Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([CH2:10][C:11]#[N:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>CN(C)C=O>[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](=[O:26])[CH:10]([C:8](=[O:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]#[N:12]
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: Cn1cccc1C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Temperature: 0 °C

Procedure:
To the solution of 4.0 g of phenylcarbamoyl-acetonitrile in 50 ml of dimethylformamide 28 g of potassium tert. butoxide are added while stirring under nitrogen. After 2 hours the resulting suspension is cooled to 5° and 4.0 g of 1-methylpyrrol-2-carboxylic acid chloride (U.S. Pat. No. 3,551,571) are added during 10 minutes. The mixture is stirred for 18 hours at room temperature, poured into 300 ml of ice water and the precipitate formed filtered off. It is washed with water, dried and recrystallized from ethanol, to yield the 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 172°-174°; it is identical with that obtained according to Example 1.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:7][CH:8]([CH3:12])[CH2:9][CH:10]=O>>[CH:1](=[O:6])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:10][CH2:9][CH:8]([CH3:12])[CH3:7]
Reactant: CC(C)CC=O
Reactant: CCCCC=O
Product: CC(C)CCCCC=CC=O

Procedure:
This example describes the process of the invention for the co-aldol condensation of n-pentanal and 3-methylbutanal (3-MBA) to give an isodecenal consisting of the isomers 2-propyl-5-methylhexenal and 2-isopropylheptenal (1+3) and also 2-propylheptenal (1+1) using the cosolvent diethylene glycol (DEG). 400kg/h of catalyst were passed through the reactor (as described in Example 3) at a temperature of 110° C. at the autogenous pressure of the reactants.
Reaction SMILES: [C:1]([CH2:4][CH:5]([O:26][CH3:27])[O:6][C@@H:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:8][C@H:9]([OH:20])[C@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:11]([OH:13])=O)(=[O:3])[NH2:2].C(N(CC)CC)C.CN(C(ON1N=N[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(#N)C>[CH2:14]([C@@H:10]1[C:11](=[O:13])[O:20][C@H:9]1[CH2:8][C@@H:7]([O:6][CH:5]([O:26][CH3:27])[CH2:4][C:1]([NH2:2])=[O:3])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:48][CH2:49][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC[C@H](C(=O)O)[C@@H](O)C[C@H](CCCCC)OC(CC(N)=O)OC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(CC(N)=O)OC
Yield: 42.2 %

Procedure:
A solution of 42.5 mg of (2S,3S,5S)-5-[(R/S)-2-carbamoyl-1-methoxyethoxy]-2-hexyl-3-hydroxydecanoic acid (Example Kd)) in 10 ml of methylene chloride/acetonitrile (1:1) was treated with 1 g of molecular sieve (4 Å), 0.1 ml of triethylamine and 50 mg of HBTU. After stirring the reaction mixture was filtered and concentrated and the residue was partitioned between hexane and methanol/water (1:1); the aqueous methanolic phase was extracted with hexane, the hexane phase was dried and concentrated; the residue was subsequently chromatographed on silica gel with 5 percent methanol in methylene chloride. There were obtained 21 mg of (R/S)-3-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-3-methoxypropionamide (epimers 3:1), m.p. 54°.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][N:4]=1)#[N:2].CCN(CC)CC.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1>[OH:8][CH2:7][C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cn1
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
To a solution of 6-cyanonicotinic acid (12 g, 0.081 mol; see step (i) above) in THF at 0° C., Et3N (12.4 mL, 0.0892 mol) was added followed by ethyl chloroformate (8.53 mL, 0.0892 mol). The reaction mixture was stirred for 15 min and NaBH4 (6.14 g, 0.162 mol) was added. Then the mixture was stirred at RT overnight, quenched with water and extracted with methylene chloride. The organic layer was concentrated and purified by column chromatography to yield 4 g (20%) of the alcohol.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1.CC[O-].[Na+].Br.Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccco2)cc(N)[nH]c1=S
Reactant: BrCCc1ccccn1
Agent: Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(-c2ccco2)cc(N)nc1SCCc1ccccn1
Yield: 75.5 %

Procedure:
To a stirred solution of 100 mg (0.46 mmol) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3-carbonitrile in 3.4 ml ethanol were added 0.60 ml (1.60 mmol) sodium ethylate solution (2.67M in ethanol) and 368 mg (1,38 mmol) 2-(2-bromoethyl)pyridine hydrobromide and the reaction mixture heated at reflux for 1 hour. The reaction mixture was then concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether to afford 112 mg (76%) 6-amino-4-furan-2-yl-2-(2-pyridin-2-yl-ethylsulfanyl)-nicotinonitrile as a white crystalline solid. ES-MS m/e (%): 323 (M+H+, 100).
Reaction SMILES: [Na+].[Cl-].[CH3:3][C:4]([CH3:28])=[CH:5][CH2:6][C:7]1[CH:8]=[C:9]([C:14]2O[C:23]3[CH:22]=[C:21]([OH:25])[CH:20]=[C:19](O)[C:18]=3[C:16](=O)[C:15]=2O)[CH:10]=[CH:11][C:12]=1[OH:13].C[OH:30]>>[OH:30][C:8]1[C:7]([CH2:6][CH:5]=[C:4]([CH3:28])[CH3:3])=[C:12]([OH:13])[CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=1
Reactant: CO
Reactant: CC(C)=CCc1cc(-c2oc3cc(O)cc(O)c3c(=O)c2O)ccc1O
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)=CCc1c(O)ccc(CCCc2ccc(O)cc2)c1O

