Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O.[C:4]([NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH2:12][C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1)(=[O:6])[CH3:5].[CH:18](=O)[CH:19](C)[CH3:20]>C(O)C>[C:4]([NH:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12](=[C:19]([CH3:20])[CH3:18])[C:13](=[O:17])[NH:14]2)=[CH:10][CH:9]=1)(=[O:6])[CH3:5]
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reactant: CC(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2=C(C)C
Reaction time: 5 h

Procedure:
A solution of 1.9 g. sodium hydroxide in 2 ml. water is added dropwise to a suspension of 9 g. (0.047 mol) 6-acetamidoindolin-2-one in 50 ml. ethanol containing 3.4 g. (0.047 mol) isobutyraldehyde. After about 5 hours, the reaction mixture is evaporated to dryness and the residue is purified on silica gel (elution agent: methylene chloride/ammonia-saturated methanol). Yield: 7.6 g. (65% of theory) of foam; m.p. 93° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].C(O)(=[S:33])C.C(N(CC)CC)C>C(N(CC)CC)C.O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)([SH:33])[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)=S
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (25 g) was added thioacetic acid (6 eq.) and triethylamine (200 μL) The solution was stirred at room temperature 2 drops of triethylamine were added. After stirring at room temperature for 24 hours, the mixture was poured in a mixture of water and ethyl acetate, extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butyryl]-2-methyl-benzoic acid tert-butyl ester (3.78 g) 1H NMR (CDCl3, 400 MHz): δ=7.89 (d, J=8.8 Hz, 1 H), 7.72-7.79 (m, 2 H), 7.53-7.57 (m, 2 H), 7.35 (t, J=1.8 Hz, 1 H), 4.30 (d, J=18.3 Hz, 1 H), 3.97 (d, J=18.3 Hz, 1 H), 3.30 (s, 1 H), 2.59-2.65 (m, 3 H), 1.58-1.66 (m, 10 H), 1.56 ppm (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][CH:19]([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30](O)=[O:31])[N:21]=1>>[F:34][CH:19]([F:18])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([CH:33]=2)[C:30]([NH:15][CH2:14][C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][CH:10]=2)([CH3:17])[CH3:16])=[O:31])[N:21]=1
Reactant: O=C(O)c1cncc(-c2noc(C(F)F)n2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cncc(-c2noc(C(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 24 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 5-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (45 mg, yield 24%). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J=2.1 Hz, 1H), 9.20 (d, J=2.1 Hz, 1H), 8.82-8.78 (m, 1H), 8.75-8.74 (t, J=2.1 Hz, 1H), 8.04-8.00 (m, 3H), 7.74-7.48 (m, 1H), 7.38-7.33 (t, J=8.9 Hz, 2H), 3.55-3.53 (d, J=6.1 Hz, 2H), 1.31 (s, 6H). MS (ESI) m/z: Calculated for C22H18F3N5O3: 457.14. found: 458.2 (M+H)+.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[NH2:9][C:10]1[N:14]([C:15]2[CH:24]=[CH:23][C:18]3[NH:19][C:20]([CH3:22])=[N:21][C:17]=3[CH:16]=2)[N:13]=[CH:12][C:11]=1[C:25]([C:27]1[N:28]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[C:31](I)[CH:30]=2)=[O:26].N12CCCN=C1CCCCC2.[CH3:58][O:59][CH2:60][CH2:61][NH2:62].O.N>CS(C)=O.[Cu]I>[NH2:9][C:10]1[N:14]([C:15]2[CH:24]=[CH:23][C:18]3[NH:19][C:20]([CH3:22])=[N:21][C:17]=3[CH:16]=2)[N:13]=[CH:12][C:11]=1[C:25]([C:27]1[N:28]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[C:29]2[C:34]([CH:35]=1)=[C:33]([NH:62][CH2:61][CH2:60][O:59][CH3:58])[CH:32]=[CH:31][CH:30]=2)=[O:26]
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(I)cc32)cc1
Reactant: COCCN
Agent: [Cu]I
Agent: N
