Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[C:17]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:18][C:19]4[C:24]([C:25]=3[C:26]([OH:28])=O)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:66]1([CH:72]([NH2:74])[CH3:73])[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]1.C1([C@@H](N)C)CCCCC1>C(Cl)Cl.CC#N.C(Cl)Cl>[ClH:1].[ClH:1].[CH:66]1([C@@H:72]([NH:74][C:26]([C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16]=2[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH2:14][CH2:13]2)=[O:28])[CH3:73])[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]1
Reactant: CC(N)C1CCCCC1
Reactant: O=C(O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[C@H](N)C1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H](NC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2ccccc2)nc2ccccc12)C1CCCCC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
4.0 g (8.0 mmol) of crude 3-[1,4′]bipiperidinyl-1′-ylmethyl-2-phenyl-quinoline-4-carboxylic acid dihydrochloride (compound of Description 2) were dissolved in 300 ml of a 1:1 mixture of CH2Cl2/CH3CN; 3.4 ml (24.6 mmol) of triethylamine (TEA) and 4.0 g (10.7 mmol) of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU) were added and the reaction mixture was cooled at 0° C. 1.22 ml (8.2 mmol) of (S) 1-cyclohexylethylamine, dissolved in 10 ml of dry CH2Cl2, were added dropwise and the reaction mixture was stirred at room temperature for 24 h. Additional 2.0 g (5.3 mmol) of HBTU and 2.0 ml (13.4 mmol) of (S)-1-cyclohexyl-ethylamine were added and the reaction mixture was heated to 40° C. for 8 h. The solvent was evaporated in vacuo to dryness and the residue was taken up with EtOAc and washed with H2O, 1 N NaOH and brine, dried over Na2SO4 and evaporated to dryness to yield a crude material which was purified by flash column cromatography on 230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 95:5 containing 0.5% NH4OH (28%). The residue was dissolved in acetone and acidified with HCl/Et2O; the precipitate so formed was recovered by suction filtration to yield 3.2 g of title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]=[C:9]([C:11]1[NH:12][CH:13]=[C:14]([CH3:20])[CH2:15][C:16]=1[C:17]([OH:19])=[O:18])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C>O1CCCC1.[Pd]>[CH2:1]([N:8]=[C:9]([CH:11]1[CH:16]([C:17]([OH:19])=[O:18])[CH2:15][CH:14]([CH3:20])[CH2:13][NH:12]1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=CNC(C(O)=NCc2ccccc2)=C(C(=O)O)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1CNC(C(O)=NCc2ccccc2)C(C(=O)O)C1

Procedure:
17.5 g (70 mmol) of 5-methyl-1,4-dihydropyridine-2,3dicarboxylic acid N-benzylimide are hydrogenated in 150 ml of tetrahydrofuran at 70° C. and under 100 bar over palladium on active charcoal. Then the catalyst is filtered off and the filtrate is concentrated by evaporation. The solid oily residue (13.0 g) is used as a crude product in the next stage.
Reaction SMILES: C([N:8]1[CH:17]([CH2:18][CH2:19][OH:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH:17]([CH2:18][CH2:19][OH:20])[NH:8]1
Reactant: OCCC1Cc2ccccc2CN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: OCCC1Cc2ccccc2CN1

