) [α]D20=−14.34° (c=24.41 mg/5 ml in CH3OH).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[S:11][C:7]=2[CH:6]=1)=[NH:4].[C:23](OC(=O)C)(=O)[CH3:24]>>[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10]2[S:11][C:7]3[CH:6]=[C:5]([C:3]4[N:4]=[C:23]([CH3:24])[O:1][N:2]=4)[CH:22]=[CH:21][C:8]=3[N:9]=2)[CH2:17][CH2:16]1)([CH3:19])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Product: Cc1nc(-c2ccc3nc(N4CCN(C(C)C)CC4)sc3c2)no1
Yield: 16.7 %

Procedure:
A solution of N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine (700 mg, 2.19 mmol) in acetic anhydride (20 mL) was heated at 130° C. for 6 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 125 mg (16.7%) of 2-(4-isopropylpiperazin-1-yl)-6-(5-methyl-[1,2,4]oxadiazol-3-yl)benzothiazole as a trifluoroacetate salt.
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[CH3:32][O:33][CH2:34][C@H:35]1[O:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH:10]=[C:6]4[S:5][C:4]([N:37]5[CH2:38][CH2:39][O:40][C@H:35]([CH2:34][O:33][CH3:32])[CH2:36]5)=[N:8][C:7]4=[O:9])=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(O)cc3C(F)(F)F)c2)S1
Reactant: COC[C@@H]1CNCCO1
Product: COC[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
5-({1-[4-Hydroxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one was prepared from 2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2S)-2-Methoxymethyl-morpholine following General Procedure C.
Reaction SMILES: [N:1]([CH:4]([C:11]1([CH3:16])[CH2:15][CH2:14][CH2:13][O:12]1)[C:5]1[O:6][C:7]([CH3:10])=[CH:8][CH:9]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[CH3:10][C:7]1[O:6][C:5]([CH:4]([C:11]2([CH3:16])[CH2:15][CH2:14][CH2:13][O:12]2)[NH2:1])=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(N=[N+]=[N-])C2(C)CCCO2)o1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(N)C2(C)CCCO2)o1
Yield: 96.1 %

Procedure:
A solution of 2.51 g (9.7 mmol, 1 eq) of 2-[azido-(2-methyltetrahydrofuran-2-yl)methyl]-5-methylfuran in 45 ml of ethanol was stirred at hydrogen atmospheric pressure in the presence of 323 mg (15% by weight) of palladium on carbon (Pd/C) at 10% for 16 hours. The reaction medium was filtered and the filtrate was evaporated. 1.82 g of (5-methylfuran-2-yl)(2-methyltetrahydrofuran-2-yl)methanamine were obtained. Yield=96%. TLC/SiO2: heptane/EtOAc (60/40), developing with KMnO4.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:4]=1.[CH3:15][C@@H:16]1[CH2:21][NH:20][CH2:19][C@H:18]([CH3:22])[NH:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][C@H:16]1[NH:17][C@@H:18]([CH3:22])[CH2:19][N:20]([CH2:2][C:3]2[CH:7]=[CH:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:4]=2)[CH2:21]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CC(C)(C)OC(=O)n1ccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccn(C(=O)OC(C)(C)C)n2)C[C@H](C)N1
Yield: 99.6 %

Procedure:
D6 (1.67 g, 6.41 mmol), (2R,6S)-2,6-dimethylpiperazine (0.73 g, 6.41 mmol) and potassium carbonate (1.95 g, 14.1 mmol) in DMF (20 ml) were heated at 50° C. for 2 h. The mixture was concentrated and the residue partitioned between DCM and water (50 ml each). The aqueous layer was re-extracted with DCM (50 ml) and the combined organics washed with brine (100 ml), dried (Na2SO4) and concentrated to yield the title compound as an orange oil (1.88 g). δH (CDCl3) 1.25 (6H, d), 1.15 (1H, br s), 1.64-1.71 (11H, m), 2.77 (2H, m), 2.93 (2H, m), 3.59 (2H, s), 6.40 (1H, d), 8.00 (1H, d). MS (ES): MH+ 295
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.FC(F)(F)S(O[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[N:32][C:33]([N:36]([CH3:47])[CH:37]3[CH2:42][C:41]([CH3:44])([CH3:43])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]3)=[CH:34][CH:35]=2)=[C:26]([OH:48])[CH:25]=1)(=O)=O.C(=O)(O)[O-].[Na+].O1CCOCC1>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.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:31]=[N:32][C:33]([N:36]([CH3:47])[CH:37]4[CH2:42][C:41]([CH3:43])([CH3:44])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]4)=[CH:34][CH:35]=3)=[C:26]([OH:48])[CH:25]=2)[CH:6]=[N:5][CH:4]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CN(c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2O)nn1)C1CC(C)(C)NC(C)(C)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: C1COCCO1
Solvent: O
Product: COc1cncc(-c2ccc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(O)c2)c1
Temperature: 100 °C
Yield: 60 %

