Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH:24]=[O:25])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[BH4-].[Na+].CO>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH2:24][OH:25])[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(C=O)c2)Cc2ccccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(CO)c2)Cc2ccccc2C1
Reaction time: 1 h

Procedure:
The compound of step 1 (0.500 g, 1.42 mmol) was dissolved in THF (5 ml) and cooled in an ice bath. Sodium borohydride (0.164 g, 4.25 mmol) was added. Subsequently methanol (2 ml) was added dropwise. After 1 h, the volatiles were evaporated, the residue was partitioned between diethyl ether and a saturated sodium hydrogencarbonate solution, and the aqueous phase extracted with diethyl ether. The combined organic phases were dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:28]5[CH:49]=[CH:48][C:31]([C:32]([NH:34][CH:35]6[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]6)=[O:33])=[CH:30][CH:29]=5)[N:26]=4)[N:21]=[N:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[NH:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([C:25]3[N:26]=[C:27]4[N:19]([CH2:18][C:14]5[CH:13]=[C:12]6[C:17](=[CH:16][CH:15]=5)[N:8]=[CH:9][CH:10]=[CH:11]6)[N:20]=[N:21][C:22]4=[N:23][CH:24]=3)=[CH:49][CH:48]=2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(-c3cnc4nnn(Cc5ccc6ncccc6c5)c4n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCNCC1)c1ccc(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 96 h
Yield: 11.6 %

Procedure:
Trifluoroacetic acid (0.33 mL, 4.2 mmol) was added to a solution of tert-butyl 4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)benzamido)piperidine-1-carboxylate (72 mg, 0.13 mmol) in DCM (1.0 mL). After 96 hours, the reaction was concentrated by rotory evaporation. The residue was purified by prep-HPLC to give N-(piperidin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)benzamide (7 mg, yield 25%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Li]CCCC.[F:10][CH:11]([F:31])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[C:20]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=[O:26])=[O:21])=[CH:15][CH:14]=1>C1COCC1.COCCOC>[F:10][CH:11]([F:31])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[C:20]([C:22]2[CH:29]=[CH:28][CH:27]=[C:24]([CH:25]([OH:26])[C:3]#[C:2][CH2:1][OH:4])[CH:23]=2)=[O:21])=[CH:15][CH:14]=1
Reactant: C#CCO
Reactant: O=Cc1cccc(C(=O)C(=O)c2ccc(OC(F)F)cc2)c1
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C(C(=O)c1cccc(C(O)C#CCO)c1)c1ccc(OC(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A stirred solution of propargyl alcohol (0.1 g, 1.78 mmol) in dry THF at −78° C. under nitrogen was treated dropwise with 1.9 M n-BuLi (1.88 mL, 3.57 mmol) over 10 min, stirred for 0.5 h and warmed to 0° C. A 3 mL portion of this solution was added to a stirred solution of 3-[2-(4-difluoromethoxyphenyl)-2-oxo-acetyl]benzaldehyde (0.15 g, 0.49 mmol) in dry DME at 0° C. under nitrogen. After 10 min, the reaction mixture was quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by flash chromatography (30% to 70% ethyl acetate/petroleum ether) gave 1-[4-(difluoromethoxy)phenyl]-2-[3-(1,4-dihydroxybut-2-ynyl)phenyl]ethane-1,2-dione as a clear oil, 52 mg (29% yield). Using essentially the same procedure described in Example 1, step c, and employing 1-[4-(difluoromethoxy)phenyl]-2-[3-(1,4-dihydroxybut-2-ynyl)phenyl]ethane-1,2-dione (0.052 g, 0.14 mmol), the title compound was obtained as a slight brown foam, 0.031 g (52% yield), identified by NMR and mass spectral analyses. MS (ES+): 416 (M+H).
Reaction SMILES: CO[C:3](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.Cl.[C:20]([NH:24][NH2:25])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>CCO>[N+:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[C:14]([C:15]#[N:16])=[C:17]([NH2:18])[N:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:25]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)NN
Reactant: COC(Cc1cccc([N+](=O)[O-])c1)=C(C#N)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)n1nc(Cc2cccc([N+](=O)[O-])c2)c(C#N)c1N