Procedure:
(+)-2-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-3-yl)-ethanol (610 mg, 2.3 mmol) was hydrogenated at 40 p.s.i.g. on a Parr Apparatus (305 mg of 10% palladium-on-carbon catalyst; methanol/concentrated hydrochloric acid solvent (15 ml and 0.25 ml, respectively) for 5 hours. The catalyst was filtered, and the filtrate was concentrated in vacuo to an oil, which was dissolved in dilute aqueous (pH 9) sodium carbonate/methylene chloride (50 ml of each). The aqueous phase was separated and extracted with two 10 ml portions of methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound as a viscous colorless oil (quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:43].C(Cl)CCl.C1[CH:49]=[CH:50][C:51]2N(O)N=[N:54][C:52]=2C=1.C1(CN)CC1>C(Cl)Cl>[CH:51]1([CH2:52][NH:54][C:22]([C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH2:12][NH:11][C:10](=[O:43])[N:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[C:14]=4[N:15]=[C:16]([N:29]4[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:42])[CH3:40])[CH2:33][CH2:34]4)[N:17]=3)[CH:20]=2)=[O:23])[CH2:49][CH2:50]1
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: On1nnc2ccccc21
Agent: NCC1CC1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{8-(2,6-Difluorophenyl)-2-[4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1-piperidinyl]-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl}-4-methylbenzoic acid (250 mg) in methylenechloride (100 mL) were added EDC (100 mg), HOBt (70 mg) and cyclopropylmethylamine (110 uL). The reaction was stirred at r.t. overnight and evaporated in vacuo. Flash chromatography then provided the title compound as a white solid. LC-MS m/z 648 (M+H)+, 2.33 min (ret. time).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:31])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NC3CCN(C)C3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(NC(=O)c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)C1
Yield: 53.2 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(1-methylpyrrolidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (150 mg, 0.36 mmol) in methanol (6 mL) and 1N sodium hydroxide aqueous solution (5.3 mL, 5.3 mmol) was heated to reflux for 4 h, LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residual was acidified with 1N hydrochloric acid solution to pH=6. The precipitated white solid was collected by filtration and washed with acetone, dichloromethane and ether sequentially to afford 78 mg of 3,3-dimethyl-2-(3-(1-methylpyrrolidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 53.8%, LC-MS (M+1)=408.2.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]2[N:25]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:27][C:23]=2[CH:22]=1)[CH3:19]>O1CCCC1>[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]2[N:25]=[C:26]([N:28]3[CH2:33][CH2:32][N:31]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:30][CH2:29]3)[S:27][C:23]=2[CH:22]=1)[CH3:19]
Reactant: CCOc1ccc2nc(N3CCNCC3)sc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Solvent: C1CCOC1
Product: CCOc1ccc2nc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)sc2c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 6-ethoxy-2-piperazin-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=1.[I-].[Na+].Br[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Br>CS(C)=O.[Cl-].[Na+].O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]([O:13][CH3:14])=[O:12])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=1
Reactant: BrCCOCCBr
Reactant: COC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1(c2ccc(Br)cc2[N+](=O)[O-])CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.32 g, 8.03 mmol, 60% dispersion in oil) was added in portions at rt to a stirred solution of methyl 2-(4-bromo-2-nitrophenyl)acetate (1 g, 3.65 mmol) in DMSO (15 mL). After the mixture was stirred at rt for 30 min, sodium iodide (0.055 g, 0.365 mmol) and bis(2-bromoethyl)ether (1.27 g, 5.47 mmol) were added. The resultant mixture was stirred at 40° C. After 19 h, the mixture was poured into brine with ice (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (3×80 mL), dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography (0 to 50% gradient of EtOAc in n-hexane) to give methyl 4-(4-bromo-2-nitrophenyl)tetrahydro-2H-pyran-4-carboxylate as an orange syrup. Mass Spectrum (ESI) m/e=344 [(M+1) (79Br)] and 346 [(M+1) (81Br)].
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:6][C:5]=2[CH:7]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2sc(Cl)nc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Clc1ccc2sc(N3CCNCC3)nc2c1
Temperature: 160 °C

Procedure:
A mixture of 0.49 mmol 2,5-dichlorobenzothiazole (CA=[2941-48-2]), 1.47 mmol of piperazine and 1.47 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 5 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:23](=O)[CH3:24])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[NH2:26]/[C:27](/[CH3:33])=[CH:28]\[C:29]([O:31][CH3:32])=[O:30]>C(O)C>[C:15]([C:14]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([CH3:33])[NH:26][C:23]=1[CH3:24])(=[O:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)c1ccccc1
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)c2ccccc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
250 mg (0.75 mmol) of 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-1-phenylbutane-1,3-dione are dissolved with 116 mg (1.0 mmol) of methyl 3-aminocrotonate in 5 ml of ethanol and heated under reflux under argon for 24 h. The reaction solution is purified by preparative HPLC. Concentration of the product fractions and crystallization from ethyl acetate result in 158 mg (49% of theory) of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:21]([NH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>S1(CCCC1)(=O)=O.[Cu]>[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH:27]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:3]=2)[CH2:26]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1ccncc1
Reactant: Clc1cccc(Oc2ccccc2)n1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CC(=O)NC1CCNC(c2cccc(Oc3ccccc3)n2)C1
Temperature: 150 °C
Reaction time: 40 h
Yield: 30 %

