Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[N:5]=[CH:4][N:3]=1.[CH:22]([C:25]1[N:29]=[C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:27][N:26]=1)([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:22]([C:25]1[N:29]=[C:28]([CH:30]2[CH2:35][CH2:34][N:33]([C:2]3[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][C:12]4[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=4)[N:5]=[CH:4][N:3]=3)[CH2:32][CH2:31]2)[O:27][N:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1noc(C2CCNCC2)n1
Reactant: CC(=O)c1c(Cl)ncnc1Oc1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(Oc2ccc(S(C)(=O)=O)cc2)ncnc1N1CCC(c2nc(C(C)C)no2)CC1
Yield: 19.6 %

Procedure:
To a solution of 1-[4-chloro-6-(4-methanesulfonyl-phenoxy)-pyrimidin-5-yl]-ethanone (0.21 mmol, 70 mg) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (0.21 mmol, 49 mg) in N,N-dimethyl formamide (500 uL) was added potassium carbonate (0.21 mmol, 29 mg). The mixture was microwaved at 100° C. for 150 seconds. Its progress was monitored by thin layer chromatography and LCMS. The reaction was treated with water and the desired compound was extracted in ethyl acetate. Organic layer was evaporated in vacuo. Purification by HPLC provided Compound A165 as a white solid (20 mg, 20%). 1H-NMR (400 MHz, CDCl3) δ(ppm): 8.24 (s, 1H); 8.01 (d, 2H); 7.32 (d, 2H); 4.02 (m, 2H); 3.22 (m, 3H); 3.10 (m, 1H); 3.08 (s, 3H); 2.69 (s, 3H), 2.18 (m, 2H), 2.02 (m, 2H); 1.35 (d, 6H). LCMS (ESI), m/z 486.3 (M+H+, 100%).
Reaction SMILES: C([Mg]Br)C.[CH2:5]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:21]([O:23]CC)C>>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:19][C:18]=1[CH:21]=[O:23]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CCOCC
Agent: CC[Mg]Br
Product: CCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethylmagnesium bromide (18 ml of 3M solution in diethyl ether) was added dropwise to a stirred solution of 4-nonylphenol (11.2 g) in diethyl ether (100 ml) at 0°-10° C. under nitrogen. Stirring was continued at 10° C. for 30 minutes, the mixture was allowed to warm to ambient temperature, the bulk of the diethyl ether was removed by distillation, toluene (100 ml) and methanol (6.5 g) were added and removal of diethyl ether and free (uncoordinated to Mg) methanol was continued by fractional distillation with vigorous stirring until the temperature of the mixture rose to 100°-105° C. The mixture was cooled to 95° C. and a slurry of paraformaldehyde (6 g) in toluene (12 ml) was added dropwise over 20 minutes, the temperature of the reaction mixture being maintained at 95°-100° C. with removal of volatile by-products by distillation. Stirring was continued at 95°-100° C. for 2 hours, the mixture was added to a cold stirred solution of sulphuric acid (12 g of 98% strength material) in water (500 ml) at 10° C., the resulting mixture was stirred at 20°-30° C. for 2 hours, the mixture was filtered and the upper organic layer separated from the lower aqueous layer. The organic layer was washed with water (3×50 ml) and solvent was removed by evaporation under reduced pressure to give crude 2-hydroxy-5-nonylbenzaldehyde.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=[O:4].[C:11](#[N:15])[CH2:12][C:13]#[N:14].CC(C)([O-])C.[K+]>O1CCCC1>[Cl:10][C:7]1[S:6][C:5]([C:3]([CH2:2][CH:12]([C:11]#[N:15])[C:13]#[N:14])=[O:4])=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1ccc(Cl)s1
Reactant: N#CCC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC(C#N)CC(=O)c1ccc(Cl)s1

Procedure:
A solution of 2-bromo-1-(5-chloro-2-thienyl)ethanone (11.50 g, 48 mmol) in tetrahydrofuran is added to a solution of malononitrile (3.17 g, 48 mmol) and potassium tert-butoxide (5.70 g, 51 mmol) in tetrahydrofuran at 0° C. The reaction mixture is stirred for several minutes, concentrated in vacuo, diluted with water and filtered to collect solids. Flash chromatography of the solids using silica gel and a (4:1) hexane/ethyl acetate solution gives the title compound as a yellow solid, mp 155°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][S:8][C:9]2[C:10]([C:15]([O:17]C)=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:10]([C:15]([OH:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ncccc1SCc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CSc2cccnc2C(=O)O)cc1