Procedure:
Reagent 2-(1-methoxy-2-(3-nitrophenyl)ethylidene)malononitrile (1.2 g; 4.7 mmol) was combined with tert-butylhydrazine-HCl (0.57 g; 5.2 mmol; Sigma-Aldrich), 1.4 mL triethylamine in 50 mL EtOH for at 2 hours at 80° C. The reaction was concentrated in vacuo, resuspended in brine and extracted with chloroform. The organic layer was dried over MgSO4. Following, the organic suspension was filtered, concentrated in vacuo, and purified on silica gel in 1% MeOH:CHCl3 to yield 3-(3-nitrobenzyl)-1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile (ESI-MS m/z [M−CH3]+ found 285.5, calculated 285.14; 1H NMR (400 MHz, DMSO): δ8.11 (s, 1H), 8.08-8.12 (m, 1H), 7.69 (d, J=8 Hz, 1H), 7.59-7.64 (m, 1H), 3.96 (s, 2H), 3.34 (br, 2H), 1.52 (s, 9H)). This product was combined with formamide as per Cmpd 1 to yield 3-(3-nitrobenzyl)-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 327.4, calculated 327.15; 1H NMR (400 MHz, DMSO): δ 8.22 (s, 1H), 8.14 (s, 1H), 8.07 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.59 (d, J=8 Hz, 1H), 7.22 (br, 2H), 4.52 (s, 2H), 1.70 (s, 9H)). Reduction of this material was completed as per Cmpd 1 to yield 3-(3-aminobenzyl)-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 297.13, calculated 297.17). The reduced precursor was coupled to 3-(trifluoromethyl)phenyl isocyanate and purified as described for Cmpd 1 to yield Cmpd 4 1-(3-((1-tert-butyl-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 484.5, calculated 484.2; 1H NMR (400 MHz, DMSO): δ 9.25 (s, 1H), 8.96 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.46-7.55 (m, 2H), 7.40 (s, 1H), 7.29 (d, J=8 Hz, 2H), 7.20 (t, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 4.39 (s, 2H), 1.73 (s, 9H). 13C NMR (400 MHz, DMSO): δ 29.25, 33.40, 60.74, 99.58, 116.43 (d), 116.95, 118.86, 122.13, 122.64, 124.69 (q), 129.29, 129.98 (q), 130.32, 139.60, 140.06, 141.16, 143.31, 149.70, 152.69, 152.92, 154.81, 159.12 (q)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccc(Br)cc12
Product: Clc1ccnc2ccc(Br)cc12
Temperature: 25 °C
Yield: 98.5 %

Procedure:
The solid 6-bromo-quinolin-4-ol (52 g, 232.1 mmol) was added to phosphorus oxychloride (213.5 mL) and then the mixture was heated to reflux for 6 h to afford a light brown solution. After cooling to room temperature, the excess phosphorus oxychloride was removed under the vacuum. The remaining residue was poured into an ice-containing beaker (2 L). Then, it was slowly neutralized with solid potassium carbonate and the resulting solids were collected by filtration and washed with water. After drying in air, 55.46 g (98.5% yield) of 6-bromo-4-chloro-quinoline was isolated as a light yellow solid: EI-HRMS m/e calcd for C9H5BrClN (M+) 240.9294, found 240.9297.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]3[C:27]([CH3:32])=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:33])[CH:11]=2)[CH:6]=1.[OH-].[Na+]>C(O)C>[Cl:33][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]([CH3:15])=[C:13]2[C:16]1[CH:17]=[CH:18][C:19]([NH:22][S:23]([C:26]2[C:27]([CH3:32])=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])=[CH:20][CH:21]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3C)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1S(=O)(=O)Nc1ccc(-c2c(C)c(CC(=O)O)cc3ccc(Cl)cc23)cc1
Reaction time: 8 h

