Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:22])[N:7]([C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl[C:24]1[C:29]([F:30])=[CH:28][N:27]=[CH:26][N:25]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Cl>O1CCCC1.O.COC(C)(C)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:24]3[C:29]([F:30])=[CH:28][N:27]=[CH:26][N:25]=3)([CH3:22])[N:7]([C@@H:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH3:13])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(Br)ccc3C2C)cc1
Reactant: Fc1cncnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(Br)ccc3C2(C)c2ncncc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
Dissolve 6-bromo-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-isoindolin-1-one (2.814 mmol, 1.014 g) in tetrahydrofuran (28 mL). Add 4-chloro-5-fluoro-pyrimidine (5.628 mmol, 518 μL) and cool to 0° C. Add potassium hexamethyldisilazide (4.502 mmol, 9 mL, 0.5 M in toluene) over 7 minutes and stir for 1 hour, then warm to ambient temperature and stir for 90 minutes. Pour into methyl-tert-butyl ether and aqueous 1 M HCl, add water and separate the layers. Wash with aqueous 1 N HCl, filter, wash with saturated aqueous sodium chloride, dry over magnesium sulfate, filter through a 2 cm pad of silica gel, and evaporate under reduced pressure to provide an oil. Purify on silica gel with 20-40% ethyl acetate/hexane to give the title compound as a foam (547 mg, 43%). ES/MS m/z: 456 (M+H).
Reaction SMILES: [C:1]1([OH:14])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:15]=[O:16].[NH2:17]C1C=CC=CC=1>O1CCOCC1.C(OCC)C>[O:16]1[C:15]2[CH:1]=[CH:2][CH:3]=[CH:4][C:7]=2[CH2:8][CH2:9][NH:17]1.[C:10]1([OH:13])[CH:9]=[CH:8][C:7]([C:4]2[CH:5]=[CH:6][C:1]([OH:14])=[CH:2][CH:3]=2)=[CH:12][CH:11]=1
Reactant: C=O
Reactant: Nc1ccccc1
Agent: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1ccc2c(c1)CCNO2
Temperature: 25 °C

Procedure:
27.9 g of 4,4′-biphenol and 48.6 g of aqueous formaldehyde (37%) were added into a 4-neck reactor equipped with a stirrer, temperature controller, and condenser, and then 80 ml of 1,4-dioxane was added as a solvent. The mixture was stirred at room temperature, and to the resulting solution 27.9 g aniline in 30 ml 1,4-dioxane was dripped at a rate of one drop per second while stirring. Upon completion of the dripping the solution was heated and reacted under refluxing for 10 hours. The reaction mixture was dried in a rotary evaporator under vacuum to obtain a pale orange solid. The pale orange solid was dissolved in ethyl ether and washed with 3N NaOH aqueous three times, followed by 1 N aqueous HCl solution several times and pure water several times, before removing the solvent in vacuo to obtain pale orange 4,4′-biphenol dihydrobenzoxazine solid. m.p. 170° C. EA: Calcd.: C: 80.00%; H: 5.71%; N: 6.66%. Found: C: 80.30%; H: 5.73%; N: 6.56%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[C:8]2[C:14]([CH3:15])=[N:13][N:12]([CH2:16][CH3:17])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:21])=[C:8]2[C:14]([CH3:15])=[N:13][N:12]([CH2:16][CH3:17])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(c(C)nn2CC)c1O
Product: CCOC(=O)c1cnc2c(c(C)nn2CC)c1Cl

Procedure:
A mixture of 24.9 g. 1-ethyl-4-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.1 mol.) and 150 ml. of phosphorus oxychloride is refluxed for 4 hours. The excess phosphorus oxychloride is removed by means of vacuum distillation. As soon as the phosphorus oxychloride has been removed, the oily residue solidifies on cooling. It is treated with water and filtered under suction (25 g., m.p. 70°-74°). The 4-chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is recrystallized from cyclohexane, yield 22.8 g. (85%), m.p. 78°-79°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cu]I.O1CCCC1>[CH2:11]([O:10][C:8]([N:1]1[CH:6]=[CH:5][CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=[CH:2]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)Cl
Reactant: c1ccncc1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOC(=O)N1C=CC(c2ccccc2)C=C1
Yield: 85.5 %

