Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCc1oc(N2CCOCC2)nc1-c1ccc(Cl)cc1
Yield: 82.4 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), morpholine (435 mg) and 2-butanone (10 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was washed with a 10% aqueous solution of citric acid (100 ml) and dried over anhydrous magnesium sulfate. After the organic layer was concentrated, the residue was recrystallized from ethyl acetate-hexane to give 4-(4-chlorophenyl)-2-(4-morpholinyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole as pale yellow prisms (353 mg, 82%). Melting point 81-82° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]([NH2:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:30]1[CH:35]([NH2:36])[CH2:34][CH2:33][CH:32]([NH2:37])[CH2:31]1>O>[NH2:36][C@H:35]1[CH2:30][CH2:31][C@H:32]([NH:37][C:2]2[CH:3]=[C:4]([N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5]3[N:6]([C:8]([C:11]([NH2:13])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:33][CH2:34]1
Reactant: NC1CCC(N)CC1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(N)=O)cnc23)cc1
Solvent: O
Product: COc1ccc(CN(c2ccccc2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(N)=O)cnc23)cc1
Temperature: 160 °C

Procedure:
To a vial containing crude 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide 35 mgs from 1a was added trans-1,4-cyclohexyldiamine (250 mgs, mmol). The resulting mixture was heated to 160° C. for 4 h. The mixture was cooled to room temperature and diluted with water causing a precipitate to form. The precipitate was collected, washed with water and dried to give crude 6-((trans)-4-aminocyclohexylamino)-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:24]>ClCCl>[O:24]=[C:2]1[O:1][CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CCC(OC(=O)C=Cc2ccccc2)CC1
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)OC1CCOC(=O)CC1
Reaction time: 24 h
Yield: 70 %

Procedure:
Product from step 2 (10.0 g, 38.5 mmol) was dissolved in 50 mL of dichloromethane and added dropwise into a solution of 3-chloroperoxybenzoic acid (99.3 g, 42.4 mmol) in dichloromethane (50 mL). The mixture was stirred for 24 h and then filtered. The solution obtained was washed twice with NaHCO3 (2 M) and once with brine. The extracted product was then purified by column chromatography (by silica gel using hexane/EtOAc gradient as eluent). The monomer was obtained as a white crystalline powder. Yield: 70%.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)([O-:20])=[O:19]>C(#N)C>[CH2:10]([N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]1=[N:21][N+:18]([O-:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])Nc1ccccn1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])N=c1ccccn1Cc1ccccc1

Procedure:
20 ml (0.114 mole) of N,N-diisopropylethylamine and 12 ml (0.1 mole) of benzyl bromide are added to a suspension containing 14 g (0.1 mole) of 2-(nitroamino)pyridine [prepared according to J. Am. Chem. Soc. 77, 3154 (1955)] in 100 ml of acetonitrile, then the mixture is refluxed for 2.5 hours. The reaction mixture is cooled down then evaporated under reduced pressure, the residue is triturated with water, the suspension obtained is filtered and washed with a great volume of water. The filter cake is thoroughly sucked, then suspended in 50 ml of petroleum ether, filtered and washed again with petroleum ether to give 14.2 g (62%) of the named product, m.p.: 125°-126° C. (recrystallized from ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:13])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1ccc(Cl)cc1
Product: ClCCc1ccc(Cl)cc1
Temperature: 58 °C
Reaction time: 2.5 h

Procedure:
Into a 250-mL round-bottom flask equipped with magnetic stirring, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, was charged 2-(4-chlorophenyl)ethanol (25.026 g, 160 mmol) N,N-dimethylformamide (0.621 mL, 7.99 mmol) was added and the mixture was heated to 58° C. Thionyl Chloride (12.25 mL, 168 mmol) was charged over 1 h while the temperature was maintained at <65° C. Upon completion of the addition, the mixture was stirred at 60 to 64° C. for 2.5 h, and then allowed to gradually cool to room temperature and stirred overnight to give a clear, golden oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[N:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:15][C:13]1[N:14]=[C:9]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Nc1cccnc1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Br)nc(Nc2cccnc2)c1=O
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with pyridin-3-amine (940 mg, 10 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (5.4 g, 20 mmol), i-propanol (50 mL), and di-i-propylethylamine (10 mL). The mixture was heated at reflux for 5 h. After the completion of the reaction, it was cooled to room temperature. The solvent was removed under reduced pressure. The crude was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 186a (1.4 g, 50%) as a yellow solid. MS-ESI: [M+H]+ 281.6.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[S:32][C:33]([Cl:36])=[CH:34][CH:35]=3)=[CH:27][CH:26]=2)[CH2:20][C:19]1=[O:37])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:36][C:33]1[S:32][C:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:21]3[CH2:22][CH2:23][N:18]([CH2:17][C:9]4[NH:8][C:16]5[CH:15]=[CH:14][N:13]=[CH:12][C:11]=5[CH:10]=4)[C:19](=[O:37])[CH2:20]3)=[CH:30][CH:29]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3ccc(-c4ccc(Cl)s4)cc3)CC2=O)cc2cnccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(Cc2ccc(-c3ccc(Cl)s3)cc2)CCN1Cc1cc2cnccc2[nH]1
Yield: 47.1 %

