Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14].O>CN(C=O)C>[CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=NNC(=O)OC(C)(C)C)CC(C)(C)C1

Procedure:
3,3,5,5-Tetramethylcyclohexanone (7.7 g, 0.05 moles) was dissolved in DMF (50 mL) and t-butyl carbazate (6.6 g, 0.05 moles) was added to give a clear solution. Left to stand over the weekend. Poured into water and extracted into ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate. Evaporated to give a white solid. Triturated with ether and dried in a desiccator to give the product as a white solid. (10.4 g, 78%). 1H NMR (300 MHz DMSO-d6) mixture of isomers 9.5 and 7.95 (brs, 1H), 2.95 (s, 1H), 2.75 (s, 1H), 2.1 (s, 2H), 1.95 (s, 2H), 1.4 (s, 9H), 0.9 (2s, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.C(OCC)C.C(OCCCC)CCC.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cnccn1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CCCCOCCCC
Product: COc1nccnc1-c1ccccc1
Yield: 12 %

Procedure:
First, in a three-neck flask, 11.30 g of 2-methoxypyrazine and 200 mL of diethylether were put, and a dibutyl ether solution (2.1 mol/L) of phenyl lithium was dropped thereto while the mixture was cooled down with ices and stirred under a nitrogen atmosphere, and stirred to be reacted for 20 hours. After the reaction, water was added to the reaction solution, and an organic layer was extracted with ethyl acetate. The obtained organic layer was washed with water, and dried with magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was distilled off. The obtained residue was refined with a column chromatography using dichloromethane as a development solvent, so that 2-phenyl-3-methoxypyrazine was obtained (light yellow powder, yield: 12%). A synthesis scheme of Step 1 is shown by the following (a2-1).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:44]4[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:15])=[O:16])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CN1CCNCC1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C)CC4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-[5-methyl-2-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 396c) was reacted with 1-methylpiperazine (CAS Reg. No. 109-01-3) to give the title compound as colorless foam. MS (ESI): m/z=650.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[CH2:8][CH2:9][N:10]2[CH2:13][C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)CC(O)C.CO>[CH3:40][O:39][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][C:23]=1[NH:22][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[N:6]([CH3:21])[C:7](=[O:20])[CH2:8][CH2:9][N:10]2[CH2:13][C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1)[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)=[O:28]
Reactant: Cc1nc(CN2CCC(=O)N(C)c3cnc(Cl)nc32)cs1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(Cc1csc(C)n1)CCC(=O)N2C
Temperature: 160 °C

Procedure:
10-chloro-6-methyl-2-[(2-methyl-1,3-thiazol-4-yl)methyl]-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 101; 58 mg, 0.18 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 49 mg, 0.19 mmol) and p-toluene sulphonic acid (70 mg, 0.37 mmol) were taken up in 4-methyl-2-pentanol (2 mL) and heated to 160° C. in microwave by microwave irradiation for 1 hour. The reaction mixture was dissolved in methanol (5 mL) and water (˜5 mL) and poured directly onto an SCX-3 cartridge (2 g). The cartridge was washed through with methanol (˜30 mL), before elution of products with 2M ammonia in methanol (˜30 mL). Evaporation of the ammoniacal fraction gave an amber film which was purified by reverse phase HPLC to yield the title compound as an off white solid (43 mg, 26%)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH2:19][C:20]3[CH:21]=NC=[CH:24][CH:25]=3)=[C:16]([OH:18])[CH:17]=2)=[CH:4][CH:3]=1.CC(C)([O-:29])C.[K+]>C(O)(C)(C)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH2:19][CH:20]3[CH2:25][CH2:24][O:29][CH2:21]3)=[C:16]([OH:18])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2ccc(Cc3cccnc3)c(O)c2)c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Nc1ccc(-c2ccc(CC3CCOC3)c(O)c2)c2ccccc12
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
To a solution of 200 mg of tert-butyl naphthyl carbamate (Example 6) (0.59 mmol, 1 equiv.) in 1.6 mL anhydrous tert-butanol was added 200 mg of 3-tetrahydrofuroic aldehyde from above (excess) and 1.78 mL potassium tert-butoxide solution in tert-butanol (1.0 M, 1.78 mmol, 3 equiv.). The mixture was heated to 40° C. overnight, then cooled and quenched with NH4Cl saturated aqueous solution. The product was extracted with a dichloromethane/MeOH mixture (3×100 mL). The combined extracts were washed with brine, dried over MgSO4, and concentrated. 1H NMR analysis revealed that only 10% of the enone was consumed. The residue (300 mg) was dissolved in 4.0 mL dichloromethane and treated with 4 mL of a 1:1 mixture dichloromethane:TFA. The mixture was stirred for 1.5 h, then neutralized with saturated NaHCO3 aqueous solution, basified with 4 N NaOH solution and extracted with dichloromethane/MeOH (3×100 mL). The combined organic extracts were washed with brine, dried (MgSO4) and filtered and concentrated. The crude product was purified by column chromatography on silica gel using 10 to 50% EtOAc in hexane eluent mixtures to give the title compound (35 mg 0.11 mmol, 19% of theoretical yield).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3]=1[C:15]([O:17]C)=[O:16].[I-].[Na+].N1C=CC=CC=1>C(C(C)=O)C.O>[Br:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1oc(-c2ccccc2)cc(=O)c1Br
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1oc(-c2ccccc2)cc(=O)c1Br

