Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:17][CH:16]=3)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC.[CH3:30]C(C)([O-])C.[K+].O>O1CCCC1>[CH3:30][N:21]([C:18]1[CH:19]=[CH:20][C:15]([C@@H:11]2[O:12][CH2:13][CH2:14][N:9]([C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])[CH2:10]2)=[CH:16][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Nc3ccccn3)cc2)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N(C)c3ccccn3)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.7 %

Procedure:
To a solution of N-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)pyridin-2-amine (0.57 g, 1.5 mmol) and iodomethane (1.6 g, 11.2 mmol) in tetrahydrofuran (50 ml) was added potassium tert-butoxide (1.6 g, 9.45 mmol). After stirring at room temperature for 4 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by column chromatography on silica gel (hexane-ethyl acetate, 1:1) to afford N-Methyl-N-(4-((2S)-4-((1R)-1-phenylethyl)-morpholin-2-yl)phenyl)pyridin-2-amine (0.57 g, 81%) as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[CH:12]1([C:15]2[S:16][CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH2:14][CH2:13]1>O.C(OCC)(=O)C>[CH:12]1([C:15]2[S:16][CH:17]=[C:18]([CH2:20][OH:21])[N:19]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1csc(C2CC2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: OCc1csc(C2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a mixture of lithium aluminium hydride (0.32 g) and anhydrous ether (40 ml) was added dropwise an anhydrous ether (10 ml) solution of ethyl 2-cyclopropyl-4-thiazolecarboxylate (1.65 g), followed by stirring for one hour at room temperature. To the reaction mixture was added dropwise water (20 ml) under cooling with ice to decompose excess amount of the reducing agent. To the resultant mixture were added ethyl acetate (50 ml) and water (25 ml), followed by extraction with ethyl acetate. The organic layer was washed with water (25 ml) and a saturated aqueous solution of sodium chloride (25 ml), successively, followed by drying over magnesium sulfate. The solvent was distilled off, and the residue was subjected to a silica gel chromatography (2.5×30 cm), eluting with ethyl acetate-hexane (2:1). The desired fraction was concentrated to give 2-cyclopropyl-4-hydroxymethyl thiazole (0.94 g) as pale yellow needles. 1H-NMR (CDCl3) δ: 0.98~1.18(4H,m), 2.24~2.39(1H,m), 3.20(1H,bs.), 4.70(2H,d,J=5 Hz), 6.93(1H,s)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].[CH2:11]=O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]#[C:9][CH2:11][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:3]1=[O:10]
Reactant: C1CCNC1
Reactant: C=O
Reactant: C#CCn1ccn(C)c1=O
Solvent: C1COCCO1
Product: Cn1ccn(CC#CCN2CCCC2)c1=O

Procedure:
The intermediate imidazolidinones and imidazolones were converted to the final products using the general procedures outlined in Scheme 2. 1,3-dihydro-1-methyl-3-(2-propynyl)-2H-imidazol-2-one was reacted with paraformaldehyde and pyrrolidine in dioxane using cuprous chloride as catalyst to give 1,3-dihydro-1-methyl-3-[4-(1-pyrrolidinyl)-2-butynyl]-2H-imidazol-2-one. The diethylamine analogue was prepared similarly and was reacted with cyanogen bromide to give the bromide XI which was reacted with imidazole to give 1,3-dihydro-1-[4-(1H-imidazol-1-yl)-2-butynyl]-3-methyl-2H-imidazol-2-one and with 1-acetyl-4-methylimidazole to give XII which was hydrolyzed to 1,3-dihydro-1-methyl-3-[4-(5-methyl-1H-imidazol-1-yl)-2-butynyl]-2H-imidazol-2-one. The imidazolidinone analogues of Table 1, imidazolones of Table 2 and imidazolidinedione and tetrahydropyrimidinones of Table 3 were prepared by these general procedures.
Reaction SMILES: [CH3:1][S-:2].[Na+].CN(C=O)C.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1>O>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:2][CH3:1])[CH:11]=1
Reactant: C[S-]
Reactant: BrCc1cccc(Br)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
Sodium thiomethoxide (0.616 g, 8.8 mmol) was added to DMF (8 mL) and cooled to 0° C. To this solution was added 1-bromo-3-bromomethyl-benzene (2 g, 8 mmol). The mixture was allowed to warm to rt and stir for 18 h. The mixture was then poured into cold water (50 mL) and extracted with EtOAc (3×20 mL). The organics were combined and dried with sodium sulfate. The solution was concentrated in vacuo to yield the crude product, which was then purified via flash chromatography (5% ethyl acetate-hexanes) to yield 1.3 g (68.5%) of 1-bromo-3-methylsulfanylmethyl-benzene as a pure product. 1H-NMR (methylene chloride -d2) δ 7.48-7.47 (m, 1H), 7.392 (dt, J=7.9, 1.5 Hz, 1H), 7.28-7.207 (m, 2H), 3.64 (s, 2H), 1.99 (s, 3H); LC-MS RT: 3.70, [M+H]+: 354.1.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(C#N)cc1
Yield: 96 %