Procedure:
2-{4-[4-(5-Chloro-thiophen-2-yl)-benzyl]-2-oxo-piperazin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.90 g, 0.17 mmol) is stirred in 30% TFA/CH2Cl2 (8 mL) for 1 h then concentrated to dryness and purified by RP-HPLC using 10-100% acetonitrile/0.1% TFA water as the eluent. The appropriate fractions are collected and lypholized to yield the title product as an amorphous white solid (0.44 mg, 0.08 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5](Cl)[C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[S:22])=[CH:19][CH:18]=1.O>CCO>[CH2:1]([O:3][C:4]([C:5]1[S:22][C:21]([C:20]2[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=2)=[N:23][C:6]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:15])[CH3:2]
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)C(Cl)C(=O)OCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)OCC
Temperature: 75 °C
Reaction time: 5.5 h
Yield: 85.1 %

Procedure:
Dissolve 2-chloro-3-oxo-pentanedioic acid diethyl ester (1370 g, 5.50 mol) in EtOH (8.5 L) and add 4-chloro-thiobenzamide (885 g, 5.00 mol). Heat the mixture to 75° C. and stir mechanically for 5.5 h. Cool the mixture to 45° C., then slowly add water (3.5 L) and stir overnight. Collect the yellow precipitate and wash the solids with 50% EtOH/water (4 L). Dry in an oven to obtain 1505 g (81%) of the title compound. 1H NMR (CDCl3, 500 MHz): δ 7.90 (d, 2H, J=7.4), 7.41 (d, 2H, J=7.4), 4.34 (q, 2H, J=6.8), 4.24 (s, 2H), 4.19 (q, 2H, J=7.4), 1.36 (t, 3H, J=6.8), 1.27 (t, 3H, J=6.8).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH:28](B(O)O)=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:29]([C:30]1[CH:35]=[CH:34][C:33]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([C:8]([C:10]3[CH:11]=[C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)=[O:9])[CH:5]=2)=[CH:32][CH:31]=1)=[CH2:28]
Reactant: OB(O)C=Cc1ccccc1
Reactant: O=C(c1cccc(Br)c1)c1cc(-c2ccccc2)cc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=Cc1ccc(-c2cccc(C(=O)c3cc(-c4ccccc4)cc(-c4ccccc4)c3)c2)cc1
Temperature: 25 °C

Procedure:
25 g of (3-bromophenyl)-[1,1′;3′,1″]terphenyl-5′-ylmethanone and 8 g of styreneboronic acid [2156-04-9] are dissolved in 300 ml of toluene, and 100 ml of a 2M sodium carbonate solution are added. The reaction mixture is carefully degassed, and 200 mg of tetrakistriphenylphosphinepalladium are added, and the mixture is heated under reflux for 20 hours. The solution is cooled to room temperature. The phases are separated. The aqueous phase is extracted three times with toluene, the combined organic phases are subsequently washed twice with water, dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo.
Reaction SMILES: Cl[CH:2]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4].[CH3:16][NH2:17]>C(O)(C)C>[CH3:16][NH:17][CH:2]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CN
Reactant: CC(C)C(Cl)c1cncnc1C(F)(F)F
Solvent: CC(C)O
Product: CNC(c1cncnc1C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
4.5 g (19 mmol) of 5-(1-chloro-2-methylpropyl)-4-trifluoromethylpyrimidine was dissolved in 50 ml of isopropyl alcohol, and 10 ml (161 mmol) of a 50% methylamine aqueous solution was added, followed by stirring at room temperature for 8 hours. The solvent was distilled off under reduced pressure, and 100 ml of water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 3.4 g (yield: 77%) of 5-(1-(N-methylamino)-2-methylpropyl]-4-trifluoromethylpyrimidine as slightly yellow liquid (refractive index nD20: 1.4529).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:58][C:59]1[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][C:9]([NH:58][C:59]1[CH:64]=[CH:63][N:62]=[CH:61][CH:60]=1)=[O:11]
Reactant: COC(=O)c1cc(Br)cc(OCC(=O)O)c1
Reactant: Nc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Br)cc(OCC(=O)Nc2ccncc2)c1
Yield: 49.3 %

