Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=O)[N:7]([CH2:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:6]=2[C:5]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:8]1[N:7]([CH2:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:6]2[C:5]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[N:9]=1
Reactant: CCC(CC)c1ccc(Cl)c2[nH]c(=O)n(CC(=O)OC(C)C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Temperature: 100 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
A mixture of isopropyl [4-chloro-7-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate (14.5 g, 42.8 mmol) and phosphorus oxychloride (60 mL) was stirred at 100° C. for 3 days. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was poured into ice-cold saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×2). The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-15% ethyl acetate/n-hexane gradient mixture to give the title compound (14.1 g, 39.5 mmol, 92%) as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]=[O:13])[CH:3]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH2:12][OH:13])[CH:3]=1
Reactant: O=Cc1cc(F)c2c(c1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: OCc1cc(F)c2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
8-fluoro-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (0.87 g: 4.8 mmol) was dissolved in ethanol (20 ml) and sodium borohydride (0.45 g; 11.95 mmol) was added at 0° C. The reaction mixture was stirred at rt for 2 h and poured into ice-water. The pH was adjusted to 5 by adding glacial acetic acid in portions and the aqueous mixture was extracted with ethyl acetate (80 ml). The organic phase was washed with water (30 ml), brine (30 ml), dried over sodium sulfate and concentrated under vacuum to give (8-fluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methanol (0.84 g; 95% yield) as a yellow oil. 1H NMR (400 MHz, CD3OD) δ 6.66 (dd, 1H), 6.64 (br. s, 1H), 4.44 (s, 2H), 4.26 (s, 4H)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[Li+].Br[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CN(C)CCBr
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)[O-])cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCN(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
To a solution of lithium 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 20) (246 mg, 0.591 mmol) and 2-bromo-N,N-dimethylethanamine (135 mg, 0.886 mmol) in DMF (5 mL) was added potassium carbonate (122 mg, 0.886 mmol). The resulting mixture was stirred at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a 1:1 MeOH/DMSO mixture and purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 2-(dimethylamino)ethyl 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (14.5 mg, 5%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.72 min, MH+=482.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26]Br)=[N:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=3)[C:4](=[O:18])[CH:3]=2)=[N:24][CH:25]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: BrCc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.23 g (5.00 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 8.0 mL DMF is added 1.26 g (5.00 mmol) 5-bromo-2-bromomethyl-pyridine and 2.07 g (15.0 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 80 mL of water, the formed precipitate is collected and dissolved in DMF. The solution is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C@H:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[OH:11])[C:23](=[O:24])[CH2:22][Cl:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: O[C@H](CNCc1ccccc1)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)N(Cc1ccccc1)C[C@@H](O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
Dissolve (1S)-2-(benzylamino)-1-(4-fluorophenyl)ethanol (1215 g, 4.96 mol) in 12.15 L DCM and cool the mixture to 0° C. Add NaOH (1M in H2O, 5.46 L, 5.46 mol) dropwise over 30 min. Stir the mixture vigorously for 10 min while maintaining it at 0-3° C.; then add a solution of chloroacetyl chloride (616.5 g, 5.46 mol) in 4.86 L of DCM dropwise over 1 h keeping the temperature below 6° C. Stir the mixture for 1 h at 0° C.; separate the layers; and extract the aqueous phase with DCM (1×2 L). Combine the organic layer and extracts; wash them with 10% hydrochloric acid (1.5 L), water (1.5 L) and 1M NaOH (1 L). Dry over Na2SO4 and filter. Collect the filtrate and remove the solvent under reduced pressure to provide the title compound as a colorless oil (1440 g, 90%). MS (m/z): 322 (M+1).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][CH:2]=1.[H-].[Na+].Cl[CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=2[CH:15]=1>CN(C=O)C>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:13][C:14]2[CH:24]=[CH:23][C:17]3[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=3[CH:15]=2)[CH:2]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: c1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of 3H-imidazo[4,5-b]pyridine (2.99 g, 25 mmol) in DMF (100 mL) was added sodium hydride (60% in mineral oil, 1.0 g, 25 mmol) slowly at 0° C. After the reaction mixture was stirred at rt for 20 min, it was treated with a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole from Step 3 of this Example (4.8 g, 21 mmol) in DMF (20 mL) at 0° C. The reaction mixture was then stirred at rt overnight. The mixture was quenched with 3 mL of saturated aq NH4Cl and concentrated under reduced pressure. The residue was diluted with 600 mL of EtOAc and washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure The crude product was purified on a silica gel column using a mixture of MeOH—CH2Cl2 (1:30, v/v) as eluent to give 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole as a tan solid (2.5 g, 38%). The regiochemistry of the alkylation was determined by a 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.38 (dd, J=1.2, 4.8 Hz, 1H), 8.11 (dd, J=1.3, 8.1 Hz, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.46 (dd, J=1.6, 8.4 Hz, 1H), 7.30 (dd, J=4.8, 8.0 Hz, 1H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]([OH:6])=[O:5])[Cl:3].[CH2:7]=[CH:8][CH2:9][CH2:10]O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COC(C)(C)C.O>[CH3:1][CH:2]([C:4]([O:6][CH2:10][CH2:9][CH:8]=[CH2:7])=[O:5])[Cl:3]
Reactant: C=CCCO
Reactant: CC(Cl)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: C=CCCOC(=O)C(C)Cl
Reaction time: 0.17 h