Procedure:
Reaction of 4-cyanobenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a white solid (96% yield). 1HNMR indicated a 95:5 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 4.02 (3H, s, OCH3), 7.07 (4H, m, aromatics), 8.06 (1H, s, CH).
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][N:16]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=1)(C)(C)C>Cl.O1CCOCC1>[Cl:30][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][CH2:21][N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH2:14][C:10]2[CH:9]=[C:8]([CH2:7][C:6]([OH:31])=[O:5])[CH:13]=[CH:12][CH:11]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)Cc1cccc(CCN(CCCc2cccc(Cl)c2)S(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CCCc1cccc(Cl)c1)CCc1cccc(CC(=O)O)c1
Yield: 13.6 %

Procedure:
A solution of [3-(2-{[3-(3-chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-acetic acid tert-butyl ester (170 mg, 0.36 mmol) in HCl/dioxane (5 mL) was stirred for 48 h at room temperature. The reaction was concentrated and the residue was taken up in dilute aqueous NaOH (10 mL, pH=9.3). The aqueous solution was washed with EtOAc (10 mL) and the layers were separated. The aqueous layer after extraction with EtOAc (10 mL) was acidified with dilute aqueous HCl to a pH of 2.5. After extraction of the acidic aqueous layer with EtOAc (10 mL) the organic solution was dried over MgSO4, filtered, and concentrated to afford the title compound as an oil (20 mg). 1H NMR (400 MHz, CDCl3) δ 6.90-7.50 (m, 8H), 3.00-3.30 (m, 4H), 2.95 (s, 3H), 2.45-2.85 (m, 4H), 1.80 (m, 2H); MS 408 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:16](=O)[CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(O)(O)(=O)=O.[CH3:24][O:25][C:26](=[NH:28])[NH2:27].CC([O-])=O.[Na+]>CN(C=O)C>[CH3:15][O:14][C:12]([C:11]1[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:28][C:26]([O:25][CH3:24])=[N:27][C:16]=1[CH3:17])=[O:13]
Reactant: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Reactant: COC(=N)N
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N=C(OC)NC1c1ccc([N+](=O)[O-])cc1
Temperature: 72.5 °C