Procedure:
To a solution of {6-chloro-3-methyl-4-[4-(toluene-2-sulfonylamino)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (85 mg, 0.17 mmol) in ethanol (7 mL) was added a solution of sodium hydroxide solution (516 uL, 1.0 N) at room temperature. The resulting clear solution was stirred overnight. Then, the solvents were removed under vacuum and the residue was diluted with water (10 mL), acidified with 1.0 N hydrochloric acid, and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum provided the desired {6-chloro-3-methyl-4-[4-(toluene-2-sulfonylamino)-phenyl]-naphthalen-2-yl}-acetic acid as a light brown foam. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.44 (br. s, 1 H), 10.54 (br. s, 1 H), 7.88-7.95 (m, 2 H), 7.82 (s, 1 H), 7.48-7.58 (m, 1 H), 7.35-7.46 (m, 3 H), 7.22 (d, J=8.5 Hz, 2 H), 7.08 (d, J=8.5 Hz, 2 H), 6.92 (d, J=1.5 Hz, 1 H), 3.80 (s, 2 H), 2.63 (s, 3 H), 1.99 (s, 3 H). HRMS calcd. for C26H21ClNO4S [(M−H)−] 478.0885, obsd. 478.0885.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: Cc1ccc(N)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing p-toluidine as the aniline component. (18%, MS=484.2 (M+H))
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([C:38]1[C:39]([N:48]2[CH2:53][CH2:52][CH:51]([N:54]3[CH2:59][CH2:58][N:57]([S:60]([CH3:63])(=[O:62])=[O:61])[CH2:56][CH2:55]3)[CH2:50][CH2:49]2)=[CH:40][C:41]([O:45][CH2:46][CH3:47])=[C:42]([NH2:44])[CH:43]=1)[CH3:37].Cl>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:42]3[CH:43]=[C:38]([CH2:36][CH3:37])[C:39]([N:48]4[CH2:49][CH2:50][CH:51]([N:54]5[CH2:55][CH2:56][N:57]([S:60]([CH3:63])(=[O:62])=[O:61])[CH2:58][CH2:59]5)[CH2:52][CH2:53]4)=[CH:40][C:41]=3[O:45][CH2:46][CH3:47])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 170 °C
Yield: 67.7 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.1 g, 0.203 mmol), (5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amine (0.083 g, 0.203 mmol) and HCl (4N,1,4-Dioxane, 0.102 mL, 0.407 mmol) in Trifluoroethanol (8 mL) was heated at 170° C. for 40 min in the microwave. LCMS analysis indicated that the starting materials had been consumed. The reaction was quenched with 7N NH3 in MeOH and then concentrated to dryness. The residue was then dissolved in DCM and concentrated onto silica gel. Purification by flash column chromatography followed by recrystallization from DCM and EtOH afforded the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzamide (0.119 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.79 (s, 1H), 9.27-9.38 (m, 1H), 8.40 (s, 1H), 8.28 (d, J=5.22 Hz, 1H), 8.13 (d, J=1.92 Hz, 1H), 7.80 (dd, J=8.39, 1.88 Hz, 1H), 7.72 (d, J=8.98 Hz, 1H), 7.58 (s, 1H), 7.35-7.51 (m, 2H), 7.29 (d, J=8.71 Hz, 1H), 7.14-7.25 (m, 2H), 6.88-6.98 (m, 1H), 6.81 (s, 1H), 6.60 (d, J=5.13 Hz, 1H), 4.06 (q, J=6.97 Hz, 2H), 4.00 (s, 3H), 3.07-3.15 (m, 4H), 2.98-3.06 (m, 2H), 2.87 (s, 3H), 2.60-2.74 (m, 6H), 2.52-2.59 (m, 2H), 2.36-2.46 (m, 1H), 1.80-1.87 (m, 2H), 1.50-1.67 (m, 2H), 1.26 (t, J=6.97 Hz, 3H), 1.09 (t, J=7.51 Hz, 3H). MS (M+H, ES+) 866.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])(=O)=O.[C-:31]#[N:32].[K+]>CS(C)=O>[C:31]([CH2:6][CH2:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:12]=[N:11][C:10]=1[C:25]([NH:27][CH:28]1[CH2:30][CH2:29]1)=[O:26])#[N:32]
Reactant: [C-]#N
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCC#N)cc1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
A solution of (4-[(cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)propyl methanesulfonate (1.31 g, 3 mmol) obtained in Example 1201a) and potassium cyanide (235 mg, 3.6 mmol, 1.2 eq.) in DMSO (10 ml) was stirred for 15 hr, ice water (20 ml) was added, and the precipitated crystals were collected by filtration and dried to give the title compound as a colorless powder (925 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([OH:33])=O)[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>>[CH:34]1([NH:37][C:31]([CH2:30][N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:20][CH:19]=3)[CH2:25]2)=[O:33])[CH2:36][CH2:35]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Reactant: NC1CC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)NC3CC3)C2)cn1
Yield: 63 %