Procedure:
CH3CHClCOOH (50 g)and CH2═CH(CH2)2OH (75 ml) were put into a flask and stirred and 10 ml of concentrated sulfuric acid was added dropwise thereto over period of 10 minutes at room temperature. The resulting reaction solution was added to 250 ml of a saturated sodium carbonate aqueous solution. Water (150 ml) and tert-butyl methyl ether (150 ml) were added thereto, followed by liquid separation to obtain a tert-butyl methyl ether layer as an organic layer. Further, the organic layer was washed with 150 ml of water, dried over magnesium sulfate and then subjected to filtration to obtain a crude liquid. The crude liquid was concentrated to obtain CH3CHClCOO(CH2)2CH═CH2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:20])=[N-]>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:20][CH:12]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1ccc(C(C)(C)C)cc1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C1CC1c1ccc(C(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a −40° C. solution of (E)-ethyl 3-(4-tert-butylphenyl)acrylate (1.0 g, 4.3 mol) in ether (20 mL), freshly prepared diazomethane was added dropwise over 10 minutes. Pd(OAc)2 (30 mg, 0.133 mol) was then added. The reaction mixture was stirred for another 10 min at −40° C., and then filtered through a pad of Celite® and precipitate washed with ether. The filtrate was concentrated in vacuo and the crude material was then purified via silica gel column chromatography to afford ethyl 2-(4-tert-butylphenyl)cyclopropanecarboxylate (0.9 g, 84%) as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=O)[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:28]>O1CCOCC1>[Cl:28][C:7]1[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(Cl)c2nc(Cl)ccc2n1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a suspension of 2-acetamido-6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (2.38 g, 10 mmol) and DIEA (5.2 mL, 30 mmol) in dioxane (120 mL) was added POCl3 (2.8 mL, 30 mmol). The mixture was heated to 80° C. for 2 hours. After removal of solvent, the residue was stirred with crashed ice for 10 minutes, then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness providing the pure title compound as a brown solid (2.01 g, yield 78%) which was characterised as follows: MS (m/z) 256.9 [M+H]+.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:30]1SC2C=C(C)C=CC=2N=1>>[CH3:30][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(Cl)sc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Cc1ccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc2c1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-6-methyl-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 3.12 (q, J=10.6 Hz, 2H), 3.42 (d, J=12.4 Hz, 2H), 4.47-4.57 (m, 1H), 7.41 (d, J=6.9 Hz, 1H), 7.96-8.02 (m, 2H), 8.05 (s, 1H), 8.31 (br. s., 1H), 8.38 (s, 1H), 8.49 (d, J=2.2 Hz, 1H). MS (ES+): m/z=391.15 [MH+]. HPLC: tR=2.22 min (ZQ2, polar—5 min).
Reaction SMILES: [CH2:1]([C:3]1[O:7][CH:6]=[N:5][CH:4]=1)[CH3:2].[CH2:8]([O:10][C:11](=[O:32])[N:12]([C:21]1[CH:26]=[C:25](Br)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:9]>>[CH2:8]([O:10][C:11](=[O:32])[N:12]([C:21]1[CH:26]=[C:25]([C:6]2[O:7][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=2)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:9]
Reactant: CCc1cnco1
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2ncc(CC)o2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 5-ethyl-oxazole (47 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (79 mg) as a yellow gum.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[C@@H:11]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCCCCC.C(O)(C)C>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([OH:15])[C@H:11]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cn1nccc1[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1O
Solvent: CCCCCC
Solvent: CC(C)O
Product: Cn1nccc1[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]1O