Procedure:
Methyl 3-bromo-4-oxo-6-phenyl-4H-pyran-2-carboxylate (587 g) was added to a stirred solution of dry sodium iodide (315 g) in dry methyl ethyl ketone (8 l). The solution was heated under reflux for 5 minutes, then pyridine (152 ml) was added and heating was continued for 31/2 hours. The mixture was cooled, the solid product was dissolved in water (2 l) and the solution was washed with dichloromethane and filtered. The filtrate was diluted to 10 l and acidified with 5M hydrochloric acid (760 ml) to precipitate the title product (mp 247° C. with decomposition).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH3:10][N:11]([CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20])[CH3:12].[Cl-:27].[NH4+]>CCOCC>[ClH:27].[CH3:12][N:11]([CH:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[OH:20])[CH3:10]
Reactant: [Cl-]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)c1ccc(F)cc1
Product: Cl
Temperature: 25 °C
Yield: 57.4 %

Procedure:
0.50 g (20.7 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.28 ml (20.7 mmole) of 4-bromofluorobenzene dissolved in 20 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 4.0 g (17.3 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 80 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 5.50 9 of crude base (97.2% of theory) were obtained. 3.61 g of 2-(dimethylaminophenylmethyl)-1-(4-fluorophenyl)cyclohexanol, hydrochloride (57.4% of theory) were obtained from the crude base according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 150° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N+:13]([O-:15])=O)[C:6]([NH2:12])=[CH:7][CH:8]=2)[CH2:3]1.[N:16]#[C:17][NH2:18].[CH]Cl.[OH-].[Na+]>O>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[CH:7][C:6]3[N:12]=[C:17]([NH2:18])[N:16]=[N+:13]([O-:15])[C:5]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2ccc(N)c([N+](=O)[O-])c2C1
Reactant: N#CN
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2ccc3nc(N)n[n+]([O-])c3c2C1
Temperature: 60 °C
Yield: 62.3 %