Procedure:
1.9 g (0.01 mole) of CuI was added to a mixture of 18.7 g (0.236 mole) of pyridine and 300 ml of tetrahydrofuran under a N2 atmosphere with stirring. The mixture was stirred at room temperature until the mixture became a homogeneous solution, and thereafter a solution of 22.8 g (0.21 mole) of ethyl chloroformate and 20 ml of tetrahydrofuran was added dropwise, on an ice bath, so that the inner temperature of the reactor could not exceed 20° C. Further, 100 ml of 2M phenyl magnesium chloride solution (0.2 mole; THF solution) was added dropwise over 1.5 hours at the inner temperature ranging from −10° C. to −5° C. The reaction mixture was stirred for 0.5 hours at the temperature of −10° C. to −5° C. Further, after stirring for 1 hour at 25° C., about 150 ml of tetrahydrofuran was removed from the mixture by a vacuum distillation, and then 180 ml of aqueous 20% ammonium chloride solution was added to the resultant mixture. The reaction product was extracted with 180 ml of ethyl acetate, and then the aqueous layer was discharged. Thereafter, 180 ml of 10% hydrochloric acid was added and stirred for 15 minutes. The resulting precipitate was removed by filtration through celite, and then the celite was washed with 40 ml of ethyl acetate. After removing the aqueous layer of the filtrate, the organic layer was washed once with 180 ml of 10% hydrochloric acid, and twice with 180 ml each of water. The organic layer was concentrated under a reduced pressure to obtain Compound I-1: obtained amount 44.6 g; purity 88.0% (determined by HPLC); yield 85.5%.
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O.Cl>O1CCCC1.CCCCCC>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:5][CH2:4][CH2:3][OH:2])[CH:36]=[CH:37][CH:38]=1
Reactant: O=Cc1cccc(F)c1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCC=Cc1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A mixture of 4.0 g of (3-hydroxypropyl)triphenylphosphonium bromide and 20 ml of tetrahydrofuran was cooled to 0° C., to which 12.5 ml of 1.6M n-butyl lithium (as a hexane solution) was slowly added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, to which a mixture of 1.24 g of 3-fluorobenzaldehyde and 10 ml of tetrahydrofuran was slowly added dropwise at the same temperature, followed by further stirring at room temperature for 6 hours. The reaction mixture was poured into ice-water, acidified by the addition of 10% hydrochloric acid, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.70 g of 4-(3-fluorophenyl)-3-buten-1-ol.
Reaction SMILES: CC1C=CC(S(O[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([CH3:29])=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]=3[OH:22])[CH:13]=2)(=O)=O)=CC=1.[B-].[Na+]>C(Cl)(Cl)Cl.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:29][C:16]1[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:18]([OH:22])[C:19]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:21][CH:20]=2
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(O)c(-c4ccccc4)c(C)cc3c2)cc1
Agent: Cl[Ni]Cl
Agent: [B-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Cc1cc2ccccc2c(O)c1-c1ccccc1
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
To a cold (5° C.) solution of 5-hydroxy-7-methyl-6-phenyl-2-naphthalenyl 4-methylbenzenesulfonate (239) (0.250 g, 0.62 mmol) in CHCl3 (5 mL) and MeOH (5 mL) was added nickel chloride hexahydrate (0.238 g, 1.24 mmol). To the above mixture sodium borohydrate (0.471 g, 12.4 mmol) was added portion-wise. The resulting black mixture was stirred at that temperature for 15 min. Reaction mixture was filtered through a pad of celite (washings were done with CHCl3). The filtrate was concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography to afford 0.064 g (44%) of the title compound (86) as an oil. 1H NMR (400 MHz, CDCl3): δ 8.22 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.59-7.55 (m, 2H), 7.52-7.46 (m, 3H), 7.40-7.36 (m, 3H), 5.28 (s, 1H), 2.22 (s, 3H). LCMS (ESI) m/z (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[C:6]([F:12])[CH:5]=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([F:12])[CH:5]=1
Reactant: COC(=O)c1cc(F)cc(CO)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(C)cc(F)c1
Reaction time: 2 h
Yield: 85.9 %