Procedure:
The (1S*,2R*,4R*)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol prepared in Example 161a was optically resolved with CHIRALFLASH IC (Daicel Corp.; hexane/isopropanol=6:4) to yield the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14][CH3:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1>CC(O)=O.[Fe]>[F:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14][CH3:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CSc1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: CSc1cc2ncnc(Oc3ccc(N)cc3F)c2s1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
To a solution of 281 (288 mg, 0.94 mmol) in AcOH (25 mL) at 90° C., was added iron powder (238 mg, 4.25 mmol), and the reaction mixture was stirred vigorously at 90° C. for 10 min, cooled, filtered through a Celite pad and concentrated. The residue was purified by flash column chromatography (eluent EtOAc) to afford the title compound 282 (248 mg, 95%) as an off-white solid. MS (m/z): 308.1 (M+H) (found).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH:35]([CH3:38])[CH2:36][CH3:37]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH:35]([CH3:38])[CH2:36][CH3:37])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CCC(C)CBr
Product: CCC(C)CN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 43.1 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 1-bromo-2-methyl butane (103 mg, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(2-methyl-butyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 42%).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](Cl)=[O:19])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[NH3:22].O>C1COCC1>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18](=[O:19])[NH2:22])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: N
Reactant: CCCCCCCCC1Cc2ccc(C(=O)Cl)cc2C1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCC1Cc2ccc(C(N)=O)cc2C1
Temperature: 0 °C
Yield: 92.1 %

Procedure:
In a 50 ml-round bottomed flask, 5.00 g (18.2 mM) of 2-octylindan-5-carboxylic acid was placed and 7.0 ml of thionyl chloride and one drop of N,N'-dimethylformamide (DMF) were added thereto, followed by heat-refluxing for 30 minute. An excessive thionyl chloride was distilled off under reduced pressure from the above mixture to obtain 2-octylindan-5-carbonyl chloride. A solution of the above-obtained 2-octylindan-5-carbonyl chloride in 50 ml of THF was gradually added dropwise to 45 ml of 30%-ammonia water which had been cooled to about 0° C. on an ice-common salt bath under stirring. After the addition, the resultant mixture was stirred for 4.5 hours at room temperature. After the reaction, 300 ml of water was added to the reaction mixture to precipitate a crystal. The crystal was recovered by filtration and successively washed with water and methanol to obtain 4.59 g of 2-octyl-5-carbamoylindan (Yield: 92.1%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21]>C(Cl)Cl>[CH2:19]([NH:22][C:23]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH3:11])=[O:9])=[O:24])[CH2:20][CH3:21]
Reactant: CCCN=C=O
Reactant: COC(=O)c1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)Nc1ccccc1C(=O)OC
Yield: 94.9 %

Procedure:
A mixture of 159 g of methyl anthranilate (1.053 mole), 5 ml of triethylamine and 134 g of n-propylisocyanate (1.58 mole) in 700 ml of petroleum ether (60°-80° C.) was refluxed for seventeen hours until TLC (CH2Cl2, silica) indicated that no methyl antranilate remained. The mixture was cooled and the precipitate was filtered off, washed with a little cold petroleum ether and dried under vacuum at room temperature to obtain 236 g (95% yield) of methyl N-(N'-n-propylcarbamoyl)-anthranilate melting at 101.5°-102.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:4]=2[NH:5][N:6]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:5]1[C:4]2[CH2:7][NH:8][CH2:9][C:3]=2[C:2]([NH2:1])=[N:6]1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1n[nH]c2c1CNC2