Procedure:
Brown powder; mp 115-116° C.; UV (MeOH) λmax (log ε) 279 (3.28), 232 (3.55) nm; IR (NaCl) γmax 3421, 2909, 1652, 1515 cm−1; 1H and 13C NMR data, see Table 3; HMBC correlations: H-1/C-1′, C-21, C-61; H-2/C-1′, C-1″; H-3/C-1″, C-2″; H-5′/C-1′, C-3′, C-4′; H-6′/C-1, C-2′, C-4′; H-2″/C-3, C-1″, C-4″; H-3″/C-1″, C-4″; H-1′″/C-2′, C-41; H-4′″ and H-5′″/C-2′″, C-3′″; EIMS m/z 312 (M+, 67), 257 (12), 191 (100), 135 (74); HREIMS m/z 312.1725, calcd for C20H24O3, 312.1725.
Reaction SMILES: C(N1CCOCC1)C.O.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.[C:31]([C@H:34]([C@@H:46]([CH2:55][CH:56]1[CH2:60][CH2:59][CH2:58][CH2:57]1)[C:47]([N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:48])[CH2:35][N:36]1[C:40](=[O:41])[C:39]([CH3:43])([CH3:42])[N:38]([CH3:44])[C:37]1=[O:45])(O)=[O:32].Cl.[CH2:62]([O:69][NH2:70])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>C(Cl)Cl>[CH2:62]([O:69][NH:70][C:31]([C@H:34]([C@@H:46]([CH2:55][CH:56]1[CH2:57][CH2:58][CH2:59][CH2:60]1)[C:47]([N:49]1[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]1)=[O:48])[CH2:35][N:36]1[C:40](=[O:41])[C:39]([CH3:43])([CH3:42])[N:38]([CH3:44])[C:37]1=[O:45])=[O:32])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reactant: NOCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)N(C[C@H](C(=O)NOCc2ccccc2)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
0.74 g of N-ethylmorpholine, 0.60 g of hydroxybenzotriazole hydrate and 0.75 g of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide were added at 0° in succession to a solution of 1.38 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperidine VI in 13 ml of methylene chloride and the mixture was stirred at 0° for 20 min. The reaction mixture was treated with 0.45 g of N-ethylmorpholine and 0.63 g of O-benzylhydroxylamine hydrochloride and stirred at 0° for 30 min. and at 22° for 17 hrs. The solution was diluted with 13 ml of methylene chloride, washed with sodium bicarbonate solution and dilute hydrochloric acid, dried and concentrated. The residue was crystallized from ethyl acetate/hexane and the crystallizate was dried, there being obtained 1.26 g (73%) of pure 1-[2(R)-[1(R)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperidine VII, m.p. 138-140°.
Reaction SMILES: [Li+].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([CH:23]=2)C([O-])=O)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.O.C(OCC)(=O)C.O>CN(C)C=O>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([NH2:39])[CH:23]=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)c(C(=O)[O-])c2)CC1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-chloro-benzoic acid lithium salt (2.1 g) in N,N-dimethylformamide (50 ml) was added diphenyl phosphorylazide (1.4 ml) and reaction mixture stirred at ambient temperature for 1 hour. Water (30 ml) was added and the reaction mixture heated to 60° C. for 2 hours. After cooling to room temperature, the reaction was poured into ethyl acetate/water, the organic layer separated, washed with water, aqueous NaHCO3 and brine. The organic layer was dried (MgSO4) and concentrated. Purification of the residue by silica gel chromatography (eluting ethyl acetate/iso-hexane (1:3 to 1:1) gave the subtitle product (1.5 g).
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:48][CH3:49])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:36][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:38]=4[C:39]([NH:41][CH3:42])=[O:40])[C:19]4[C:24]([F:25])=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[OH-].[K+].C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:48][CH3:49])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[C:24]([F:25])[C:19]4=[C:18]([NH:36][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:38]=4[C:39]([NH:41][CH3:42])=[O:40])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)nc2c1c(F)cn2S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2ncc(F)c1-2
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A solution of 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (102 mg, 0.15 mmol) in dioxane (10 mL) and a 1N aqueous KOH solution (2 mL, 2.0 mmol) was heated at 80° C. for 6 h. The resulting mixture was allowed to cool to rt and diluted with EtOAc (50 mL) and a saturated NaHCO3 solution (50 mL). The organic layer was washed with a saturated NaCl solution (50 mL), concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-5-fluoro-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a brown solid (44 mg, 55%). 1H NMR (400 MHz, THF-d8) δ ppm 2.31 (s, 6H), 2.93 (d, J=4.58 Hz, 3H), 3.06 (t, J=8.24 Hz, 2H), 3.14 (s, 2H), 3.84 (s, 3H), 4.18 (t, J=8.33 Hz, 2H), 6.64 (s, 1H), 6.67-6.85 (m, 2H), 7.22-7.49 (m, 2H), 7.77 (br s, 1H), 8.75 (d, J=8.61 Hz, 1H), 9.35 (s, 1H), 10.50 (s, 1H), 10.76 (s, 1H); ESIMS (M+H)+=551.24.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>S1C=CC=C1.[Pd]>[C:14]1([CH2:13][CH:4]2[CH2:3][CH:2]([NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:7][CH2:6][N:5]2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)N1CCC(=O)CC1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CCOC(=O)N1CCC(NCc2ccccc2)CC1Cc1ccccc1