Procedure:
Ethanol (2 ml) was added to round bottom flask containing 3-fluoro-5-hydroxymethyl-benzoic acid methyl ester (667 mg, 3.6 mmol) and palladium (10 wt. % on activated carbon, 300 mg) under argon. The flask was evacuated using a water aspirator and then filled with hydrogen from a balloon. After stirring for 2 h, the palladium on carbon was removed by filtration through celite. The filtrate was then concentrated to afford 520 mg (87%) of 3-fluoro-5-methyl-benzoic acid methyl ester. 1H NMR (CDCl3), δ (ppm): 7.65 (s, 1H), 7.51 (d, 1H), 7.08 (d, 1H), 3.91 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[NH:21][C:22]([C:24]1([CH3:27])[CH2:26][O:25]1)=[O:23]>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:27][C:24]([OH:25])([CH3:26])[C:22]([NH:21][C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[CH3:11])=[O:23])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)C1(C)CO1
Reactant: N#Cc1ccc(O)cc1F
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)C(C)(O)COc1ccc(C#N)c(F)c1

Procedure:
3-(4-Cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1c starting from 2-fluoro-4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (2-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.3% methanol). 1H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.37 (3H, s), 4.13 (1H, d, J=10.1 Hz), 4.37 (1H, d, J=10.1 Hz), 6.51 (1H, s), 6.95-6.98 (1H, m), 7.17-7.21 (1H, m), 7.78-7.83 (1H, m), 8.05-8.12 (2H, m), 8.18 (1H, d, J=2.3 Hz), 9.57 (1H, s).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:6](=O)[CH2:5]1)(O)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N([OH:38])N=NC=2C=1.[NH3:39].O1CCOCC1>ClCCl>[C:1]([CH:4]1[CH2:5][CH2:6][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:8]1=[O:38])(=[O:2])[NH2:39]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CC(=O)N(Cc2ccc(Cl)cc2)C1
Reactant: N
Agent: CCN=C=NCCCN(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)C1CCN(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 4-carboxy-1-(4-chlorobenzyl)pyrrolidin-2-one (5.05 g, 20 mmol), EDCI (2.85 g, 22 mmol), HOBt (2.97 g, 22 mmol) and dichloromethane (100 mL) was added 0.5 M ammonia in dioxane (60 mL, 30 mmol). The reaction mixture was stirred at room temperature for 15 h and washed with 2N HCl (3 times) and 2 N NaOH aqueous solution (100 mL×4). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 3-carbamoyl-1-(4-chlorobenzyl)pyrrolidin-2-one (1.49 g) as a colorless solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[CH:22][N:23]=[C:17]3[CH:16]=2)=[N:11]1>CN(C=O)C>[I:1][C:21]1[N:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[N:14][N:10]([CH3:9])[N:11]=3)=[CH:16][C:17]2=[N:23][CH:22]=1
Reactant: Cn1nnc(-c2ccn3ccnc3c2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccn3c(I)cnc3c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
N-Iodo succinimide (300 mg, 1.3 mmol) was added in one portion to a stirred suspension of 7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (240 mg, 1.2 mmol) in dry DMF (2 ml) at RT under N2. After 5 hours, the reaction was quenched with saturated aqueous sodium thiosulphate/saturated aqueous NaHCO3 (1:1, 2 ml). Water (2 ml) was then added and the mixture was stirred at RT for 15 minutes. The solid was collected by filtration and dried in vacuo to give the title compound (360 mg) as a cream solid. 1H NMR (400 MHz, DMSO-d6): 8.51 (1H, dd), 8.20 (1H, dd), 7.86 (1H, s), 7.65 (1H, dd), 4.47 (3H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.CN1CCOCC1.C1CN([P+](O[N:47]2N=[N:54][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[N:47]1[C:16](=[O:17])[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]1([C:9]1[CH:10]=[CH:11][C:5]2[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1)[OH:13]
Reactant: O=C1COc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1ccccc1N1C(=O)c2ccccc2C1(O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 3 %