Procedure:
A mixture of 8-nitroaniline 254 (510 mg, 2.5 mmol) and cyanamide (460 mg, 10.9 mmol) was melted at 100° C. The mixture was cooled to 60° C. and cHCl (4 mL) was added slowly. The solution was heated at 100° C. for 1 h, then three more aliquots of cyanamide (460 mg, 10.9 mmol) and cHCl (5 mL) were added over 3 h. The solution was cooled to 60° C. and the solution made basic with NaOH solution (7.5 M, 10 mL). The solution was heated at 100° C. for another 1 h, cooled and diluted with water (50 mL). The solid was filtered and washed with water (30 mL) to give 1-oxide 262 (360 mg, 63%) as a brown solid: mp 226-229° C.; 1H NMR [(CD3)2SO] δ 7.50 (d, J=8.6 Hz, 1H, H-5), 7.32 (d, J=8.6 Hz, 1H, H-6), 7.09 (br s, 2H, NH2), 4.09 (s, 2H, H-10), 2.88 (t, J=5.7 Hz, 2H, H-7), 2.58 (t, J=5.7 Hz, 2H, H-8), 2.40 (s, 3H, NCH3); MS (APCI) m/z 232 (MH+, 100%). Anal. calcd for C11H13N5O.¼CH3OH: C, 56.5; H, 5.9; N, 29.3. Found: C, 56.6; H, 5.6; N, 29.1%.
Reaction SMILES: ClC1C=C(C=C(Cl)C=1)N.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22](=[O:23])[CH:21]([CH3:24])[S:20][CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1.C(O)(=S)C(C)[OH:27].C1NCSC1=O.ClC1C=C(C=CC=1)C(OO)=O>>[Cl:17][C:15]1[CH:14]=[C:13]([N:18]2[C:22](=[O:23])[CH:21]([CH3:24])[S:20](=[O:27])[CH2:19]2)[CH:12]=[C:11]([Cl:10])[CH:16]=1
Reactant: CC(O)C(O)=S
Reactant: CC1SCN(c2cc(Cl)cc(Cl)c2)C1=O
Agent: Nc1cc(Cl)cc(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C1CNCS1
Product: CC1C(=O)N(c2cc(Cl)cc(Cl)c2)CS1=O

Procedure:
3,5-Dichloroaniline was converted to 3-(3,5-dichlorophenyl)-5-methyl-4-thiazolidinone in accordance with the procedure of Example 4. The only difference was that thiolactic acid was used instead of mercaptoacetic acid. The 3-(3,5-dichlorophenyl)-5-methyl-4-thiazolidinone had a melting point of 80°-88° C. This thiazolidinone (18 g) was oxidized with one equivalent of m-chloroperoxybenzoic acid (14 g) in the same manner as described in Example 2. After removal of the solvent, the reaction product was recrystallized from isopropyl alcohol to yield 3-(3,5-dichlorophenyl)-5-methyl-4-thiazolidinone 1-oxide, m.p. 146°-149° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.C([Li])CCC.[S:12](=[O:14])=[O:13].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[CH3:16][C:15]([NH:19][S:12]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)(=[O:14])=[O:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: O=S=O
Reactant: Cn1cccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
A solution of 10 g (0.12 mol) of N-methyl-pyrrole in 120 ml, of anhydrous THF under nitrogen atmosphere was cooled to below -70° C. then treated with 56 ml, of 2.4M n-butyllithium in hexanes (0.13 mol) dropwise at such a rate as to keep the temperature below -60° C. The resulting brown colored mixture was stirred for 16 h at ambient temperature, then recooled to below -70° C. at which time liquified sulfur dioxide (9.0 mL, 0.21 mol) was added rapidly, causing an exotherm at -20° C. and the formation of a thick golden colored precipitate. After stirring for 1 h at ambient temperature, the THF was removed under reduced pressure. The solids were triturated with ether and collected by filtration with an ether rinse then dried under nitrogen. This intermediate sulfinate salt was added to a well stirred mixture of 350 water and 250 mL dichloromethane chilled to 0° C. N-Chlorosuccinimide was then added in portions so as to keep the temperature below 3° C. The mixture was stirred vigorously for 30 min at ambient temperature, after which time, the layers were separated and the organic layer was washed successively with 10% aq NaHSO3, twice with aq NaHCO3, dried (MgSO4) and filtered. This dichloromethane solution was then cooled to 0° C. and stirred while 32 ml, (0.30 mol) of t-butylamine was added over 2 min. After stirring for 1 h at ambient temperature, solids had precipitated from the brown solution which was then left stirring for 3 days. The mixture was diluted with more dichloromethane then washed three times with 1N HCl, once with saturated aq NaCl, dried (MgSO4) and evaporated. The resulting solid residue was triturated and collected with a mixture of hexanes and n-chlorobutane to afford 7.4 g of the title compound as tan crystals, m.p. 125°-126° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14].C(N(CC)CC)C.[C:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])[CH3:26]>C1COCC1>[F:17][C:2]([F:1])([F:16])[CH2:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH:13][C:30](=[O:31])[CH2:29][O:28][C:25](=[O:27])[CH3:26])[C:7]=1[OH:14]
Reactant: Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Reactant: CC(=O)OCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6.3 (25 mmol) of crude 3-amino-5-fluoro-2-hydroxybenzoic acid-(2,2,2,-trifluoro-ethyl)amide is dissolved in 30 ml of THF, 3.04 g (30 mmol) of triethylamine as well as 4.1 g (30 mmol) of acetoxyacetylchloride are added and stirred for 12 hours at room temperature. The reaction solution is then concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel 60 with ethyl acetate/hexane. 5.52 g=62.7% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].[CH:10]([O-])([O-])OCC.[NH2:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1>C(#N)C>[NH2:7][C:6]1[N:16]([C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)[CH:10]=[N:8][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: CCOC([O-])[O-]
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)C(N)C#N
Solvent: CC#N
Product: CCOC(=O)c1ncn(-c2ccn(C)n2)c1N
Yield: 61 %