Procedure:
A mixture of methyl 2-{(4-nitrophen-yl)methylene}-3-oxobutyrate (12.46 g, 0.05 mol), O-methylisourea hydrogen sulfate (10.32 g, 0.06 mol), and NaOAc (9.84 g, 0.06 mol) in DMF (50 mL) was stirred and heated at 70-75° C. for 4 hours. The mixture was cooled and poured into ice-water (300 mL). The precipitate formed was filtered, washed with water, and dried. The crude product was purified by flash column chromatography on silica gel using 10% through 30% EtOAc in hexane as the gradient eluent (9.8 g, 64%). The 1H-NMR analysis of the product showed it to be a 19:1 mixture of the amine/imine tautomers which was used as such in the next step. 1H-NMR (CDCl3): δ 2.32, 2.38 (2 s, 3H), 3.59, 3.70 (2 s, 3H), 3.70, 3.85 (2 s, 3H), 5.40, 5.66 (s, d, J=3 Hz, 1H), 5.50, 6.08 (s, d, J=3 Hz, 1H), 7.43, 7.45 (2 d, J=9 Hz, 2H), 8.10, 8.11 (2 d, J=9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:30]=[CH:29][C:12]3[NH:13][C:14]([NH:16][C:17]([C:19]4[N:20]=[C:21]5[CH:26]=[CH:25][C:24](Cl)=[N:23][N:22]5[CH:28]=4)=[O:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:30]=[CH:29][C:12]3[NH:13][C:14]([NH:16][C:17]([C:19]4[N:20]=[C:21]5[CH:26]=[CH:25][C:24]([N:31]6[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]6)=[N:23][N:22]5[CH:28]=4)=[O:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1CCNCC1
Reactant: O=C(Nc1nc2cc(-c3cc(F)cc(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2cc(-c3cc(F)cc(Cl)c3)ccc2[nH]1)c1cn2nc(N3CCC(O)CC3)ccc2n1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
To a solution of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (0.07 g) in N-methylpyrrolidone (1 mL), was added piperidin-4-ol (0.08 g) and the mixture was heated to 80° C. for 12 hours. After cooling the reaction mixture, 10 mL of water was added and the reaction mixture was stirred for 10 minutes. The reaction was then filtered through a fine fritted funnel and the crude product was washed with water. After air drying, purified by column chromatography (pre-packed silica column) using a gradient of 0 to 10% 2M ammonia-methanol in DCM to obtain 6-(4-hydroxy-piperidin-1-yl)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (32 mg). LCMS (m/z): 506.7. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (1H, s) 7.93 (1H, d) 7.80-7.86 (1H, m) 7.48-7.65 (4H, m) 7.35-7.43 (2H, m) 4.79 (1H, br. s.) 3.95 (2H, ddd) 3.70-3.80 (1H, m) 3.18-3.45 (2H, m) 1.79-1.90 (2H, m) 1.39-1.53 (2H, m).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:27][C:28]1[C:29]([CH3:37])=[CH:30][C:31]2[N:32]([N:34]=[CH:35][N:36]=2)[N:33]=1>O1CCCC1>[ClH:27].[ClH:27].[C:21]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:28]3[C:29]([CH3:37])=[CH:30][C:31]4[N:32]([N:34]=[CH:35][N:36]=4)[N:33]=3)[CH2:14][CH2:15]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1cc2ncnn2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ncnn2nc1OCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: Cl
Temperature: 0 °C
Yield: 58.7 %

Procedure:
240 mg of a 60% sodium hydride dispersion in mineral oil was suspended in 20 ml of tetrahydrofuran; 0.99 g of 4-(diphenylmethyl)-1-piperazinebutanol was added, followed by heating and refluxing for 1 hour. After cooling, 510 mg of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 3 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (20:20:1). The desired fraction was collected and dissolved in 5 ml of ethyl acetate; 0.64 ml of a 4 N hydrogen chloride solution in ethyl acetate was added; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 470 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:5][CH:4]=1)#N.O.[PH2]([O-])=[O:28].[Na+].C(O)(=O)C.N1C=CC=CC=1>[Ni].O>[CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:5][CH:4]=1)=[O:28]
Reactant: O=[PH2][O-]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C#N)cc23)c(OC)c1
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(Cc2cccc3ccc(C=O)cc23)c(OC)c1
Temperature: 50 °C
Yield: 47.3 %

Procedure:
To a mixture of methyl 4-(7-cyanonaphth-1-ylmethyl)-3-methoxybenzoate (1.06 g), sodium hypophosphite hydrate (2.25 g), glacial acetic acid (4 ml), pyridine (8 ml) and water (4 ml) was added Raney nickel (330 mg of material resulting from decanting water from a 50% (w/w) slurry in water). The reaction mixture was heated to 50° C. for 1 h and cooled, ethyl acetate was added and the mixture filtered through diatomaceous earth with ethyl acetate wash. The organic layer was washed (1N HCl twice, brine), dried (MgSO4) and evaporated. Purification by flash chromatography, eluting with methylene chloride, and trituration with ether afforded methyl 4-(7-formylnaphth-1-ylmeth-yl)-3-methoxybenzoate (506 mg, 47%) as a colorless solid; mp 103°-4° C., MS(CI), m/e=336(M+H).
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[CH:26][N:25]=[C:24]4[CH3:28])=[CH:19][CH:18]=3)[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[OH-:29].[K+]>C(O)(C)(C)C>[F:15][C:13]1[CH:12]=[C:11]([S:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])=[CH:19][CH:18]=2)[CH:10]=[C:9]([C:3]2([C:1]([NH2:2])=[O:29])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:14]=1
Reactant: [OH-]
Reactant: Cc1nccn1-c1ccc(Sc2cc(F)cc(C3(C#N)CCOCC3)c2)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nccn1-c1ccc(Sc2cc(F)cc(C3(C(N)=O)CCOCC3)c2)cc1
Yield: 31.2 %