Procedure:
tert-Butyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (3670 mg, 16.36 mmol) was treated with TFA/CH2Cl2 (v/v=1/1) for 1 h. The reaction mixture was concentrated and the residue was treated with CH2Cl2/hexanes and then concentrated to give a solid. The product was passed through ion-exchange resin Strata X—C™ to give the title product (LC-MS: 125.05 (M+1)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[C:7]1([CH2:13][CH2:14][NH2:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:1][O:2][CH2:3][C:4]([NH:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COCC(=O)Cl
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)NCCc1ccccc1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Methoxyacetyl chloride (19.57 g, 0.18 mol) was added over 10 minutes to a stirred, ice-cooled solution of 2-phenylethylamine (21.85 g, 0.18 mol) and N-ethyldiisopropylamine (23.26 g, 0.18 mol) in dichloromethane (200 ml). After 2 hours at room temperature, the solvent was removed under reduced pressure and the residue partitioned between ether and water. The organic phase was washed successively with 1M aqueous citric acid solution, water, saturated aqueous sodium bicarbonate solution and water, dried (MgSO4) and evaporated under reduced pressure to provide the required product (29.65 g) as an oil, Rf 0.32 (SS 2), which was used without further purification in the next step.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].Cl[C:10]1[N:14]2[N:15]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:18][C:13]2=[N:12][N:11]=1>C1COCC1>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:16]1[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:18][C:13]2[N:14]([C:10]([O:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:11][N:12]=2)[N:15]=1
Reactant: OC1CCCCC1
Reactant: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Agent: [Na]
Solvent: C1CCOC1
Product: Clc1ccc(-c2cc3nnc(OC4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.6 %

Procedure:
To a solution of cyclohexanol (0.5 g, 5 mmol) in anhydrous THF (1 mL) at room temperature was added freshly cut sodium metal (35 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 20 min, then at 60° C. for 30 min, and then allowed to cool to room temperature. Into this mixture was added 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (115 mg, 0.3 mmol), the resulting mixture was stirred at room temperature under argon for 16 h. The reaction was carefully quenched by addition of methanol, then diluted with EtOAc. The solution was washed with H2O, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated. The obtained residue was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-40%) in hexanes to afford 10 mg (7.6%) of the title compound as a pale-yellow solid. HPLC/MS (method A): retention time=4.06 min, (M+H)+=439.1. 1H NMR (CDCl3, 400 MHz): δ 7.84 (s, 1H), 7.46 (dd, J=5.62, 3.67 Hz, 1H), 7.32-7.37 (m, 2H), 7.25-7.30 (m, 1H), 7.20 (d, J=8.56 Hz, 2H), 7.03-7.08 (m, 2H), 5.21-5.29 (m, 1H), 2.28 (d, J=12.96 Hz, 2H), 1.88 (d, J=4.40 Hz, 2H), 1.60-1.80 (m, 3H), 1.45-1.52 (m, 2H), 1.20-1.40(m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH:11]3[C:18]#[N:19])[CH2:9]1)[CH2:15]2)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH:11]3[C:18]#[N:19])[CH2:9]1)[CH2:15]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(C#N)C(C3)C2
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1C2CC3CC1CC(N)(C3)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7C (30 mg, 0.10 mmol) in 2 mL of 1,4-dioxane was added HCl (4N in 1,4-dioxane, 1.0 mL). The mixture was stirred at rt for overnight. The solvent was removed under vacuum. The resulting residue was dissolved in 2 mL of water and was washed with EtOAc (5 mL×3). The water was the removed under vacuum to give the title compound as hydrogen chloride salts (7) respectively (20 mg). LC-MS (ESR): m/z=177 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:4]([CH3:21])[CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.CC([O-])=O.[Na+]>CC(O)=O.C(Cl)Cl>[Br:29][C:10]1[S:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:21])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)ccc1-c1ncsc1-c1ccc(Cl)cc1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1-c1nc(Br)sc1-c1ccc(Cl)cc1C
Yield: 93 %

Procedure:
A solution of 4,5-Bis(4-chloro-2-methylphenyl)thiazole (170 mg, 0.51 mmol), NBS (100 mg, 0.56 mmol) and NaOAc (82 mg, 1.0 mmol) in AcOH (5 mL) and DCM (3 mL) was stirred overnight at rt, and then quenched with water (25 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography to afford 196 mg of product.