Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:14][C:15]#[CH:16])[CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:17]2[CH:21]=[C:20]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH:19]=[N:18]2)[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: C#CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (prepared in Example 730) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([Si:9]([CH3:12])([CH3:11])Cl)[CH3:8].C(N(CC)CC)C.[OH2:20]>CCOCC>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([Si:9]([CH3:12])([CH3:11])[OH:20])[CH3:8]
Reactant: C=CCCCCC(C)[Si](C)(C)Cl
Reactant: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCCCCC(C)[Si](C)(C)O
Temperature: 0 °C

Procedure:
A solution of 7-oct-1-enyldimethylchlorosilane (2.56 mL) in ether (2 mL) was added dropwise over 1 hour to a stirring mixture of triethylamine (1.5 mL), water (0.18 mL) and ether (15 mL) in an ice/water bath. The resultant was stirred a further 1 hour in the ice/water bath and filtered washing the filtered solid with ether (10 mL). The filtrate was evaporated with a rotary evaporator and the residue partitioned between hexane (30 mL) and water (30 mL). The organic layer was separated, dried (MgSO4) and filtered through silica gel (70-230 mesh, 60 Å), washing with hexane (100 mL). The filtrate was evaporated with a rotary evaporator to afford a colorless oil which was vacuum dried and weighed (1.06 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:27][CH2:28][CH3:29])=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN(C)C=O>[CH2:28]([NH:27][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[N:15][CH:16]=[N:17]2)=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[CH3:29]
Reactant: C1CSCCN1
Reactant: CCNc1cc2ncnc(NCCCCCCl)c2cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCNc1cc2ncnc(NCCCCCN3CCSCC3)c2cc1[N+](=O)[O-]
Yield: 98.4 %

Procedure:
Thiomorpholine (6 ml, 59.7 mmol) was added to a dimethylformamide solution (30 ml) of 4-(5-chloropentylamino)-7-ethylamino-6-nitroquinazoline (2.50 g, 7.41 mmol) obtained in Reference Example 66 and the mixture was heated under reflux for 3 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give the title compound (2.95 g, 98.7%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([N:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([N:19]([CH3:21])[CH3:20])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].O>C(O)C>[CH3:17][N:16]([CH3:18])[C:14]1[CH:13]=[C:12]([N:19]([CH3:20])[CH3:21])[N:11]=[C:10]([N:7]2[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]2)[N:15]=1
Reactant: CC(=O)N1CCN(c2nc(N(C)C)cc(N(C)C)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1cc(N(C)C)nc(N2CCNCC2)n1
Yield: 80.9 %

Procedure:
A solution of 1-acetyl-4-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine (1.3 g) and sodium hydroxide (0.5 g) in ethanol (15 ml)—water (15 ml) was refluxed under heating for 9.5 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give the title compound (0.9 g) as a pale-brown oil.
Reaction SMILES: [CH:1]([C@@:4]12[CH2:9][C@@H:8]1[C@H:7]([CH3:10])[C@@H:6]([C:11]1[CH:24]=[CH:23][C:22]3[C:13](=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][CH:16]=[N:15]4)[N:12]=1)[CH2:5]2)([CH3:3])[CH3:2].[I-].[I-].[Sm+2].[CH3:28][C@@H:29]1[C:34](=[O:35])[CH2:33][C@:32]2([CH:36]([CH3:38])[CH3:37])[C@H:30]1[CH2:31]2>>[CH:1]([C@@:4]12[CH2:9][C@@H:8]1[C@H:7]([CH3:10])[C@@H:6]([C:11]1[CH:24]=[CH:23][C:22]3[C:13](=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[CH:17][C:16]([C@:34]3([OH:35])[C@@H:29]([CH3:28])[C@@H:30]5[C@@:32]([CH:36]([CH3:38])[CH3:37])([CH2:31]5)[CH2:33]3)=[N:15]4)[N:12]=1)[CH2:5]2)([CH3:2])[CH3:3]
Reactant: CC(C)[C@]12C[C@H](c3ccc4ccc5cccnc5c4n3)[C@@H](C)[C@H]1C2
Reactant: CC(C)[C@@]12CC(=O)[C@@H](C)[C@@H]1C2
Agent: [I-]
Agent: [Sm+2]
Product: CC(C)[C@]12C[C@H](c3ccc4ccc5ccc([C@@]6(O)C[C@]7(C(C)C)C[C@@H]7[C@@H]6C)nc5c4n3)[C@@H](C)[C@H]1C2