Procedure:
To a solution of 4-cyano-4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)phenylthio ]phenyl]-3,4,5,6-tetrahydro-2H-pyran (Example 25, 1.71 g, 4.36 mmol) in tert-butanol (20 ml) was added powdered potassium hydroxide (85%, 860 mg, 13 mmol). The resulting mixture was heated at reflux temperature for 4 h, cooled and concentrated in vacuo. Water (50 ml) was added and the precipitates were collected by filtration and washed with 50 ml of ethyl acetate. After drying in vacuo, 560 mg (31%) of the titled compound was obtained as a yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]3[N:21]([C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)[N:22]=[CH:23][C:16]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.C(#N)C.ClCCl.Cl>O1CCOCC1>[CH3:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:17]3=[N:18][CH:19]=[N:20][C:15]([O:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:16]3[CH:23]=[N:22]2)=[CH:25][CH:26]=1)(=[O:31])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
Into a 200 mL round-bottomed flask was placed a stir bar, Compound A1 (1.2 g), anhydrous acetonitrile (50 mL), and dichloromethane (15 mL). 4M HCl in 1,4-dioxane (15 mL) was added under nitrogen and the mixture was stirred at 40° C. for 10 minutes. The solution turned cloudy. The precipitate was isolated and purified by HPLC to give Compound A6. 1H NMR (DMSO-d6, 400 MHz) δ 2.04 (m, 2H), 2.25 (m, 2H), 3.21 (m, 2H), 3.28 (s, 3H), 3.32 (m, 2H), 5.60 (m, 1H), 8.16 (d, 2H), 8.61 (d, 2H), 8.70 (s, 1H), 8.79 (s, 1H). LCMS: calculated for C17H19N5O3S 373.12, observed 374.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc(Br)cc1

Procedure:
4-Bromophenol (0.870 g, 5.00 mmol), 2-chloro-N,N-diethylethanamine hydrochloride (0.90 mg, 5.24 mmol) and Cs2CO3 (8 g, 25 mmol) were combined in DMF (20 mL) and the mixture was heated at reflux over night. H2O (20 mL) was added and the mixture was extracted with EtOAc, then washed with 2N NaOH and brine. The organic layers were combined, dried over Na2SO and concentrated to a brown oil which was then purified by flash chromatography (eluent: 20% EtOAc in hexanes).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[NH:22][N:21]=3)[C:7]=2[CH:27]=1)#[N:2].[Cl:28][CH2:29][C:30]#[C:31][CH2:32]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][O:13][CH3:14])([CH2:15][O:16][CH3:17])[C@@H:9]([OH:18])[C@H:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:32][C:31]#[C:30][CH2:29][Cl:28])[N:21]=3)[C:7]=2[CH:27]=1)#[N:2]
Reactant: ClCC#CCCl
Reactant: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)[nH]n2)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](Nc2ccc(=O)n(CC#CCCl)n2)[C@@H]1O
Yield: 24.8 %