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COCCNc1cccc2c1cc(C(=O)c1cnn(-c3ccc4[nH]c(C)nc4c3)c1N)n2S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Copper (I) iodide (16 mg, 0.086 mmol), L-proline (37 mg, 0.32 mmol), and [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-iodo-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (104 mg) were dissolved in anhydrous dimethylsulfoxide (DMSO), and then 1,8-diazabicyclo[5.4.0]undec-7-ene (49 μl) and 2-methoxyethylamine (43 μl) were added thereto. The mixture was heated at 80° C. with stirring under a nitrogen atmosphere for 18 hours. After the reaction mixture was cooled to room temperature, 25% ammonia water was added thereto. The resulting mixture was extracted with ethyl acetate. The organic layer was isolated, washed with an aqueous solution of 1 M hydrochloric acid and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the desiccant was removed by filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography (dichloromethane/methanol=100/5) using a small amount of silica gel to give crude product of [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[4-(2-methoxy-ethylamino)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone. The obtained crude product was used in subsequent reactions without purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[C:21]([CH3:24])[CH:20]=[C:19]([OH:25])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:26](=[O:28])[NH2:27])[CH:7]=[CH:8][CH:9]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[C:21]([CH3:24])[CH:20]=[C:19]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:26](=[O:28])[NH2:27])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc(O)c2c3c(C(N)=O)cccc3n(Cc3cccc(F)c3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc(C)cc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
60% Sodium hydride in mineral oil (25.9 mg, 0.65 mM) was added to a solution of 9-[(3-fluorophenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole (181 mg, 0.52 mM) in 18 mL DMF and 3.9 ml THF. After 10 minutes, methyl bromoacetate (66 μl, 0.70 mM) was added and the resultant mixture stirred at room temperature for 1.25 hours. The mixture was diluted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layers were extracted with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with methylene chloride/acetone gradient) to afford 170 mg (78%) of the {9-[(3-fluorophenyl)methyl]-2-methyl-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester. 1H NMR (DMSO-d6) δ7.55 (d, 1H, J=8 Hz), 7.5 (bs, 1H), 7.4-7.25 (m, 2H), 7.2 (bs, 1H), 7.05 (m, 3H), 6.95 (d, J=8 Hz, 1H), 6.9 (d, J=8 Hz), 6.45 (s, 1H), 5.65 (s, 2H), 4.9 (s, 2H), 3.75 (s, 3H), 2.4 (s, 3H). MS (FD) m/e 404, 421.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][N:9]=[C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11]1.[N:19](OC(C)(C)C)=[O:20].Cl>C(O)(C)(C)C>[CH3:7][O:8][N:9]=[C:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][C:11]1=[N:19][OH:20]
Reactant: CC(C)(C)ON=O
Reactant: CON=C1COc2ccccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CON=C1C(=NO)Oc2ccccc21
Yield: 47.4 %

Procedure:
3.92 g (0.035 mol) of potassium tert-butoxide are dissolved in 40 ml of tert-butanol. A solution of 5.7 g (0.035 mol) of benzofuran-3-one O-methyl-oxime and 7.2 g (0.07 mol) of tert-butyl nitrite in 10 ml of tert-butanol is added to this solution. The mixture is stirred without cooling for two hours and then admixed with 20 ml of 2N aqueous hydrochloric acid. The crystalline product is filtered off, washed repeatedly with water and dried in a desiccator. 3.19 g (47.1% of theory) of benzofuran-2,3-dione 3-(O-methyl-oxime) 2-oxime are obtained as a mixture of two stereoisomers comprising 86.33% of isomer A and 12.98% of isomer B (HPLC).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].O>CN(C)C=O>[CH2:30]([N:19]1[CH2:20][CH2:21][N:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:17][CH2:18]1)[CH:29]=[CH2:28]