Procedure:
A mixture of (±)-ethyl 4-oxo-2-(phenylmethyl)-1-piperidinecarboxylate (10 g) and benzylamine (4 g) was hydrogenated at 50° C. in thiophene (4% solution; 1 ml) and methanol (150 ml) with palladium on activated carbon (10%; 3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the solvent was evaporated, yielding (±)-ethyl 2-(phenylmethyl)-4-[(phenylmethyl)amino]-1-piperidine-carboxylate (interm. 22).
Reaction SMILES: Br[C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[CH:9][N:4]2[N:3]=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C@@H:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([C:33]4[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][CH:32]=4)[N:28]=3)[CH:9]=2)=[CH:13][CH:14]=1)[C:25]#[C:26][CH3:27])[CH3:24]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(Br)nn3c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(O)cc4)nn3c2)cc1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To a stirred solution of ethyl (3S)-3-[4-[(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methoxy]phenyl]hex-4-ynoate (1.0 g, 2.2 mmol) and 4-hydroxy phenyl boronic acid (0.37 g, 2.7 mmol) in 1,4-dioxane (30 mL) is added K2CO3 (0.91 g, 6.6 mmol). The mixture purged with nitrogen for 10 minutes. Pd(PPh3)2Cl2 (0.14 g, 0.2 mmol) is added and the mixture is heated at 100° C. for 12 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth, and washed with EtOAc (2×10 mL). The filtrate is dried over anhydrous sodium sulphate, filtered, and concentrated to dryness. The crude material is purified by silica gel chromatography (combiflash using 24 g redisep column) eluting with 15-20% EtOAc/hexane to give the title compound (0.75 g, 73.52%). LCMS m/z 456.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:19][CH2:20][CH3:21])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[CH2:19]([N:8]([C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[CH:29][C:24]([CH:22]=[O:23])=[CH:25][CH:26]=2)[CH:7]=[CH:6][CH:5]=1)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH2:20][CH3:21]
Reactant: CCCCCCCNC(=O)N(CCC)c1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(CCC)c1cccc(-c2ccc(C=O)cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
135 mg (5 mol %) of tetrakis(triphenyl-phosphine)palladium are added to a solution of 830 mg (2.34 mmol, 1 eq) of 1-(3-bromophenyl)-1-propyl-3-heptylurea and 460 mg (3.0 mmol, 1.3 eq) of 4-formylphenylboronic acid in 10 mL of a mixture of dimethylformamide and of 2M potassium phosphate solution (8/2). The reaction mixture is stirred for 3 hours at 90° C. The reaction is stopped by addition of 50 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 735 mg of 1-propyl-1-(4′-formylbiphenyl-3-yl)-3-heptylurea are obtained in oil form. Yield=82%
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]([NH2:31])[CH3:30])[CH:25]=[CH:26][C:27]=1[CH3:28].C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([CH:29]([NH:31][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:30])[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: Cc1ccc(C(C)N)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1ccc(C(NC(C)c2ccc(C)c(C)c2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 95.5 %