Procedure:
To a solution of 3 g. of methyl 3-(p-methoxybenzylthio)picolinate in 50 ml. of ethanol is added 10 ml. of 20% aqueous sodium hydroxide solution and the mixture is warmed on a steam bath for two hours. The alcohol is evaporated off and the residue is cooled and acidified with dilute hydrochloric acid. The precipitate is filtered off, washed with water, dried and recrystallized from methanol to give 3-(p-methoxybenzylthio)picolinic acid, m.p. 170°-172°C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][CH:14]=1.N1CCCCC1>C1C=CC=CC=1>[CH2:26]([O:25][C:23]([C:22]([C:21](=[O:28])[CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=1)=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CC(=O)CCc1ccc(F)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(C(=O)O)cc1)C(=O)CCc1ccc(F)cc1
Yield: 25.4 %

Procedure:
A mixture of 4-carboxybenzaldehyde (2.07 g, 13.81 mmol), ethyl 5-(4-fluorophenyl)-3-oxopentanoate (3.29 g, 13.81 mmol) and piperidine (0.25 mL, 2.53 mmol) in benzene (60 mL) was heated at reflux overnight under Dean-Stark conditions. The reaction mixture was concentrated and the crude material was dissolved in EtOAc. The EtOAc solution was washed with 0.1 M HCl and brine and then dried, filtered, and concentrated. Recrystallization of the resulting material from EtOAc/hexanes produced the title compound as a yellow solid (1.3 g, 3.51 mmol, 25%): 1H NMR (400 MHz, CDCl3) δ 8.09 (d, 2H, J=8), 7.98 (d, 2H, J=8), 7.70 (s, 1H), 7.60 (s, 1H), 7.49 (d, 2H, J=8), 7.32 (d, 2H, J=8), 7.16 (dd, 2H, J=8, 6), 7.07 (dd, 2H, J=8, 6), 6.97 (t, 2H, J˜9), 6.91 (t, 2H, J˜9), 4.29 (q, 2H, J=7), 4.27 (q, 2H, J=7), 3.03 (m, 2H), 2.99 (m, 2H), 2.90 (m, 2H), 2.84 (m, 2H), 1.29 (t, 3H, J=7), 1.23 (t, 3H, J=7) ppm (carboxyl proton not found).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=1[Cl:30])[C:18]([NH2:20])=[O:19].Cl>O>[Cl:30][C:22]1[CH:23]=[C:24]([Cl:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=1[C:17]1[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: COc1cc(C(N)C(N)=O)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ncc(C(F)(F)F)[nH]c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 16.7 g of sodium carbonate and 60 ml of water was added dropwise 10.6 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 80 ml of water and then 7.42 g of 2-amino-2-(2,4-dichloro-5-methoxyphenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 9.0 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=4:1), which afforded 2.2 g (yield, 22%) of the desired compound, 3-(2,4-dichloro-5-methoxyphenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1009).
Reaction SMILES: C(OC(N1CCC(NC([N:16]2[CH2:21][CH2:20][N:19]3[C:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:23]([Cl:28])[C:24]([C:25](=[O:27])[NH2:26])=[C:18]3[CH2:17]2)=O)CC1)=O)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:28][C:23]1[C:24]([C:25]([NH2:26])=[O:27])=[C:18]2[CH2:17][NH:16][CH2:21][CH2:20][N:19]2[C:22]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)OC(=O)N1CCC(NC(=O)N2CCn3c(c(C(N)=O)c(Cl)c3-c3ccccc3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8-carbamoyl-7-chloro-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (2.75 g, Reference Example 2) in dichloromethane (60 mL) was treated with trifluoroacetic acid (5.64 mL). After stirring at room temperature for a further 3 hours the reaction mixture was further treated with trifluoroacetic acid (0.5 mL) and then further stirred for 1 hour. The reaction mixture was evaporated to afford an oil, which was azeotroped with toluene and then triturated with diethyl ether to give the title compound (2.61 g) as a white solid, m.p. 205–208° C. [Elemental Analysis: C, 49.32; H, 3.88; N, 10.78%. Calculated for C16H15ClF3N3O3: C, 49.30; H, 3.88; N, 10.78%].
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>C1COCC1>[CH3:34][N:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:43][CH:42]=2)[CH2:39][CH2:40]1
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C(C)(C)C)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)cc2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 42.4 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 65, 100 mg, 0.225 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (47 mg, 0.25 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 42% (59 mg, 0.0955 mmol) of the title compound.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=1[CH3:25])(=[O:15])=[O:14])(=O)=O.[I-:26].[Na+]>CC(C)=O>[I:26][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=1[CH3:25])(=[O:15])=[O:14]
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COS(C)(=O)=O)c(C)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CI)c(C)c1
Temperature: 120 °C