Procedure:
A mixture of 0.116 moles of 2-chloro-6-phenoxypyridine, 21.5 g of anhydrous potassium carbonate, 0.151 moles of 4-acetamidopyridine and 0.118 mole of copper in powder form in 100 ml of sulfolane is heated to 150° C. with stirring for 40 hours. The sulfolane is distilled, the residue is taken up with water, the suspension is treated with water and it is extracted with methylene chloride. The organic phase is washed with water, dried and concentrated to dryness. By crystallisation of the residue in diisopropylic ether, 4-acetamido-2-(6-phenoxy-2-pyridyl)piperidine is obtained; m.p. 104° to 106° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH2:39][C:40]2[NH:49][C:43]3=[N:44][CH:45]=[C:46](I)[CH:47]=[C:42]3[N:41]=2)[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:30][O:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH2:39][C:40]2[NH:49][C:43]3=[N:44][CH:45]=[C:46]([C:2]4[CH:3]=[CH:4][C:5]([S:8]([N:11]5[CH2:16][CH2:15][N:14]([C:17]6[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=6)[CH2:13][CH2:12]5)(=[O:9])=[O:10])=[CH:6][CH:7]=4)[CH:47]=[C:42]3[N:41]=2)[CH:33]=1
Reactant: N#Cc1ccc(N2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCN(c6ccc(C#N)cc6)CC5)cc4)cnc3[nH]2)c1
Temperature: 85 °C
Yield: 84.9 %

Procedure:
A mixture of 0.406 g of 1-(4-bromo-benzene-sulfonyl)-4-(4-cyanophenyl)-piperazine, 0.28 g of bis-(pinacolato)-diboron, 0.017 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.022 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.294 g of potassium acetate in 6 ml of degassed dioxane are heated to 85° C. in a sealed tube under N2 for 18 hours. To the resulting mixture 4 ml of degassed dioxane, 0.228 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.069 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.165 g of potassium carbonate and 0.051 g of lithium chloride in 4 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 110° under N2 for 5 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with ethylacetate. The combined organic phases are dried over sodium sulfate, concentrated and the residue is crystallized from ethylacetate. Recrystallization from ethylacetate and then from acetonitril gives 0.295 g of the title compound as a brownish solid of m.p. 217-219° C. The mass spectrum shows the molecular peak MH+ at 580.5 Da.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C([O:8][CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17])(=O)C.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[CH3:17][C:11]1[C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][OH:8]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OCc1c(C)cccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Reaction time: 2.5 h

Procedure:
Fuming nitric acid (0.52 ml) was added dropwise to a solution of 2,6-dimethylbenzyl acetate (1.78 g) in acetic anhydride (8.9 ml) at 0° C. and then stirred for 2.5 hours. After being stirred for an additional 30 minutes at room temperature, the mixture was poured onto crushed ice, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and evaporated in vacuo. To the residue were added methanol (24 ml) and 1N sodium hydroxide solution (12 ml) and the mixture was stirred at room temperature for 1 hour and evaporated in vacuo. The residue was washed with water, air-dried, and recrystallized from a mixture of benzene and n-hexane to give 2,6-dimethyl-3-nitrobenzyl alcohol (1.26 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:33])=[C:8]2[C:16](=[C:17]([C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]1[O:13][CH2:14][O:15][C:11]=1[CH:10]=[CH:9]2)=[O:5])[CH3:2].[CH3:34][Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][CH3:34])=[C:8]2[C:16](=[C:17]([C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:12]1[O:13][CH2:14][O:15][C:11]=1[CH:10]=[CH:9]2)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2c3c(ccc2c1O)OCO3
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2c3c(ccc2c1OC)OCO3
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
Compound 33 (95 mg, 0.21 mmol) was dissolved in a mixture of MeOH (3 mL) and THF (6 mL). (Trimethylsilyl)diazomethane (2 M in hexanes, 0.6 mL, 1.2 mmol) was added to the solution. The mixture was stirred for 12 h at room temperature, and then concentrated in vacuo. The crude material was purified by column chromatography on silica gel using CH2Cl2 to afford 35 (97 mg, 99%) as a yellow oil. 1H NMR (CDCl3) δ 7.86 (d, 1H, H5, J=8.7 Hz), 7.26 (d, 1H, H6, J=8.7 Hz), 6.75-6.82 (m, 3H, H2′+H5′+H6′), 6.00 (AB, 2H, 3′,4′-OCH2O—, Δδ=11.7 Hz, J=1.2 Hz), 5.87 (AB, 2H, 7,8-OCH2O—, Δδ=9.0 Hz, J=1.2 Hz), 4.39 (q, 2H, OCH2CH3, J=7.2 Hz), 4.06 (s, 3H, 4-OCH3), 4.03 (q, 2H, OCH2CH3, J=7.2 Hz), 1.38, 1.04 (each t, 2×3H, 2×OCH2CH3, J=7.2 Hz); MS (EI) m/z 466 [M]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[C:8]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:7][N:6]=1.Cl[C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34](C1C=CC([N+]([O-])=O)=CC=1Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C>CC(N(C)C)=O.C(OCC)(=O)C>[NH:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[N:10][C:5]([NH:4][CH2:3][CH2:2][NH:1][S:34]([C:26]2[CH:25]=[CH:30][C:29]([N+:31]([O-:33])=[O:32])=[CH:28][CH:27]=2)(=[O:35])=[O:36])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(-c2nc(NCCN)ncc2-c2ncc[nH]2)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2nc(NCCNS(=O)(=O)c3ccc([N+](=O)[O-])cc3)ncc2-c2ncc[nH]2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
A mixture of 4-{2-[(2-aminoethyl)amino]-5-imidazolylpyrimidin-4-yl}benzenecarbonitrile (30 mg, 0.098 mmol), chloro(4-nitrophenyl)sulfone (22 mg, 0.1 mmol), and Hünig's base (70 uL, 0.4 mmol) in DMA (500 uL) were heated to 80° C. After stirring for 12 hours, the reaction was diluted with ethyl acetate (10 ml) and extracted with sat. aq. NaHCO3 (2×5 ml), water (3×5 ml), brine (5 ml), dried with Na2SO4, filtered, and concentrated. The resulting product, 4-{5-imidazolyl-2-[(2-{[(4-nitrophenyl)sulfonyl]amino}ethyl)amino]pyrimidin-4-yl}benzenecarbonitrile weighing 27 mg (56% yield) was approximately 90% pure by LCMS and HPLC.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=1.CO>[Pd].CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)CCc1cccnc1
Yield: 100.6 %