Reactant: c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 5.0 g of 1-phenyl-3-(1-piperazinyl)-1H-indazole and 2.7 g of potassium carbonate in 50 ml of dimethylformamide was added 2.4 g of allyl bromide. The reaction mixture was stirred at 70° C. for 16 hours, poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to yield 3-[4-(2-propenyl)-1-piperazinyl]-1-phenyl-1H-indazole as an oil. The oil was diluted with diethyl ether and filtered. Treatment of the filtrate with ethereal hydrogen chloride precipitated the hydrochloride salt. Recrystallization from ethanol/diethyl ether gave 2.0 g (21%) of 3-[4-(2-propenyl)-1-piperazinyl]-1-phenyl-1H-indazole hydrochloride, mp 234°-236°.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]3[C:22]([OH:23])=[C:21]([C:24]([O:26]CC)=[O:25])[CH:20]=[N:19][C:18]=23)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][N:17]3[C:22]([OH:23])=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=[N:19][C:18]=23)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(-c3ccc(Cc4ccccc4)cc3)cnn2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc2c(-c3ccc(Cc4ccccc4)cc3)cnn2c1O
Yield: 99.3 %

Procedure:
A mixture of 3-(4-benzylphenyl)-6-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine (1.35 g), sodium hydroxide (1.50 g), ethanol (35 ml) and water (35 ml) was stirred under heating reflux for 2 hours. Then, to the reaction mixture was added water (50 ml), and hydrochloric acid was added at 0° C. to adjust to acid. After stirring for 30 minutes, the precipitate was separated by filtration, washed with water, and dried to give the title compound (1.24 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.C(OC=C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C([Zn]CC)C.CCC[CH2:49][CH2:50][CH3:51].ICI>ClC1C=CC=CC=1Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:49]2[CH2:50][CH2:51]2)[C:24]([F:25])([F:26])[F:27])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Reactant: CCCCCC
Agent: CC[Zn]CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C=COC(C)=O
Solvent: Clc1ccccc1Cl
Solvent: ICI
Product: FC(F)(F)C(OC1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 27 h
Yield: 36.7 %

Procedure:
A suspension of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (135 mg, 0.300 mmol), vinyl acetate (277 μL, 3.00 mmol), di-μ-chlorobis[(η-cycloocta-1,5-diene)iridium (I)] (50.4 mg, 0.0750 mmol) and sodium carbonate (19.1 mg, 0.180 mmol) in o-dichlorobenzene (3.0 mL) was stirred for 27 h at 100° C. The reaction mixture was purified by flash column chromatography on silica gel eluting with a 25% ethyl acetate/n-hexane. The obtained compound was dissolved in dichloromethane (1.6 mL). A solution of diethyl zinc in hexane (1.0 M, 818 μL, 0.818 mmol) and diiodomethane (132 μL, 1.64 mmol) was added at 0° C. After being stirred for 4 h at room temperature, the reaction mixture was diluted with ethyl acetate, quenched with aqueous ammonium chloride, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on NH silica gel eluting with a 0-12% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (62.9 mg, 0.110 mmol, 37%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4](/[CH:7]=[CH:8]/[N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1.[CH:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(NC1CCCCC1)(C)C>C(Cl)Cl>[Br:1][C:2]1[O:3][C:4]([CH:7]([S:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH2:8][N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)o1
Agent: CC(C)NC1CCCCC1
Solvent: ClCCl
Product: O=[N+]([O-])CC(Sc1ccccc1)c1ccc(Br)o1

Procedure:
2-Bromo-5-((E)-2-nitrovinyl)furan (1.50 g, 0.006880 mol), thiofenol (0.91 ml, 0.99 g, 0.008945 mol) and N-isopropylcyclohexylamine (0.1 ml, 0.085 g, 0.0006017 mol) in dry methylene chloride (150 ml) was stirred in nitrogen atmosphere at RT for 4.5 h. Then the solution was washed with water, dried with Na2SO4 and evaporated. The product was stored in a freezer. 1H NMR (400 MHz, DMSO-d6): 4.94-5.01 (1H, m), 5.11-5.17 (2H, m), 6.37 (1H, d), 6.49 (1H, d), 7.38 (5H, m).