Procedure:
(1-(4-Methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methyl methanesulfonate (0.25 g, 0.639 mmol) and sodium iodide (0.383 g, 2.554 mmol) were dissolved in acetone (7 ml) and the solution was heated at 120° C. in a microwave oven (CEM Discover; 100 watt) for 1 h. The solvent was removed in vacuo, the residue was dissolved in sodium thiosulfate solution (20 ml, 5 mmol/l) and diethyl ether (40 ml), the phases were separated and the aqueous phase was extracted with diethyl ether (2×20 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether/methylene chloride (3:1:1). Yield: 0.2 g (74%)
Reaction SMILES: [Cl:1][C:2]1[C:7](OC2C=CC=CC=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH3:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[NH2:25]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)c(Cl)c1Oc1ccccc1
Reactant: N
Solvent: Cc1ccccc1
Product: Nc1c([N+](=O)[O-])ccc(Oc2ccccc2)c1Cl
Temperature: 120 °C
Yield: 98 %

Procedure:
68.3 gm of 2-chloro-4-nitro-1,3-diphenoxy-benzene were dissolved in 300 ml of toluene, and the solution was admixed with 100 ml of concentrated aqueous ammonia in an autoclave. The autoclave was then closed, the internal pressure was increased to 3 bar with gaseous ammonia, and the contents were heated for 12 hours at 120° C., whereby the internal pressure rose to about 13 bar. Thereafter, the contents were allowed to cool, and the organic phase was separated, extracted with dilute hydrochloric acid, dried with sodium sulfate and the toluene was distilled off. The reaction product was obtained with virtually quantitative yield (54 gm). Gas-chromatographic analysis revealed that the reaction product contained 98% of the title compound, m.p. 81°-82° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:29])([C:23]2[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=2)[C:10](O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)=[O:11])=[CH:5][CH:4]=1)#[N:2].[Li+].[BH4-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[OH:29][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([C:23]1[N:27]([CH3:28])[CH:26]=[N:25][CH:24]=1)[CH2:10][OH:11]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(O)(c1ccc(C#N)cc1)c1cncn1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(CO)c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of Example 93B (2.15 g, 78% potency, 4.24 mmol) in THF (6.5 mL) was treated with a solution of 2M LiBH4 in THF (3.3 mL, 6.1 mmol), heated to 55° C. for 3 hours, cooled to room temperature, treated with 20% citric acid (12 mL), warmed to 50° C. for 30 minutes, and extracted with MTBE (2×20 mL). The aqueous phase was adjusted to pH>10 with 50% NaOH and extracted with 5:1 THF/ethyl acetate (2×30 mL). The combined organic phases were concentrated, treated with citric acid (1.0 g), and concentrated to a volume of approximately 6 mL. The solution was adjusted to pH>10 with 50% NaOH, stirred for 2 hours, and filtered. The filter cake was washed with water (2 mL) and dried under vacuum with an air bleed to provide 670 mg (61% potency, 40% potency adjusted yield) of the desired product as one enantiomer in high excess. MS (ACPI) m/e 244 (M+H)+; 1H NMR (CD3OD) δ 7.70 (d, 2H) 7.55 (s, 1H) 7.54 (d, 2H) 7.18 (s, 1H) 4.00 (d, 1H) 3.89 (d, 1H) 3.30 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH2:26][C@H:27]([OH:31])[C:28]([OH:30])=[O:29])=[O:24])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH2:26][C@H:27]([OH:31])[C:28]([OH:30])=[O:29])=[O:24])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(C(=O)NC[C@H](O)C(=O)O)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H](O)C(=O)O)c1ccc(OCCC2CCNCC2)cc1
Yield: 83.2 %