Procedure:
(-)-(3S,4R)-6-Cyano-3,4-dihydro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol (556 mg, 1.5 mmol) obtained in Example 8 and 1,4-dichloro-2-butyne (2.9 ml, 30 mmol) were dissolved in dimethylformamide (10 ml). Potassium carbonate (413 mg) was added and the mixture was reacted at 120° C. overnight. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (methanol:chloroform=1:30) to give 171 mg of crude (3S,4R)-6-cyano-4-[(1-(4-chloro-2-butyn-1-yl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino]-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol. The compound was dissolved in dimethylformamide (3 ml), added with diethylamine and stirred at 70° C. for 2.5 hours. Water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 71 mg of the title compound (38%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.B(O)O.C(=O)(O)[O-].[Na+].O.[CH2:38](O)[CH3:39]>C1(C)C=CC=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([C:5]5[N:6]([CH3:8])[N:7]=[CH:39][CH:38]=5)[CH:3]=[C:4]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH3:23])[CH2:20][CH2:19]1
Reactant: Cc1cc(-c2cnc3c(NCC(C)C)cc(Cl)nn23)ccc1C(=O)NC1CC1
Reactant: CCO
Agent: O=C([O-])O
Agent: OBO
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cnc3c(NCC(C)C)cc(-c4ccnn4C)nn23)ccc1C(=O)NC1CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a mixture of 100 mg (251 μmol) 4-[6-chloro-8-(isobutylamino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide, which was prepared according to example 194a, 95 mg (750 μmol) 1-methyl-1H-pyrazol-5-yl) boronic acid, 35 mg Tetrakis(triphenylphosphin)palladium in 2 mL of ethanol and 2 mL of toluene was added 0.5 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then water and was added and the organic layer was washed with water and brine, concentrated and purified by chromatography to give 99 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Al].[CH2:14]([CH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17]>[Fe].[Ni].[Ni].[Fe].O>[CH2:4]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([OH:11])[CH2:9][CH2:10]1)[CH2:3][CH:2]([CH3:12])[CH3:1].[CH2:14]([C@H:19]1[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][CH2:24]1)[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)=CCc1ccc(O)cc1
Reactant: CC(C)CCC1CCC(O)CC1
Agent: [Fe]
Agent: [Ni]
Agent: [Al]
Solvent: O
Product: CC(C)CC[C@H]1CC[C@@H](O)CC1
Product: CC(C)CC[C@H]1CC[C@H](O)CC1
Reaction time: 6 h

Procedure:
165 g 4-(3-methyl-but-2-enyl)-phenol, 2 wt. % Raney nickel-iron (composition of the catalyst: 45% nickel, 3% aluminium, 8% iron; water content 44%) are initially introduced into a stirred autoclave with a gassing stirrer. Hydrogenation is carried out for 6 hours at 170° C. under a hydrogen pressure of 20 bar. After filtration, 165 g of crude product are obtained. 158 g 4-isoamylcyclohexanol (b.p.: 65° C., 0.6 mbar), which has the following composition: 33.1% cis-4-isoamylcyclohexanol and 66.3% trans-4-isoamylcyclohexanol, are obtained by distillation of the crude product.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[N:4]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[Li+].CCC[CH2-].CN([CH:29]=[O:30])C.O>C1(OC)C=CC=CC=1.CCOCC>[CH2:14]([O:13][CH2:12][N:4]1[C:5]2[C:10]([Cl:11])=[N:9][CH:8]=[N:7][C:6]=2[C:2]([CH:29]=[O:30])=[CH:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Clc1ncnc2c(Br)cn(COCc3ccccc3)c12
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: COc1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=Cc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Yield: 57.2 %

Procedure:
7-Bromo-5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (3.73 g, 10.6 mmol) was dissolved in anhydrous anisole (48 ml) and then diluted with Et2O (145 ml) before being cooled to −78° C. at which point N-butyllithium (1.48M in hexane, 9.2 ml, 13.6 mmol) was added dropwise such that the temperature did not exceed −70° C. Within 2 minutes of the addition, DMF (8.5 ml, 0.123 mol) was introduced quickly (T≦−68° and the mixture stirred whilst warming to −40°, at which point water (20 ml) was added. The mixture was then extracted with EtOAc and the extract washed with brine and then dried and concentrated to an orange solid. Purification of this material was accomplished by chromatography over silica, eluting with 20→40% EtOAc/hexane, to give (a heart fraction of) the title aldehyde (1.83 g, 57.3%) as an off-white solid. 1H NMR (CDCl3) δ 10.35 (s, 1H), 8.89 (s, 1H), 8.14 (s, 1H), 7.35-7.20 (m, 5H), 5.90 (s, 2H), 4.60 (s, 2H).