Procedure:
2-[(3-Oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]benzoic acid (100 mg, 0.34 mmol.) was taken into DMF (1 mL) followed by addition of 4-methylmorpholine (75 uL, 0.7 mmol.) and PyBOP (177 mg, 0.34 mmol.) and the resulting solution was stirred for 15 minutes at room temperature. o-Phenylenediamine (37 mg, 0.34 mmol.) was added to the solution thus obtained and the mixture was allowed to stir an additional hour then partitioned with ethyl acetate and water. The organic layer was washed with water (3×), 10% aqueous citric acid (2×), saturated aqueous sodium bicarbonate (1×) and brine then dried over anhydrous sodium sulfate. A portion of the residue obtained on filtration and concentration of the organic solution was purified by silica gel flash chromatography (2:1 ethyl acetate:hexanes to 100% ethyl acetate) gave 6-[2-(2-aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one (4.0 mg, 3% yield). The remainder of the crude residue was taken into acetic acid (5 mL) and heated to reflux for one hour. The solvent was removed in vacuo and the residue partitioned with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and the residue was purified by silica gel flash chromatography (2.5:1 ethyl acetate:hexanes) to give 6-{[2-(1H-benzimidazol-2-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one (28 mg, 22% yield). 6-[2-(2-Aminophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2H-1,4-benzoxazin-3(4H)-one: MS (EI) for C22H17N3O4: 388 (MH+). 6-{[2-(1H-Benzimidazol-2-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one: 1H NMR (400 MHz, d6-DMSO): 12.84 (br s, 1H), 10.75 (br s, 1H), 8.00 (d, 1H), 7.73 (tr, 1H), 7.59 (tr, 1H), 7.44-7.37 (m, 3H), 7.32 (s, 1H), 7.15-7.06 (m, 3H), 6.87 (d, 1H), 4.58 (s, 2H). MS (EI) for C22H15N3O3: 370 (MH+).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[C:14]2[C:10]=1[C:11]1[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:12]=1[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S(C1C=C(C2C=C([C:46]([N:48]3[CH2:53]C[N:51](C)[CH2:50][CH2:49]3)=O)C=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:8][C:9]1[CH:17]=[C:16]([C:18]([NH:51][CH2:50][CH2:49][N:48]([CH3:53])[CH3:46])=[O:20])[CH:15]=[C:14]2[C:10]=1[C:11]1[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:12]=1[NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc2[nH]c3cc(C(=O)O)cc(SCc4ccccc4)c3c2c1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)N3CCN(C)CC3)cc3[nH]c4ncc(C)cc4c23)c1
Product: Cc1cnc2[nH]c3cc(C(=O)NCCN(C)C)cc(SCc4ccccc4)c3c2c1

Procedure:
The title compound was synthesized from Compound 150 using an analogous procedure to that described in the preparation of Compound 140. 1H NMR (400 MHz, MeOD) δ ppm 2.53 (s, 3 H) 3.02 (s, 6 H) 3.43 (t, J=5.81 Hz, 2 H) 3.82 (t, J=5.81 Hz, 2 H) 4.42 (s, 2 H) 7.16-7.26 (m, 3 H) 7.31 (d, J=7.83 Hz, 2 H) 7.82 (d, J=1.26 Hz, 1 H) 7.96 (s, 1 H) 8.30 (s, 1 H) 8.80 (s, 1 H) [M+H] calc'd for C24H26N4OS, 419; found, 419.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([F:22])[C:10]([C:13]#[C:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[N:11][CH:12]=1.[CH3:23][CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1.CCOC(C)=O>C(OCC)C>[Si:15]([C:14]#[C:13][C:10]1[N:11]=[CH:12][C:7]([C:27]2([OH:30])[CH2:28][CH2:29][CH:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:8][C:9]=1[F:22])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC1CCC(=O)CC1
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ncc(Br)cc1F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1CCC(O)(c2cnc(C#C[Si](C)(C)C(C)(C)C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Under an argon atmosphere 9.38 mL (15.0 mmol, 1.6 M) of n-butyllithium was slowly added to a solution of 4.71 g (15.0 mmol) of 5-bromo-2-[(tert-butyldimethylsilanyl)ethynyl]-3-fluoropyridine in 100 mL of diethyl ether at −70° C., so that the internal temperature did not rise above −65° C. After 2 minutes, 1.84 mL (15.0 mmol) of 4-methylcyclohexanone was added and then the cooling bath was removed. The reaction solution was heated to RT and then combined with 50 mL of aqueous saturated ammonium chloride solution. The organic phase was separated off, the aqueous phase was extracted twice with MTBE, and the combined organic phases were dried over magnesium sulfate, filtered through activated charcoal, and the solvent was removed in vacuo. The residue was taken up in DIPE, cooled in the cooling bath, and the precipitate formed (1.4 g) was suction filtered. The mother liquor was concentrated in vacuo and the residue was purified by column chromatography (silica gel, PE/EtOAc 8:2). A further 2.1 g were obtained, which were combined with the above precipitate. The product was obtained as a cis/trans mixture. Yield: 3.50 g (67% of theoretical); C20H30FNOSi (M=347.542); calc.: molpeak (M+H)+:348; found: molpeak (M+H)+:348; Rf value: 0.5 (silica gel, PE/EtOAc 8:2).
Reaction SMILES: [C:1](=O)([O:7]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:6][CH2:5]1.[C:18]([CH2:20][C:21]1([N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[N:34][N:33]4[C:36]([C:39]5[CH:40]=[C:41]([NH:45][C:46]([NH:48][CH2:49][C:50]([F:53])([F:52])[F:51])=[O:47])[CH:42]=[CH:43][CH:44]=5)=[CH:37][N:38]=[C:32]4[CH:31]=3)[CH:27]=[N:26]2)[CH2:24][NH:23][CH2:22]1)#[N:19].C(N(CC)CC)C>CN(C)C=O.CO>[C:18]([CH2:20][C:21]1([N:25]2[CH:29]=[C:28]([C:30]3[CH:35]=[N:34][N:33]4[C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([NH:45][C:46]([NH:48][CH2:49][C:50]([F:52])([F:53])[F:51])=[O:47])[CH:40]=5)=[CH:37][N:38]=[C:32]4[CH:31]=3)[CH:27]=[N:26]2)[CH2:22][N:23]([C:1]([O:2][CH2:3][CH:4]2[CH2:6][CH2:5]2)=[O:7])[CH2:24]1)#[N:19]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: O=C(OCC1CC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)OCC2CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropylmethyl 4-nitrophenyl carbonate (11 mg, 0.045 mmol) was added to a mixture of N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (15.0 mg, 0.0303 mmol) and triethylamine (13 μL, 0.093 mmol) in N,N-dimethylformamide (0.5 mL) and methanol (0.1 mL). The reaction mixture was stirred at r.t. for 2 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=594.2.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1>>[CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCC
Reactant: O=Cc1ccc(Br)cc1
Product: CCCCCCc1ccc(C=O)cc1
Yield: 94.4 %