Procedure:
By following General Procedure I, 2-((1S,3S,4S,5R)-(1-isopropyl-4-methylbicyclo[3.1.0]hex-3-yl))-1,10-phenanthroline prepared as described by Example 18, is reacted with samarium diiodide and (−)-thujone to form the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.Cl.[F:13][C:14]1([F:22])[CH2:19][CH2:18][CH2:17][C@@H:16]([NH2:20])[C@H:15]1[NH2:21].CCN(C(C)C)C(C)C.O>CN(C=O)C.CCOC(C)=O>[NH2:21][C@H:15]1[C:14]([F:22])([F:13])[CH2:19][CH2:18][CH2:17][C@H:16]1[NH:20][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([C:9]#[N:10])=[N:4][CH:5]=1
Reactant: N[C@@H]1CCCC(F)(F)[C@@H]1N
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Yield: 90.8 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (102 mg, 0.586 mmol), (1R,2R)-3,3-difluorocyclohexane-1,2-diamine dihydrochloride (132 mg, 0.591 mmol) and DIEA (0.400 mL, 2.30 mmol) in DMF (2 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (153 mg).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[C:19]([CH3:27])[N:18]=1>ClCCl>[Cl:16][C:17]1[N:22]=[C:21]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:20]([N+:24]([O-:26])=[O:25])=[C:19]([CH3:27])[N:18]=1
Reactant: NC1CCCC1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Cl)nc(NC2CCCC2)c1[N+](=O)[O-]
Yield: 84.8 %

Procedure:
Cyclopentylamine (5.2 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitro-6-methylpyrimidine (10.7 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 1 hour. Purification was conducted by a column chromatography to obtain a bright-yellow solid (11.2 g) in a yield of 84.8%. 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 2H), 4.41 (m, 1H), 2.64 (s, 3H), 2.01-2.15 (m, 2H), 1.61-1.76 (m, 4H), 1.45-1.63 (m, 2H) ppm.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(O)CO>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:18][CH:17]=1
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: COc1ccc(N)cc1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-4-fluorobenzene (12b, 88 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 2e (173 mg, 75%); mp: 169-171° C.; 1H NMR (500 MHz, CDCl3) δ 10.26 (s, 1H), 8.23 (dd, J=4.0, 1.5 Hz, 1H), 7.74 (dd, J=8.0, 1.5 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.29-7.24 (m, 4H), 7.06 (t, J=9.0 Hz, 2H), 6.83 (d, J=9.0 Hz, 2H), 6.59-6.50 (m, 1H), 5.47 (s, 2H), 4.64 (d, J=5.2 Hz, 2H), 3.78 (s, 3H); MS (ESI m/z): 433 [M+H]+. Yield: 75%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=2)[N:11]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:10]=1.[OH-].[Na+]>CO.O1CCCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[N:11]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[N:10]=1
Reactant: COC(=O)c1ccc2c(-c3c(F)cccc3F)nn(-c3ccc(C)cc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(-c3c(F)cccc3F)c3ccc(C(=O)O)cc32)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
Methyl 3-(2,6-difluorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylate (101.2 mg, 0.267 mmol) was dissolved in methanol (1.30 mL) and tetrahydrofuran (1.90 mL). 1M sodium hydroxide (1.60 mL, 0.267 mmol) was added. The reaction mixture was heated to 50° C. and allowed to stir for 1.5 h. Reaction stopped, cooled to room temperature, quenched by addition of 1M hydrochloric acid (ca 1.60 mL) till pH<3, and the solvent evaporated under reduced pressure. The title compound (199.5 mg, 0.265 mmol, 99% yield, with 6 equivalents of sodium chloride) was recovered as a white solid. LC-MS: [M+1]=365.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:10]=2[N:11]=[C:12]([S:14][CH3:15])[N:13]=1.[H-].[Na+].I[CH3:24]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:24])[C:10]=2[N:11]=[C:12]([S:14][CH3:15])[N:13]=1
Reactant: CSc1nc(-c2ccccc2F)c2ccc(=O)[nH]c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(-c2ccccc2F)c2ccc(=O)n(C)c2n1
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (120 mg, 0.42 mmol) in 20 mL of anhyd THF was added NaH (50 mg, 1.2 mmol, 60% dispersion in mineral oil, 3 eq) followed by iodomethane (74 μL, 1.2 mmol, 3 eq). The reaction mixture was stirred 1 h at 23°, quenched with saturated aq NH4Cl. (20 mL), Et2O (100 mL) was added and the layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and evaporated. The yellow residue was then purified by Flash chromatography to afford 100 mg (92% yield) of 4-(2-Fluoro-phenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR δ 2.68 (s, 3H), 3.81 (s, 3H), 6.61 (d, 1H, J=9.8 Hz), 7.22 (m, 3H), 7.50 (m, 3H). LC MS (m/e)=302 (MH+). Rt=2.17 min.
Reaction SMILES: C(O[C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[N:9]=[CH:8][N:7]=1)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(C)C=CC=CC=1>O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:4]([NH:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:9]=[CH:8][N:7]=2)=[O:20])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOC(=O)Nc1cc(-c2ccccc2OC)ncn1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cc(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A mixture of [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-carbamic acid ethyl ester (XL) (0.30 g, 1.1 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.23 g, 1.1 mmol) and toluene (4 ml) was subjected to microwave conditions at 120° C. and 100 psi pressure for 10 minutes. The reaction was monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide 0.250 g of 4-{3-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester (XLIV).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Br:1])[CH:7]=[CH:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1cccc2cc[nH]c12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc2ccn(Cc3ccccc3)c12
Reaction time: 1 h