Procedure:
A solution of 2-(5-bromo-3-methoxycarbonyl-phenoxy)-acetic acid (10.6 g), TBTU (19.3 g) and HOBt (5.1 g) in dry DMF (50 ml) was treated with DIPEA (9.9 ml). The resulting solution was stirred under a nitrogen atmosphere and was then treated with 4-aminopyridine (3.6 g) after 30 min. The resulting mixture was stirred for 18 h and then concentrated at reduced pressure to give a yellow viscous gum which was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase washed with further water, 1M sodium hydroxide solution, aqueous saturated ammonium chloride, water and dried with brine and over sodium sulphate. The organic phase was concentrated under reduced pressure giving the title compound as a yellow solid (6.60 g).
Reaction SMILES: O.[NH2:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9].[C:14]([CH2:16][C:17](O)=[O:18])#[N:15]>>[C:14]([CH2:16][C:17]([NH:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9])=[O:18])#[N:15]
Reactant: N#CCC(=O)O
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: O
Product: Cn1c(N)c(NC(=O)CC#N)c(=O)n(C)c1=O

Procedure:
5,6-Diamino-1,3-dimethyluracil hydrate is reacted with cyanoacetic acid to yield 5-cyanoacetamido-6-amino-1,3-dimethyluracil of the formula: ##STR4## The 5-cyanoacetamido-6-amino-1,3-dimethyluracil is treated with sodium hydroxide within a temperature range of 145°-155° C. to yield 8-carboxymethyltheophylline of the formula: ##STR5## The 8-carboxymethyltheophylline is treated with an alkylated inhibitor of the formula: ##STR6## to yield the compounds of formula (II).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:8]2)=[O:4].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=1)[C:9]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(COc3ccccc3)cc2c1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)cc(COc1ccccc1)n2Cc1ccc(SC(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
30 mg of 2-phenoxymethyl-1H-indole-5-carboxylic acid methyl ester were dissolved in 1 ml of THF and treated with 5 mg NaH (60%) at 0° C. for 15 min. 1.2 eq. of 1-bromomethyl-4-trifluoromethylsulfanyl-benzene were added and the reaction stirred for 1.5 h. The solvent was evaporated and the product extracted from methylenchloride/water. The product was purified by preparative HPLC. MS(ISP): 472.5 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1([O:21][C:22]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][O:24][C:22]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:21])[CH3:30]
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A suspension of 5.09 g (25.42 mmol) of 1,1-dimethylethyl 4-aminopiperidine-1-carboxylate and 13.45 g (59.99 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate (J. Med. Chem., 1999, 42, 277-90) in 300 ml of toluene is heated at reflux for 30 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH:11]=C.[F-].[Cs+].Cl.[C:16](OCC)(=O)C>C(N(CC)C1C=CC=CC=1)C>[CH3:1][O:2][C:3]1[C:4]2[O:9][C:10]([CH3:11])=[CH:16][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(C)=O
Reactant: C=CCOc1ccccc1OC
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(CC)c1ccccc1
Product: COc1cccc2cc(C)oc12
Temperature: 217.5 °C

Procedure:
To a well stirred solution of 1-methoxy-2-(2-propenyloxy)benzene (from step 1) (13.0 g, 80.24 mmol) in N,N-diethyl aniline (130 mL) was added cesium fluoride (15.85 g, 104 mmol) and the mixture was heated to 215-220° C. for 4-5 hours. Reaction mixture was cooled to room temperature and 10% aqueous HCl solution (1.0 lit) was added followed by addition of ethyl acetate (300 mL). The mixture was the filtered through Celite bed. The organic layer was separated and washed with water (2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave crude product (11.0 g) as dark brown oil. It was then purified through silica gel column using petroleum ether: ethyl acetate (9:1) as an eluent to afford the product as pale yellow oil (4.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: SCc1ccccc1Cl
Reactant: C#Cc1ccc(Br)cc1
Agent: [Na]
Product: Clc1ccccc1C(/C=C\c1ccc(Br)cc1)SC(/C=C\c1ccc(Br)cc1)c1ccccc1Cl

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-bromostyryl 2-chlorobenzylsulfide. The title compound was obtained in 84% yield following oxidation. 1HNMR (CDC13) δ4.57 (2H, s), 6.70 (1H, d, JH,H=11.58), 7.18-7.58 (8H aromatic+1H ethylenic).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[I-:10].[Na+]>CC(C)=O>[I:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: [I-]
Reactant: C=CCCCCCCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCCCCCCI
Yield: 91.4 %