Reaction SMILES: [Si:1]([O:8][CH:9](C)[C:10](=[O:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[CH:15](C)C(=O)C.[Si](Cl)(C(C)(C)C)(C)C.N1C=CN=C1.C(OC1C=C([Mg]Br)C=C(F)C=1)C1C=CC=CC=1.BrC1C=C(OCC2C=CC=CC=2)C=C(F)C=1.[Mg]>C(OCC)C.O1CCCC1>[Si:1]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][CH3:15])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=O)C(C)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)C(C)O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: Fc1cc(OCc2ccccc2)cc([Mg]Br)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41 %

Procedure:
A solution of 3-tert-butyldimethylsilyloxybutan-2-one (5.56 g; prepared by reacting 3-hydroxybutan-2-one with tert-butyldimethylsilyl chloride in diethyl ether and using imidazole as a suitable base) in tetrahydrofuran (5 ml) was added to a solution of 3-benzyloxy-5-fluorophenylmagnesium bromide [prepared by heating a mixture of benzyl 3-bromo-5-fluorophenyl ether (6.7 g), magnesium powder (0.58 g) and tetrahydrofuran (50 ml) to 40° C. for 1 hour] in tetrahydrofuran (50 ml) and the mixture was stirred at ambient temperature for 2.5 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 3:2 v/v mixture of petroleum ether (b.p. 40°-60° C.) and methylene chloride as eluent. There was thus obtained an erythro isomer, (2RS,3SR)-2-(3-benzyloxy-5-fluorophenyl)-3-(tert-butyldimethylsilyloxybutan-2-ol (3.8 g, 41%), as an oil; and a threo isomer, the corresponding (2RS,3RS)-isomer (1.73 g, 18%), as an oil.
Reaction SMILES: C([C:5]1[C:10]([CH3:11])=[C:9]([OH:12])[C:8]([C:13]2[C:14]([OH:25])=[C:15]([CH3:24])[C:16](C(C)(C)C)=[CH:17][C:18]=2[CH3:19])=[C:7]([CH3:26])[CH:6]=1)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:19][C:18]1[CH:17]=[CH:16][C:15]([CH3:24])=[C:14]([OH:25])[C:13]=1[C:8]1[C:9]([OH:12])=[C:10]([CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:26]
Reactant: Cc1cc(C(C)(C)C)c(C)c(O)c1-c1c(C)cc(C(C)(C)C)c(C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1ccc(C)c(-c2c(C)ccc(C)c2O)c1O

Procedure:
To a 50 mL flask were added 0.5 g of 5,5′-Bis(t-butyl)-3,3′,6,6′-tetramethyl-2,2′-biphenol, 5 mL of xylenes and 0.05 g of p-toluenesulfonic acid. The mixture was refluxed for about 2 hours. The mixture was cooled and water added. The mixture was extracted with hexanes; the organic layer was washed with water and dried over MgSO4. After removing the solvent, the residue was recrystallized from petroleum ether.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 110 °C
Reaction time: 24 h
Yield: 141.7 %

Procedure:
In 300 mL of dimethyl sulfoxide were suspended 181.8 g (560 mmol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine, 100.0 g (374 mmol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate and 79.18 g (747 mmol) of sodium carbonate, which were then heated to 110° C. while bubbling a nitrogen gas and stirred for 24 hours. After cooling to room temperature, 1000 mL of ethyl acetate and 1000 mL of water were added, followed by separation into two layers. The organic layer was washed with 500 mL of water twice and concentrated under reduced pressure. To the residue was added 500 mL of ethanol and concentrated under reduced pressure to yield 294.6 g of crude ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily material (HPLC purity area percentage 76.6%). This oily material was dissolved in 700 mL of ethanol, and 29.88 g of sodium hydroxide dissolved in 300 mL of water was added thereto. The reaction solution was heated to 60° C. and stirred for 1 hour. The reaction solution was concentrated under reduced pressure. To the residue were added 1000 mL of water and 1000 mL of ethyl acetate, followed by separation into two layers. The aqueous layer was washed with 500 mL of ethyl acetate twice, and 1000 mL of ethanol was added to the aqueous layer. The aqueous layer was adjusted to about pH 6 by the addition of 500 mL of 1N hydrochloric acid and stirred at room temperature for 30 minutes and at 10° C. for 1 hour. The crystals formed were collected by filtration, washed with 400 mL of water and 400 mL of ethanol:water (1:1), and dried to yield 159.5 g of the title compound. HPLC purity area percentage 98.0%, Yield 74.1%.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>CCOCC>[CH2:2]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCI
Reactant: C1COCCN1
Solvent: CCOCC
Product: C#CCCCN1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of 5-iodo-pent-1-yne (2.40 g, 12.3 mmol) and morpholine (2.70 g, 30.9 mmol) was heated to 80° C. for 15 min. The mixture was diluted with Et2O and filtered. The solid residue was discarded, and the mother liquor was extracted with 3N HCl. The aqueous layer was made basic with NaOH, and back-extracted into EtOAc. Drying (Na2SO4), and concentration gave the title compound as a pale orange oil. 1H NMR (CDCl3) δ 3.67 (t, 4H), 2.39 (m, 6H), 2.21 (td, 2H), 1.93 (t, 1H), 1.67 (quint., 2H).