Procedure:
1-Benzyl-7-bromo-1H-indole was prepared from 7-bromo-1H-indole (0.500 g, 2.55 mmol), sodium hydride (0.285 g, 7.13 mmol of 60% dispersion on mineral oil), benzyl bromide (0.67 mL, 5.6 mmol) in DMF (5 mL). The reaction mixture was stirred for 1 hour after the addition of sodium hydride and for 1 hour after the addition of benzyl bromide. The compound was purified by flash chromatography (using hexane as an eluant) and dried at 60° C. for 30 minutes to yield a cream-colored solid (0.508 g, 70%), mp: 74-75° C. 1HNMR (300 MHz, DMSO-d6): δ 7.5-7.65 (m, 2H), 7.15-7.35 (m, 4H), 6.8-7.0 (m, 3H), 6.6 (s, 1H), and 5.8 ppm (s, 2H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH3:8].C([Li])CCC.CN([CH:17]=[O:18])C.Cl>C1COCC1.O>[CH2:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH:17]=[O:18])[CH3:8]
Reactant: CN(C)C=O
Reactant: CCc1ccsc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccsc1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of 3-ethyl-thiophene (12.14 g, 54.4 mmol) in acetonitrile (60 mL) is cooled to 10° C. before a solution of N-bromo-succinimide (9.31 g, 52.3 mmol) in acetonitrile (90 mL) is added dropwise. The reaction is slightly exothermic. The mixture is stirred and warmed to rt. Another portion of N-bromo-succinimide (2.0 g, 11.2 mmol) dissolved in acetonitrile (40 mL) is added dropwise. Stirring is continued for 2 h before a third portion of N-bromo-succinimide (0.5 g, 2.81 mmol) dissolved in acetonitrile (10 mL) is added. After additional 1 and 2 h, a further portion of N-bromo-succinimide (0.75 g, 4.21 mmol, and 500 mg, 2.81 mmol, respectively) is added. Stirring is continued for another hour before the solvent is evaporated. The residue is dissolved in DCM, washed twice with 2 M aq. NaOH followed by brine, dried over MgSO4, filtered and concentrated. The crude product is purified by distillation at 180° C./50 mbar to give 2-bromo-3-ethyl-thiophene (11.0 g) as a colourless liquid; LC-MS*: tR=0.92 min. 1H NMR (CDCl3): δ 1.22 (t, J=7.5 Hz, 3H), 2.62 (q, J=7.8 Hz, 2H), 6.85 (d, J=5.5 Hz, 1H), 7.22 (d, J=5.8 Hz, 1H) b) A solution of 2-bromo-3-ethyl-thiophene (1.00 g, 5.23 mmol) in THF (25 mL) is cooled to −75° C. before n-butyl lithium (3.6 mL of a 1.6 M solution in THF) is added. The mixture is stirred at −75° C. for 1 h. DMF (765 mg, 10.5 mmol) is added and stirring is continued at −75° C. for 2 h. The mixture is warmed to 10° C., treated with 1 N aq. HCl (5 mL), diluted