Procedure:
As described for example 42, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid (70 mg, 0.16 mmol) was converted, using cyclopropylamine instead of methylamine, to the title compound (52 mg, 63%) which was obtained as a white solid. MS: m/e=490.5 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:14]1[CH2:20][C:18](=[O:19])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1=[S:16].[Cl-].[NH4+].N>C(O)C>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[C:20]3[S:14][C:15](=[S:16])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18]3=[O:19])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1csc(N2CCCCC2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(N3CCCCC3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated. but using 1.8 g of 2-piperidinothiazole-4-carbaldehyde, 1.4 g of rhodanine-3-acetic acid, 1.0 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 40 ml of ethanol, giving the title compound as yellow needles.
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17](Br)[CH3:18])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([CH2:26][NH2:27])[OH:25]>C(O)C>[OH:25][CH2:24][CH2:26][NH:27][CH2:18][CH2:17][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:21]=[CH:22][CH:23]=[C:8]([CH:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:7])[CH:9]=1)=[O:20]
Reactant: NCCO
Reactant: CC(Br)C(=O)NCCCOc1cccc(C(C)N2CCCC2)c1
Solvent: CCO
Product: CC(c1cccc(OCCCNC(=O)CCNCCO)c1)N1CCCC1

Procedure:
500 mg of the amide compound obtained in step (A) was heated under reflux for 2 hours in 1 ml of ethanolamine and 1 ml of ethanol. The solvent was distilled off under reduced pressure, and potassium carbonate was added. The mixture was extracted with chloroform. The solvent was distilled off, and the residue was purified by TLC (developing solvent: chloroform/diethylamine=10:1) to afford 355 mg of N-[3-(2-hydroxyethylamino)propionyl]-3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propylamine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([CH:30]=[O:31])[CH:28]=4)[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C(OCC)C>[F:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([CH:30]([OH:31])[C:2]5[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=5)[CH:28]=4)[CH2:23][CH2:22]3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Solvent: CCOCC
Product: OC(c1cccnc1)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 68.8 %

Procedure:
3-Bromopyridine (0.44 ml), 1-[1-(4-fluorophenethyl)-piperidin-4-yl]-6-formylindoline (0.4 g) and diethyl ether employed as the solvent were treated as in Example 93 to give the title compound (0.337 g) as a yellow oil (yield: 68.8%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1OC2C=CC=CC=2N=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].[Br-]>CCOC(C)=O>[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=2[N:1]=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ccccc2o1
Reactant: Cc1ccc(O)c(N)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc2oc(C(O)[C@H](C)NC(=O)OCc3ccccc3)nc2c1
Yield: 53 %