Procedure:
8-Iodooct-1-ene was prepared by refluxing 5 g of 8-bromooct-1-ene (26 mmol) and 10 g of sodium iodide in 50 ml of acetone for 1 hour. The acetone was stripped and the residue was partitioned between water and ether. The aqueous phase was washed with brine, dried over magnesium sulfate and stripped to give 5.66 g of 8-iodooct-1-ene.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:20])[C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:52]([C:56]1[CH:57]=[C:58]([NH2:68])[N:59]([C:61]2[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=2)[N:60]=1)([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C>[C:52]([C:56]1[CH:57]=[C:58]([NH:68][C:17](=[O:19])[C:16]([C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)=[O:20])[N:59]([C:61]2[CH:62]=[CH:63][C:64]([CH3:67])=[CH:65][CH:66]=2)[N:60]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(O)C(=O)c1ccc(-n2cnc3cccnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)C(=O)c2ccc(-n3cnc4cccnc43)cc2)cc1
Reaction time: 4 h

Procedure:
A solution of (4-imidazo[4,5-b]pyridine-3-yl-phenyl)-oxo-acetic acid, HATU (104 mg, 0.27 mmol, 1.1 equiv) and triethylamine (0.102 mL, 0.73 mmol) in DMF (4 mL) is stirred for 5 minutes under N2. 5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-ylamine is then added and after 2 h, a further 1.2 equiv of HATU is added and after a further 2 h an additional 1.2 equiv of HATU is added. After 4 h, DMF is removed and the residue taken up in EtOAc and washed with 1N HCl, 1N NaOH and finally with brine. The organic layer is dried with MgSO4, filtered and concentrated. The residue is purified by MPLC on reverse phase with ACN/water to give N-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-2-(4-imidazo[4,5-b]pyridin-3-yl-phenyl)-2-oxo-acetamide as a yellow oil. Title compound: 479.05 [M+H]+; tR=1.9 min (System 2).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([NH2:16])=[O:15].CO[C:19]([C@H:21]1[C@H:25]([CH3:26])[CH2:24][N:23]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22]1)=O>>[CH2:27]([N:23]1[CH2:24][C@@H:25]([CH3:26])[C@H:21]([C:19]2[NH:16][C:14](=[O:15])[C:3]3[C:4]([CH3:13])=[N:5][N:6]([CH:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)[C:2]=3[N:1]=2)[CH2:22]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C
Reactant: Cc1nn(C2CCOCC2)c(N)c1C(N)=O
Product: Cc1nn(C2CCOCC2)c2nc([C@@H]3CN(Cc4ccccc4)C[C@H]3C)[nH]c(=O)c12

Procedure:
Following the procedure for the preparation of 6-[(3,4-trans)-1-benzyl-4-methylpyrrolidin-3-yl]-1-(2-methoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 5-amino-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide and (3S,4S)-methyl-1-benzyl-4-methylpyrrolidine-3-carboxylate provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.51-7.30 (m, 5H), 4.75-4.68 (m, 1H), 4.13-4.08 (m, 2H), 3.84-3.73 (m,1H), 3.63-3.48 (m, 2H), 3.40 (m,1 H), 3.10-2.78 (m, 2H), 2.55 (s, 3H), 2.50-2.24 (m, 3H), 1.87-1.80 (m, 2H), 0.61-1.41 (m, 3H), 1.19 (d, J=6.6 Hz, 3H). MS: (M+H m/z=408.1).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](Cl)=[O:34])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C(Cl)Cl>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[O:34])=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)NCCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of 2-(4-Phenyl-piperazin-1-yl)-ethylamine 4a (0.5 g, 2.44 mmol) and Et3N (0.34 g, 3.41 mmol) in 40 mL of dry CH2Cl2 under nitrogen at 0° C. was added a solution (4-Nitro-phenyl)-acetyl chloride (0.58 g, 2.92 mmol). The temperature was allowed to rise to room temperature, the mixture was stirred for 2 h, and then washed with water. The aqueous layer was extracted with dichloromethane. The combined organic phase was washed with saturated sodium chloride, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography over silica gel (EtOAc) to produce 26a: 0.8 g, (89% yield) as a white solid (mp: 138-139° C.). 1H NMR (CDCl3, 400 MHz): δ2.52 (2H, t, J=5.6, CH2—CH2NH), 2.57 (4H, t, J=5.2, (CH2)2N—), 3.11 (4H, t, J=5.2, (CH2)2—NPh), 3.36−3.34 (2H, m, CH2—NHCO), 3.65 (2H, s, CH2Ar), 6.19 (1H, bs, NHCO), 6.86-6.91(3H, m, ArH), 7.25-7.29 (2H, m, ArH), 7.47 (2H, d, J=8.8, ArH), 8.16-8.19 (2H, m, ArH).