with water and extracted with EA (3×50 mL). The organic extracts are washed with water (30 mL) followed by brine (30 mL), combined, dried over MgSO4, filtered and concentrated to give crude 3-ethyl-thiophene-2-carbaldehyde (650 mg) as a yellow oil; LC-MS*: tR=0.78 min, 1H NMR (CDCl3): δ 1.34 (t, J=7.5 Hz, 3H), 3.03 (q, J=7.5 Hz, 2H), 7.06 (d, J=5.0 Hz, 1H), 7.67 (d, J=5.0 Hz, 1H), 10.08 (s, 1H). c) The title compound is prepared in analogy to the procedures described in the literature (G. Constantino et al., II Farmaco 59 (2004), 93-99; A. J. Carpenter et al., Tetrahedron 41 (1985) 3803-3812) starting from the above 3-ethyl-thiophene-2-carbaldehyde; LC-MS*: tR=0.15 min, [M−1]−=183.16; 1H NMR (D6-DMSO): δ1.24 (t, J=7.5 Hz, 3H), 3.00 (q, J=7.5 Hz, 2H), 7.72 (s, 1H), 10.11 (s, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]2[N:12]3[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]3=[N:10][C:9]=2[CH3:23])=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.CCCCCC.[O:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[O:35]1[CH2:36][CH:37]=[C:38]([C:2]2[S:3][C:4]([C:8]3[N:12]4[N:13]=[C:14]([CH3:22])[CH:15]=[C:16]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]4=[N:10][C:9]=3[CH3:23])=[C:5]([CH3:7])[N:6]=2)[CH2:39][CH2:40]1
Reactant: O=C1CCOCC1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C4=CCOCC4)nc3C)c(C)nc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
370 mg of 3-(2-Bromo-4-methyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.93 mmol) is dissolved in 10 ml of dry THF and cooled to −78° C. 0.6 ml of n-BuLi 2.0 M in hexane (1.2 mmol) is added and stirred at −78° C. for 30 min. 141 mg of tetrahydro-4H-pyran-4-one (1.41 mmol) is added and stirred at −78° C. for 2 h. The reaction mixture is diluted with AcOEt, washed with sat. NH4Cl, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=10:3:1) to give 152 mg of the title compound. Yield 40%: mass spectrum (m/e): 415 (M+1). 1H NMR (CDCl3): δ 6.74 (s, 1H), 3.99 (t, J=2.2 Hz, 4H), 3.97 (t, J=2.2 Hz, 4H), 3.35 (m, 1H), 3.20 (s, OH), 2.56 (s, 3H), 2.48 (s, 3H), 2.36 (s, 3H), 1.88 (m, 4H), 0.91 (t, J=7.3 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].[Cl:15][CH2:16][C:17](OC)(OC)OC>>[Cl:15][CH2:16][C:17]1[O:14][C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:7][C:2]=2[N:1]=1
Reactant: COC(CCl)(OC)OC
Reactant: Nc1cc(-c2ccccc2)ccc1O
Product: ClCc1nc2cc(-c3ccccc3)ccc2o1
Temperature: 160 °C
Reaction time: 0 h