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][CH:10]([F:25])[O:11][C:12]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([NH2:24])=[CH:17][C:13]=1[C:14]([OH:16])=O.[F:26][C:27]([F:36])([F:35])[C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.N1C=CC=CC=1>C(Cl)Cl.C1COCC1>[F:26][C:27]([F:35])([F:36])[C@H:28]1[CH2:29][CH2:30][C@H:31]([NH:34][C:14](=[O:16])[C:13]2[CH:17]=[C:18]([NH2:24])[C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:12]=2[O:11][CH:10]([F:9])[F:25])[CH2:32][CH2:33]1
Reactant: Nc1cc(C(=O)O)c(OC(F)F)cc1[N+](=O)[O-]
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OC(F)F)cc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethylamine (102 μl) is added to a mixture of 2-(difluoro-methoxy)-5-amino-4-nitro-benzoic acid (175 mg, 0.705 mmol, prepared in analogy to WO2010/034797), 5 mL THF and 10 mL DCM and it is stirred for 5 h. Then trans-4-trifluoromethyl-cyclohexylamine (158 mg, 0.776 mmol) and pyridine (139 μL, 1.77 mmol) are added and it is stirred overnight. The solvent is removed i. vac., half-saturated aq. NaHCO3— solution is added and it is extracted with DCM. The organic layers are dried with Na2SO4, filtered, concentrated and purified via preparative HPLC (Method F).
Reaction SMILES: [CH3:1][S-].[Na+].[ClH:4].[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:27]C)=[C:10]([CH2:12][C:13]([CH:21]2[O:26][CH2:25][CH2:24][NH:23][CH2:22]2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)[CH:11]=1.CO>CN(C=O)C>[ClH:4].[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:27])=[C:10]([CH2:12][C:13]([CH:21]2[O:26][CH2:25][CH2:24][NH:23][CH2:22]2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:1])[CH:11]=1
Reactant: C[S-]
Reactant: COc1ccc(F)cc1CC(O)(c1ccccc1)C1CNCCO1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(Cc1cc(F)ccc1O)(c1ccccc1)C1CNCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
Sodium thiomethoxide (13 eq, 186 mg) was added at once to a solution of 2-{2-[5-fluoro-2-(methyloxy)phenyl]-1-methyl-1-phenylethyl}morpholine hydrochloride (75.2 mg, 0.204 mmol, synthesized as described in Example 8 above) in anydrous DMF (3 ml) in a microwave vessel. Upon addition, the reaction vessel was sealed and heated up in a CEM-Discovery microwave at 150 Watts, reaching 110° C. in 5 minutes and maintaining this temperature 6 minutes. The reaction vessel was cooled to room temperature and the reaction mixture taken into methanol (5 ml) and purified by SCX-2 chromatography to obtain the free base as clear oil (50 mg). The hydrochloride salt was obtained following general procedures as a white solid (52 mg, 72% after salt formation.). MW 353.83; C18H22NO3FCl; 1H NMR (CD3OD): 7.29-7.26 (2H, m), 7.20-7.08 (2H, m), 6.53-6.50 (2H, m), 6.30-6.26 (1H, m), 4.18 (1H, dd, 12.6 Hz, 2.6 Hz), 4.02 (1H, dd, 10.9 Hz, 2.3 Hz), 3.86 (1H, td, 12.6 Hz, 2.6 Hz), 3.60 (1H, 1/2 AB), 3.16 (1H, d, 12.6 Hz), 3.08-2.90 (3H, m), 2.58 (1H, m); 19F NMR (CD3OD)-128.4; LCMS: (12 min method) m/z 318.1 [M−HCl+H]+ @ Rt 3.954 min.