Procedure:
General procedure G was used to couple 8.1 mmols of 1-hexene to 5.4 mmols of 4-bromobenzaldehyde. 5.1 mmols of the title product was recovered after purification by flash chromatography. Spectral data was consistent with previously described compounds.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH:5]1([C:8]([CH2:10][CH:11]2[CH2:13][CH2:12]2)=O)[CH2:7][CH2:6]1.CO.[BH4-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.O>[CH:5]1([CH:8]([NH:4][CH2:1][CH2:2][CH3:3])[CH2:10][CH:11]2[CH2:13][CH2:12]2)[CH2:7][CH2:6]1
Reactant: CCCN
Reactant: O=C(CC1CC1)C1CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCNC(CC1CC1)C1CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Add 6.9 ml of propylamine to 2.2 g of cyclopropylmethyl cyclopropyl ketone in 85 ml of methylene chloride. Add 7 ml of a 1M solution of titanium (IV) chloride in methylene chloride dropwise at room temperature. After 18 hours stirring, add 40 ml of anhydrous methanol. Cool to 0° C. and add 1.0 g of sodium borohydride in small amounts. After overnight stirring at room temperature, add 10 ml of water and evaporate under vacuum. Take up in water and extract with methylene chloride. Extract with 2N hydrochloric acid. Wash with ethyl ether. Neutralise the aqueous phase with concentrated sodium hydroxide solution. Extract with methylene chloride, dry over anhydrous sodium sulphate and evaporate to dryness to obtain a colourless oil.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]I)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O.O1CCCC1>[CH2:1]([C:3]([CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:25][CH:26]=1)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: ICCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC)(CCc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 94.5 %

Procedure:
Diethyl ethylmalonate (50 g) was added to a suspension of sodium hydride (11 g) in dimethylformamide (200 ml) and tetrahydrofuran (50 ml), at 0° C., and the mixture was stirred at room temperature for 35 minutes. A solution of 2-(4-benzyloxyphenyl)ethyl iodide (90 g) was added to the reaction mixture at 0° C. and the whole mixture was stirred at 0° C. for 20 minutes and allowed to stand at room temperature overnight. The resultant mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:9) to give the subject compound (100 g).