Procedure:
2-amino-4-phenylphenol (0.180 g, 0.97 mmol) was placed in a Smith Process Vial™ (Personal Chemistry, Inc., Uppsala) (3 mL glass vessel) followed by the addition of 1-chloro-2,2,2-trimethoxyethane (1 mL). The vial was sealed and the mixture was heated in the Emrys Optimizer™ (Personal Chemistry, Inc., Uppsala) microwave at 160° C. for 300 s, fixed hold time on, absorption level normal, pre-stirring 10 s. It was then cooled to room temperature, diluted with 2 mL of methanol and purified by semi-prep HPLC. The HPLC fractions were evaporated under reduced pressure to furnish 2-(chloromethyl)-5-phenyl-benzoxazole as an off-white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1)(=O)C>Cl.[Hg]>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1
Reactant: COc1ccnc(COC(C)=O)c1
Agent: Cl
Agent: [Hg]
Product: COc1ccnc(CO)c1
Yield: 66.8 %

Procedure:
A solution of 2-acetoxymethyl-4-methoxypyridine (20.72 g, 0.114 mole) in 3M hydrochloric acid (100 ml) was heated under reflux for 1 hour. The resulting solution was concentrated under reduced pressure and the residue neutralised by addition of potassium carbonate. The mixture was extracted with dichloromethane and the organic solution dried over anhydrous sodium sulphate, filtered and evaporated to give a light coloured viscous oil which solidified on standing to yield the title compound (10.6 g, 67%) b.p. 135° C. at 0.1 mm mercury.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COc1cccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1
Product: COc1cccc(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)c(=O)c2)c1
Yield: 10.1 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-[4-(3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 25) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as an off-white solid (14.6 mg, 10.1%); ES+-HRMS m/e calcd for C26H33N5O5 [M+Na+] 518.2374 found 518.2378. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.21-1.74 (m, 8H), 1.91 (m, 1H), 2.27 (m, 1H), 3.78 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.45 (m., 1H), 5.78 (br.s., 1H), 6.40 (s, 1H), 6.81-6.98 (m, 3H), 7.37-7.49 (m, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.11 (d, J=2.4 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][CH2:13][C:14]#[C:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=1)=[O:11].[NH2:26][OH:27].[OH-].[Na+].Cl>C1COCC1.CO>[OH:27][NH:26][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([C:15]#[C:14][CH2:13][NH:12][C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[O:11])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(C#CCNC(=O)c2cc3ccccc3s2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1ccc(C#CCNC(=O)c2cc3ccccc3s2)cc1
Reaction time: 14 h

Procedure:
To a solution of methyl 4-[3-(benzothiophen-2-ylcarbonylamino)prop-1-ynyl]-benzoate (0.5 mmol) in THF/methanol (10 ml/10 ml) was added 50 wt. % aqueous hydroxylamine (3 ml) followed by 1M aqueous NaOH (1 ml) adjusting the pH to 10-11. The reaction mixture was stirred for ˜14 h, neutralized to pH=7-8 with 6M aqueous HCl, and concentrated in vacuo. The precipitate was collected and purified by HPLC providing the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:9][CH2:8][C:4]1[S:3][CH:7]=[CH:6][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1cccs1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCc2cccs2)cc1
Temperature: -40 °C
Reaction time: 0.42 h
Yield: 70.7 %

Procedure:
Sodium hydride (0.41 g, 20 mmol) was added to a solution of 2-thiophene methanol (2.0 g, 18 mmol) in THF (20 ml) at -40° C. The reaction was stirred at -40° C. for 25 min., then neat benzylbromide (3.6 g, 20 mmol) was added by syringe. The solution was stirred at -40° C. for 0.5 hr, then at room temperature for 1 hr. The THF was evaporated off and the remaining residue was taken up in ether (~50 ml). The organic solution was washed with water (1×10 ml), brine (1×10 ml) and dried over MgSO4. Evaporation of solvents left an oil which was purified by column chromatography using 1% ether-hexanes to give 2.6 g of the thiophene as a pale yellow oil (78% yield).