Procedure:
In 200 ml of acetonitrile, 6.7 g of ethyl-aminocyanoacetate, 8.5 g of ethyl orthoformate and 5.6 g of 3-amino-1-methylpyrazole were refluxed under heating for 4.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Crystals precipitated was filtered out, followed by washing with ether to give 7.5 g of the desired compound. m.p.: 168° to 170° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][CH2:19][CH:20]([CH2:23][CH:24]=[CH2:25])[CH2:21]O)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C.[CH3:33][O:34][C:35]([CH:37]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:36]>C(Cl)Cl>[Si:11]([O:18][CH2:19][CH:20]([CH2:23][CH:24]=[CH2:25])/[CH:21]=[CH:37]/[C:35]([O:34][CH3:33])=[O:36])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C=CCC(CO)CO[Si](C)(C)C(C)(C)C
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCC(/C=C/C(=O)OC)CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C

Procedure:
Dimethyl sulfoxide (4.71 mL, 66.3 mmol) was added to a methylene chloride solution (70 mL) of oxalyl chloride (2.84 mL, 33.2 mmol) with stirring at −78° C., and the mixture was stirred at this temperature for 5 minutes. Then, a methylene chloride solution (30 mL) of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)pent-4-en-1-ol (J. Chem. Soc., Perkin Trans. 1 1991, 2073) (5.10 g, 22.1 mmol) was added thereto. The mixture was stirred at this temperature for 15 minutes. Then, triethylamine (12.3 mL, 88.4 mmol) was added thereto, and the mixture was heated to room temperature and stirred. The mixture was separated into aqueous and organic layers by the addition of 0.1 M hydrochloric acid. The organic layer was washed with 0.1 M hydrochloric acid, water, and saturated saline and then dried over anhydrous magnesium sulfate. The residue was filtered and concentrated under reduced pressure, and the obtained residue was dissolved in toluene (50 mL). To the solution, (methoxycarbonylmethylene)triphenylphosphorane (11.1 g, 33.2 mmol) was added, and the mixture was stirred at room temperature for 4 hours and further stirred at 60° C. for 2 hours. The reaction solution was concentrated under reduced pressure, then filtered through Celite, and concentrated again under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (5.69 g, 91%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[NH:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=C2N=C(CCC3NC(=O)CCCC3)NC2=NC=1.[CH3:46][N:47]([CH3:66])[S:48](C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)(=[O:50])=[O:49]>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:46][N:47]([CH3:66])[S:48]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:25])[NH:24]4)[NH:13][C:10]3=[N:11][CH:12]=2)=[CH:6][CH:5]=1)(=[O:50])=[O:49]
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)N1
Reactant: CN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: O=C1CCCCC(CCc2nc3cc(Br)cnc3[nH]2)N1
Agent: [Na+]
Product: CN(C)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1