Procedure:
A solution of 17-3 (45 mg, 0.10 mmol), TFA (1 mL), and CH2Cl2 (1 mL) was stirred at ambient temperature for 1.0 h. Concentration and flash chromatography (silica, 10:1:1 ethanol H2O/NH4OH) gave 17-4 (28 mg) as a white solid. Rf 0.17 (10:1:1 ethanol) H2O/NH4OH).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[CH:4]2[CH2:12][CH2:13][CH:14]([NH:15]CC3C=CC=CC=3)[CH:3]12>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:15][CH:14]1[CH:3]2[N:2]([CH3:1])[C:10]3[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=3[CH:4]2[CH2:12][CH2:13]1
Reactant: CN1c2ccc(O)cc2C2CCC(NCc3ccccc3)C21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN1c2ccc(O)cc2C2CCC(N)C21
Yield: 110.1 %

Procedure:
20% Palladium hydroxide on carbon (1.4 g) was added to a solution of 1,2,3,3a,4,8b-hexahydro-4-methyl-3-phenylmethylaminocyclopent[b]indol-7-ol (14 grams) in ethanol (100 ml) and the mixture was hydrogenated at 45 psi H2 pressure using a Parr apparatus at 50° C. for 5 hours. The mixture was filtered and the solution was concentrated to give 3-amino-1,2,3,3a,4,8b-hexahydro-4-methylcyclopent[b]indol-7-ol (10.7 grams).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([Cl:12])=[C:10]([N:13]([CH2:15][CH2:16][Cl:17])[CH3:14])[CH:9]=[CH:8][N:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:12][C:11]1[C:6]([CH2:5][OH:4])=[N:7][CH:8]=[CH:9][C:10]=1[N:13]([CH2:15][CH2:16][Cl:17])[CH3:14]
Reactant: CC(=O)OCc1nccc(N(C)CCCl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(CCCl)c1ccnc(CO)c1Cl
Yield: 92.1 %

Procedure:
1.83 g of 3-chloro-4-[(2-chloroethyl)-methylamino]-pyridin-2-ylmethyl acetate and 250 mg of potassium carbonate in 20 ml of methanol are stirred at room temperature for 8 h. The mixture is then filtered and the filtrate is concentrated. The residue is triturated with diethyl ether. 1.43 g (92%) of the title compound are isolated as a beige solid. M.p. 91-96° C.
Reaction SMILES: COC1C=C(C=CC=1OC)C[NH:7][C:8]1[N:9]=[C:10]([C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[O:18])[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1.C(O)(C(F)(F)F)=O>>[NH2:7][C:8]1[N:9]=[C:10]([C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[O:18])[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COc1ccc(CNc2nc(C(=O)c3cccs3)c3sccc3n2)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C(=O)c2cccs2)c2sccc2n1
Yield: 102 %