Procedure:
Following GENERAL METHOD 1-3 for Suzuki Coupling, to a 25 mL microwave vial, was added 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (94 mg, 0.400 mmol), 3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl trifluoromethanesulfonate (Intermediate 9-2, 105 mg, 0.2 mmol), sodium bicarbonate (50.4 mg, 0.600 mmol) and Pd(PPh3)4 (11.56 mg, 10.00 μmol), followed by dioxane (2 mL) and water (0.5 mL). The reaction mixture was purged with N2 for 10 minutes, and heated in a microwave at 100° C. for 1 h, then diluted with EtOAc and filtered through celite. The filtrate was acidified to pH ˜3 with 1N HCl, and loaded onto an SCX column. The column was washed with MeOH, and eluted with 2N NH3 in MeOH. After concentration, the residue was purified by preparative HPLC to provide 5-(5-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (55 mg, 0.120 mmol, 60% yield), LCMS: Rt=0.50 min [Method Q]; MS (M+1)=448.4; 1H NMR (METHANOL-d4) δ 8.17 (d, J=5.1 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.85 (d, J=7.1 Hz, 1H), 7.22-7.33 (m, 4H), 7.06 (s, 1H), 5.10 (m, 1H), 3.97 (s, 3H), 3.03 (s, 3H), 1.74 (dd, J=12.6, 3.0 Hz, 2H), 1.59 (t, J=12.4 Hz, 2H), 1.42 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]C(OCC)=O)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.CC[O-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[CH2:39]/[C:40](=[N:43]/[H])/[NH:41][OH:42]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[O:42][N:41]=[C:40]([CH2:39][C:33]4[C:34]([Cl:38])=[CH:35][CH:36]=[CH:37][C:32]=4[Cl:31])[N:43]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: [H]/N=C(/Cc1c(Cl)cccc1Cl)NO
Reactant: CCCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3c(Cl)cccc3Cl)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 80.1 %

Procedure:
Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1Z)-2-(2,6-dichlorophenyl)-N-hydroxyethanimidamide (46 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was decanted off and concentrated by nitrogen blowdown. The crude product was purified on the MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (80 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([N:25]1[CH2:33][C:32]2([C:34]([O:36][CH3:37])=[O:35])[CH:27]([C:28](I)=[CH:29][CH2:30][C:31]2([CH3:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO.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>[CH2:18]([N:25]1[CH2:33][C:32]2([C:34]([O:36][CH3:37])=[O:35])[CH:27]([C:28]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:29][CH2:30][C:31]2([CH3:44])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2(C)c1ccccc1
Reactant: COc1ccc(B(O)O)cc1
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: CO
Solvent: Cc1ccccc1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc(OC)cc1)=CCC2(C)c1ccccc1
Yield: 51.7 %

Procedure:
A solution of 20.1 g (0.132 mol) of 4-methoxyphenylboronic acid in 580 cm3 of methanol and 1170 cm3 of a 2N aqueous sodium carbonate solution were successively added to a solution of 58.6 g (0.12 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-methyl-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate and of 7 g of tetrakis(triphenylphosphine)palladium in 30 cm3 of toluene and then the mixture was brought to reflux for twenty-four hours. After returning to a temperature in the region of 20° C., the reaction mixture was extracted with ethyl acetate, washed with distilled water, dried over magnesium sulphate and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (98/02 by volume) mixture. 29 g (52%) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(4-methoxyphenyl)-4-methyl-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were thus obtained in the form of a brown powder, the characteristics of which were as follows:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][N:5]=[C:4]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:3]=12.S(Cl)([Cl:18])=O>>[Cl:1][C:2]1[C:7]([CH2:8][Cl:18])=[CH:6][N:5]=[C:4]2[N:10]([CH2:14][CH3:15])[N:11]=[C:12]([CH3:13])[C:3]=12
Reactant: O=S(Cl)Cl
Reactant: CCn1nc(C)c2c(Cl)c(CO)cnc21
Product: CCn1nc(C)c2c(Cl)c(CCl)cnc21

Procedure:
Into a three necked flask, fitted with a stirrer, reflux condenser and dropping funnel are added 94.6 g. of 4-chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-methanol (0.42 mol.) (U.S. Pat. No. 3,983,128; Example 2). While stirring 475 ml. of thionyl chloride are added dropwise within 45 minutes and the mixture is then refluxed for one and a half hours. The excess thionyl chloride is removed by a rotary evaporator and the residue is dissolved in benzene. The solvent is again removed and the remaining solid product is triturated with ligroin, filtered and dried at 70°, yield 91 g. of 4-chloro-5-chloromethyl-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine, which, after recrystallization from hexane, gives 83.5 g. of pure product, m.p. 96°-97°. Evaporation of the ligroin mother liquor and recrystallization of the residue gives a second crop of 5.7 g. (m.p. 95°-96°). Total yield: 89.2 g. (87%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]2[N:7]=C[S:9][C:5]=2[CH:4]=1)#[N:2].O.NN>CCO>[NH2:7][C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[SH:9]
Reactant: N#Cc1ccc2ncsc2c1
Agent: NN
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(N)c(S)c1
Temperature: 80 °C
Yield: 97.2 %

Procedure:
A mixture of 6-cyanobenzothiazole (532 mg, 3.33 mmol) and hydrazine monohydrate (1.2 ml, 24.76 mmol) in EtOH (10 ml) was heated at 80° C. under N2 atmosphere for 2 hours. The solvent was evaporated, H2O was added to the residue, and the solution was adjusted to pH˜5-7 with AcOH. The resulting yellow precipitate was filtered and washed with H2O, dried under high vacuum to yield the title compound as yellow solid (486 mg, 97%).