Procedure:
The title compound is analogously synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound B1) from 100 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1), 890 μl of aqueous sodium carbonate solution (strength 2.0 M), 138 mg N,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (compound C2), and 26 mg of trans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) at 160° C. for 30 min (microwave irradiation, power ≦300 W). Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) yields 93 mg of the title compound as a waxy solid. ESI-MS: 442.4 (MH+). TLC: Rf=0.41 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]1.C(N(CC)CC)C.[CH2:20]([O:27][C:28](ON1C(=O)CCC1=O)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[N:1]1([C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH2:5][CH2:4][CH:3]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[NH:2]1
Reactant: CC(C)(C)OC(=O)C1CCNN1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 110.9 %

Procedure:
At 0° C., to a 50 mL round bottomed flask charged with 1,1-dimethylethyl 3-pyrazolidinecarboxylate (0.054 g, 0.259 mmol) and stirrer in dichloromethane (DCM) (3 mL), was added triethylamine (0.079 mL, 0.569 mmol). After a couple of minutes, N-(benzyloxycarbonyloxy)succinimide (CBz-OSu) (0.064 g, 0.259 mmol) in dichloromethane (DCM) (1.5 mL) was added dropwise. The reaction mixture stirred at 0° C. for one hour, then warmed to r.t. After 2 hr at r.t., the solvent was evaporated and the residue was dissolved in EtOAc (30 mL), washed with water (15 mL×2), sat. NaHCO3 (15 ml), brine (15 mL), dried over Na2SO4 and concentrated to afford the crude product as a colorless gum (88 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH:23]=[CH:24][CH2:25][CH3:26])([CH3:7])[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[C:5]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][CH2:25][CH3:26])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCC=Cc1ccc(OCc2ccccc2)cc1OC(C)(C)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCc1ccc(O)cc1OC(C)(C)C(=O)OCC
Yield: 90 %

Procedure:
A solution of 2-(5-Benzyloxy-2-but-1-enylphenoxy)-2-methylpropionic acid ethyl ester (0.76 g, 2.06 mmol) in ethanol (50 mL) was treated with 5% Pd/C (0.10 g) and hydrogen (60 psi) at ambient temperature for 6 h. The mixture was filtered and concentrated in vacuo to give a colorless oil (0.52 g, 90%). 1H NMR (400 MHz, CDCl3) δ6.96 (d, J=7.8 Hz, 1H), 6.37 (dd, J=8.3, 2.4 Hz, 1H), 6.20 (s, 1H), 4.66 (br s, 1H), 4.24 (q, J=7.2 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 1.60 (s, 6H), 1.53 (quintet, J=7.6 Hz, 2H), 1.34 (sextet, J=7.3 Hz, 2H), 1.25 (t, 7.1 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), MS (ES) m/e 281 (M+1).
Reaction SMILES: C(OC1C=CC2SC([NH:12][C:13]([C:15]3[O:16][C:17]4[C:22]([C:23](=[O:25])[CH:24]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:14])=NC=2C=1)C.N[C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][N:44]([C:47](=[O:50])[CH2:48][CH3:49])[CH2:43][CH2:42]2)=[CH:37][CH:36]=1.[O:51]1CCN(C2C=CC(N)=CC=2)[CH2:53][CH2:52]1>>[C:47]([N:44]1[CH2:45][CH2:46][N:41]([C:38]2[CH:39]=[CH:40][C:35]([NH:12][C:13]([C:15]3[O:16][C:17]4[C:22]([C:23](=[O:25])[CH:24]=3)=[CH:21][C:20]([O:51][CH2:52][CH3:53])=[CH:19][C:18]=4[N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[O:14])=[CH:36][CH:37]=2)[CH2:42][CH2:43]1)(=[O:50])[CH2:48][CH3:49]
Reactant: CCC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCOc1ccc2sc(NC(=O)c3cc(=O)c4cccc(N5CCN(C)CC5)c4o3)nc2c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: CCOc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)CC)CC4)cc3)cc(=O)c2c1
Yield: 12 %

Procedure:
This compound was prepared from 250 mg (0.68 mmol, 1.0 equiv.) of 6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carbonyl chloride (Reference Example 23) and 175 mg (0.748 mmol, 1.1 equiv.) of 1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-1-one by an analogous procedure to that used to prepare the 4-morpholino aniline derivative, to give 45 mg (12%) of the desired product as a yellow solid.