Procedure:
A mixture of 2-[N-(3,4-dimethoxybenzyl)]aminothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (0.06 g, 0.15 mmol) and TFA (2 mL) was refluxed for 2 h, cooled, concentrated in vacuo to half its original volume, diluted with CH2Cl2 (50 mL), washed with saturated sodium bicarbonate solution (3×25 mL) then brine (25 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane-EtOAc (3:1)] to give the title compound (40 mg, 100%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][O:28]C6CCCCO6)[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:42])C(=O)C1.O1CCOCC1>C(Cl)Cl.Cl>[Br:42][C:3]1[N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: CC(c1ccc2nccn2c1)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(c1ccc2ncc(Br)n2c1)c1cnc2ccc(-c3cnn(CCO)c3)nn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(rac)-3-(1-Imidazo[1,2-a]pyridin-6-yl-ethyl)-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-imidazo[1,2-b]pyridazine (obtained by analogy of Stage 185.1 by replacing (rac)-6-chloro-3-[1-(3-methyl-3H-benzoimidazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine with (rac)-6-chloro-3-(1-imidazo[1,2-a]pyridin-6-yl-ethyl)-imidazo[1,2-b]pyridazine (Example 292), 150 mg, 0.328 mmol) was dissolved in DCM (3.3 mL) and NBS (64.2 mg, 0.984 mmol) was added. It was stirred at rt for 3 h then the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated and dissolved in DCM (1 mL) with 4 N HCl in dioxane (0.246 mL, 0.984 mmol). The RM was stirred at rt for 2 min. The solvent was removed and the residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford after evaporation of the solvent the title compound as a white solid (tR 0.7 min (conditions 2), MH+=452, 1H-NMR in DMSO-d6: 8.46 (s, 1H); 8.40 (s, 1H); 8.04 (m, 2H); 7.78 (s, 1H); 7.67 (s, 1H); 7.52 (m, 2H); 7.33 (d, 1H); 4.95 (t, 1H); 4.76 (q, 1H); 4.18 (t, 2H); 3.75 (q, 2H); 1.80 (d, 3H)).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[N:7][N:6]=[C:5]2[CH2:15]O)[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20](=[O:31])[CH:21](P(OCC)(OCC)=O)[CH3:22])[CH3:18].C1CCN2C(=NCCC2)CC1>C(#N)C.O=[Mn]=O>[CH2:17]([O:19][C:20](=[O:31])[C:21]([CH3:22])=[CH:15][C:5]1[N:4]([CH:1]2[CH2:2][CH2:3]2)[C:8]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[N:7][N:6]=1)[CH3:18]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: OCc1nnc(-c2ccncc2)n1C1CC1
Agent: O=[Mn]=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C(C)=Cc1nnc(-c2ccncc2)n1C1CC1
Temperature: 80 °C

Procedure:
(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (6.8 g, 31.4 mmol) was mixed with MnO2 (40 g, 0.46 mol) in acetonitrile at r.t. for 2 hours and then heated at 80° C. for another 30 min. The reaction mixture was filtered through celite. The filtrate was mixed with 2-(diethoxy-phosphoryl)-propionic acid ethyl ester (12.35 g, 51.8 mmol) and DBU (7.17 g, 47 mmol) at 80 to 90° C. for 4 h. The reaction mixture was concentrated, dissolved in EA and washed with water and brine. The organic layer was dried, concentrated and triturated with hex. to give the title compound in 5.76 g (61%) yield. 1H-NMR: 8.78(d, 2H), 7.78 (d, 2H), 7.67 (s, 1H), 4.32 (q, 2H), 3.43 (m, 1H), 2.53 (s, 3H), 1.38 (t, 3H), 1.24 (m, 2H) and 0.73 (m, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]23[CH2:22][N:19]([CH2:20][CH2:21]2)[CH2:18][CH:17]=[CH:16]3)=[CH:11][N:10]=1>CN(C)C=O>[N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][N:19]([CH2:20][CH2:21]3)[CH2:18][CH:17]=[CH:16]4)=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Brc1ccc(C23C=CCN(CC2)C3)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=CC2(c3ccc(-n4ccnc4)nc3)CCN(C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
0.64 g (9.42 mmol) of imidazole dissolved in 3 ml of dimethylformamide is introduced into a 10 ml three-necked round-bottomed flask. 0.415 g (10.4 mmol) of sodium hydride as a 60% dispersion in oil is then added and the mixture is stirred at room temperature for 1 hour. The mixture is then added to a solution of 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (WO 03/057 697) (0.5 g, 1.89 mmol) in dimethylformamide and the reaction medium is heated at 85° C. for 15 hours and then at 110° C. for 24 hours and the solvent is evaporated off under reduced pressure. The residue is taken up in 10 ml of chloroform and 10 ml of saturated aqueous sodium carbonate solution. The aqueous phase is extracted again with 10 ml of chloroform and the combined organic phases are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 95/5/0.5 proportions. 0.235 g of 5-[2-(−1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene is obtained and is dissolved in 3 ml of isopropyl alcohol to add 0.327 ml of a 5.7N solution of hydrobromic acid in acetic acid. The crystals formed are collected by filtration and dried under vacuum.