Procedure:
Following a similar procedure to that described in Example (1a), 1.0 g of 4-methoxyphenyl 3-nitrophenyl ketone, 1.44 g of 1-(3,4-dimethylphenyl)ethylamine hydrochloride, 3.25 ml of triethylamine, 0.51 ml of titanium tetrachloride, 1.03 g of sodium cyanoborohydride and 0.33 ml of acetic acid were reacted, to obtain 1.45 g of the title compound as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[CH:37]=[CH:36][C:17]3[C:18]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26]([C:29](OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[N:19][O:20][C:16]=3[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:38]1(SC)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C.C(Br)C1C=CC=CC=1>C(Cl)Cl>[N:8]1([C:14]2[CH:37]=[CH:36][C:17]3[C:18]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:25][CH2:24]4)=[N:19][O:20][C:16]=3[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2noc3cc(N4CCOCC4)ccc23)CC1
Reactant: CSc1ccccc1
Agent: BrCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(CN2CCC(CCc3noc4cc(N5CCOCC5)ccc34)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Trifluoroacetic acid (TFA) (5 mL) was added to a cold (0° C.) solution of the piperidine formed in step b (0.40 g, 0.96 mmol) and thioanisole (1.13 mL, 9.60 mmol) in CH2Cl2 (10 mL). The resulting mixture was stirred at 0° C. for 30 min. Volatiles were removed under reduced pressure and 1N sodium hydroxide (NaOH) was added to the residue. The aqueous layer was extracted with EtOAc (2 times) and the combined organic layer was washed with water and brine and dried (MgSO4), filtered, and concentrated. The yellow oil obtained was redissolved in CH2Cl2 (10 mL), and triethylamine (0.267 mL, 1.92 mmol) and benzyl bromide (0.148 mL, 1.25 mmol) were added. The resulting mixture was stirred overnight at room temperature. The mixture was washed with water and brine and dried (MgSO4), filtered, and concentrated. Purification by silica gel flash chromatography (CH2Cl2 →10% MeOH/CH2Cl2) gave the title compound (0.285 g, 73%) as a white solid. A small sample was further purified by recrystallization (EtOH) to give a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.COC1C=C(C2C=CC=CC=2)N=C(N2C=CC(C(F)(F)F)=N2)N=1>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Agent: COc1cc(-c2ccccc2)nc(-n2ccc(C(F)(F)F)n2)n1
Product: COc1cc(-c2ccc(C)cc2)nc(-n2ccc(C(F)(F)F)n2)n1
Yield: 75 %

Procedure:
4-Methoxy-6-(4-methyl-phenyl)-2-(3-trifluoromethyl-pyrazol-1-yl)-pyrimidine 307c was synthesized from compound 305 (1 g, 3.59 mmol) and (4-methyl-phenyl)-boronic acid 306c (732 mg, 5.39 mmol), according to the procedure as described for compound 307b, as a white solid in 75% yield. MS (ESI, EI+): m/z=335 (MH+).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[N:22][O:23][CH:24]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)Cl.O>[O:23]1[CH:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][NH2:10])=[CH:15][CH:16]=2)[CH:21]=[N:22]1
Reactant: O=C(NCCOc1ccc(-c2cnoc2)cc1)OCc1ccccc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NCCOc1ccc(-c2cnoc2)cc1
Temperature: 35 °C
Yield: 35.2 %

Procedure:
[2-(4-Isoxazol-4-yl-phenoxy)-ethyl]-carbamic acid benzyl ester (1.00 g, 2.81 mmol) was dissolved in methylene chloride (14 ml) and methanesulfonic acid (2.73 ml, 42.2 mmol) was added. The resulting mixture was heated to about 35° C. for about two hours, and was then diluted with methylene chloride and water. The pH of the mixture was adjusted to about 12 with 5N sodium hydroxide, and the mixture was extracted with methylene chloride. The combined extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography (20% methanol/methylene chloride) to afford 202 mg (53% yield) of the desired amine. LRMS ([M+H]+)=205.3.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[O:34][C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>O1CCCC1>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[O:34][C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4o3)CC2)c2ccccc2-c2ccccc21

Procedure:
A solution of 0.3 g (0.7 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide, 0.2 g (0.98 mmol) of 2-(piperazin-1-yl)-benzoxazole and 1 ml of triethylamine in 10 ml of tetrahydrofuran is refluxed for 48 hours. The reaction mixture is then poured onto water, extracted twice with dichloromethane and the combined organic phases are dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=1:1).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]1.CS(C)=O>CCOC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)C1CCN(c2ccc(C=O)cc2[N+](=O)[O-])CC1
Temperature: 100 °C
Yield: 43.7 %

Procedure:
To a mixture of 4-chloro-3-nitrobenzaldehyde 57 (5.099 g, 27 mmol), cesium carbonate (9.48 g, 29 mmol), and methyl piperidine-4-carboxylate (4 mL, 27 mmol) was added DMSO (27 mL). The reaction mixture was heated to 100° C. for 30 min and diluted with EtOAc. The organic phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 30% to 50% EtOAc in hexanes) gave methyl 1-(4-formyl-2-nitrophenyl)piperidine-4-carboxylate 58 (3.45 g, 43% yield) as a yellow oil. Mass spectrum: calculated for C14H16N2O5 292.1. found 293.1 (M++1).