Procedure:
A mixture of 5.0 g of 3-(3-pyridyl)acrylic acid, 0.4 g of 10% palladium on activated carbon, 150 ml of methanol, and 50 ml of dimethylformamide is hydrogenated at room temperature and atmospheric pressure. After removal of the catalyst by filtration, the filtrate is concentrated to give 5.1 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:10]([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: O=c1cc(Br)cc[nH]1
Product: CC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O

Procedure:
6.0 g (34.5 mmol) of 4-bromopyridin-2(1H)-one and 7.9 g (37.9 mmol) of tert-butyl 2-bromopropanoate (racemate) were reacted according to General Method 4B. After removal of the DMF, the desired product was precipitated with water and then purified further by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 7.4 g (69% of theory)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]>CC(C)=O.BrCCCCC(OC)=O>[CH3:28][O:27][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.8 %

Procedure:
A mixture in acetone of 4-phenylphenol (0.85 g, 5.0 mmol) and potassium carbonate (0.76 g, 5.5 mmol) was stirred for 30 minutes. Neat methyl 5-bromovalerate (0.78 mL, 5.5 mmol) was added dropwise via syringe and the reaction mixture was stirred for 2 hours at ambient temperature and overnight at reflux. Catalytic KI was then added and the reaction mixture was heated overnight at reflux. An additional 10 drops of methyl 5-bromovalerate was then added and reflux was continued for 8 hours. The reaction mixture was cooled to ambient temperature and filtered. The collected solid was washed with acetone and the combined filtrate and washings were concentrated in vacuo. The residue was partitioned between ethyl ether and water. The aqueous phase was extracted with ethyl ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give 5-(4-phenylphenoxy)pentanoic acid methyl ester (1.66 g) as a white powder.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[N:15]=[C:16]=[S:17])([CH2:3][CH3:4])[CH3:2].[CH:18]([NH2:21])([CH3:20])[CH3:19].Cl>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[C:6]=1[NH:15][C:16]([NH:21][CH:18]([CH3:20])[CH3:19])=[S:17])([CH2:13][CH3:14])[CH3:12]
Reactant: CC(C)N
Reactant: CCC(C)c1cccc(C(C)CC)c1N=C=S
Agent: Cl
Product: CCC(C)c1cccc(C(C)CC)c1NC(=S)NC(C)C
Reaction time: 3 h

Procedure:
15.0 g of 2,6-di-sec.-butyl-phenyl isothiocyanate are introduced, whilst cooling, into 20 g of a 65% strength aqueous solution of isopropylamine. After stirring for 3 hours at 20°, the batch is stirred into dilute hydrochloric acid, the reaction product which has precipitated in a crystalline form is filtered off and washed until neutral, and the paste is triturated with 50% strength methanol, again filtered off and dried.