Procedure:
This material was prepared as a 1:1 mixture of isomers in 53% yield from the above cyanohydrin (1.10 g, 4.70 mmol) and 2-amino-p-cresol (636 mg, 5.17 mmol) using the procedure described above for compound 16. An analytical sample was obtained by recrystallization from EtOAc in hexanes (7 : 1 mixture of isomers). mp: 134-135° C.; IR (KBr) υ 1718, 1691 cm−1; 1H-NMR (400 MHz, CDC13) δ 7.47-7.09 (m, 8H), 5.47 (d, J=8.6 Hz, 1H), 5.12-4.87 (m, 4H), 4.54-4.30 (m, 1H), 2.44 (s, 3H), 1.32 and 1.13 (2×d, J=6.7 and 6.7 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3) δ 165.90, 165.19, 156.09, 149.04, 140.24, 136.28, 134.38, 128.34, 128.09, 127.91, 126.32, 119.87, 119.69, 110.23, 70.84, 70.57, 66.92, 66.67, 50.48, 50.29, 21.34, 17.24, 15.32; FAB MS m/z: 341 (MH+); HRMS calcd for C19H21N2O4 (MH+) 341.1501, found: 341.1490; Anal (C19H20N2O4) C, H, N.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:21]3[CH:22]=[CH:23][S:19][CH:20]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2noc(-c3cncc(-c4ccsc4)c3)n2)nc1
Yield: 7.5 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (42 mg, 0.1385 mmol), 3-thiopheneboronic acid (26.6 mg, 0.208 mmol), and Pd(PPh3)4 (24.0 mg, 0.021 mmole) in a solution of 2M sodium carbonate (1.5 mL) and ethylene glycol dimethyl ether (1.5 mL) was heated overnight at 105° C. Standard work up afforded 3.2 mg (8%) of 3-(2-pyridyl)-5-[5-(3-thienyl)-pyrid-3-yl]-1,2,4-oxadiazole.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]3([CH3:24])[CH3:23])[CH3:10])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.O.[Fe]>[CH3:21][C:17]1([CH3:22])[CH2:16][CH2:15][C:14]([CH3:23])([CH3:24])[C:13]2[CH:12]=[C:11]([C:9]([CH3:10])=[CH:8][C:7]3[CH:25]=[CH:26][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH:20]=[CH:19][C:18]1=2
Reactant: CC(=Cc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(=Cc1ccc(N)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
6 g of 6-[p-nitro-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene are dissolved in 200 ml of acetic acid and after heating to 90°, treated within 2 minutes with 4.5 g of activated iron powder. Thereafter, 60 ml of water are added thereto and, after a further 30 minutes, the mixture is again treated with 60 ml of water. After stirring at 90° for 1 hour the reaction mixture is cooled, diluted with water and extracted with ether. The organic phase is washed with water, dilute soda solution and again with water. After drying with sodium sulphate the organic phase is evaporated and there is obtained a brown oil which is purified by filtration over silica gel (elution agent hexane/acetic acid 4:1). Recrystallization from hexane gives 4.5 g of p-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]aniline in colourless crystals, melting point 106°-108°.
Reaction SMILES: C([O-])C.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][O:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)[CH3:21]
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)CCCCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc(F)cc1

Procedure:
Under cooling (0° C.), sodium ethanolate (2.18 g, 32 mmol) was added to a mixture of 4-fluorophenol ([371-41-5], 3.00 g, 27 mmol), ethyl 4-chlorobutyrate ([3153-36-4], 4.84 g, 32 mmol) and ethanol (15 ml), and the reaction mixture was then refluxed overnight. The solvent was evaporated, the residue was taken up in ethyl ester and was washed with water. After drying (Na2SO4), the solvent was evaporated, and 4-(4-fluoro-phenoxy)-butyric acid ethyl ester was isolated from the residue by column chromatography (silica gel, ethyl acetate/heptane). 1H NMR (d6-DMSO): 1.29 (t, 3H), 2.11 (tt, 2H), 2.51 (t, 2H), 3.96 (t, 2H), 4.13 (q, 2H), 6.79-6.85 (m, 2H), 6.92-6.99 (m, 2H).