Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:34][O:35][NH2:36]>CO>[CH3:34][O:35][NH:36][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: O=C(O)Cn1nnnc1S
Reactant: CON
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CONC(=O)Cn1nnnc1S
Temperature: 0 °C
Reaction time: 7 h
Yield: 495.6 %

Procedure:
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-acetic acid (320 mg) in methanol (3 ml) are added triethylamine (0.33 ml) and N,N'-dicyclohexylcarbodiimide (495 mg), and th mixture is stirred for 7 hours. To this solution is added a solution of methoxyamine hydrochloride (33.4 mg) and triethylamine (56 μl) in methanol (0.3 ml). After the addition of a further amount of N,N'-dicyclohexylcarbodiimide (124 mg), the mixture is left stand at room temperature overnight. The reaction mixture is concentrated under reduced pressure to about 1 ml and then diluted with ethyl acetate (8 ml) and 5% sodium hydrogen carbonate (7 ml). After the separated solid (461 mg) is removed by filtration, the filtrate is saturated with sodium chloride and diluted with ethyl acetate-methyl ethyl ketone mixture (1:1). The mixture is acidified to pH 1 with hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated under reduced pressure to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester (375 mg), identical with the product prepared with N,N'-carbonyldiimidazole.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1.[C:17]([O:21][C@@H:22]([C:28]1[C:43]([CH3:44])=[CH:42][C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][N:38]=[C:37](Cl)[CH:36]=3)[S:34][C:30]=2[C:29]=1[C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])([CH3:20])([CH3:19])[CH3:18]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[OH-].[K+].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[C:17]([O:21][C@@H:22]([C:28]1[C:43]([CH3:44])=[CH:42][C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([N:8]4[C:16]5[CH:15]=[CH:14][N:13]=[CH:12][C:11]=5[CH2:10][CH2:9]4)[CH:36]=3)[S:34][C:30]=2[C:29]=1[C:45]1[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])([CH3:18])([CH3:19])[CH3:20]
Reactant: c1cc2c(cn1)CCN2
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCc5cnccc54)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 105 °C

Procedure:
In a 5 mL microwave reaction tube, 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine TFA salt (excess), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (26 mg, 0.05 mmol), bis(tri-tert-butylphosphine)palladium(0) (4 mg, 15%), cetyltrimethylammonium bromide (3 mg) were charged with 1 mL toluene, then 1 drop of 50% KOH aqueous solution was added. The reaction was heated to 105° C. for 1 hour. LC-MS of the reaction crude show desired product. The reaction crude was extracted using ethyl acetate form brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C34H34ClN4O3S: 613.1 (M+H+); Found: 613.3 (M+H+).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[F:33][C:31]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:4]([C:6]2[N:7]=[C:8]([C:15]3[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=3[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:32]=1
Reactant: NCc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(F)cc2C(F)(F)F)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro -pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2-trifluoromethyl-4-fluorobenzylamine (97 mg, 0.5 mmol). The title product was obtained as an off-white solid (25.7 mg, 56% yield). 1HNMR (500 MHz, CDCl3) δ: 12.07 (1H, s), 7.92 (1H, t, J=5.34), 7.53–7.47 (1H, m), 7.36 (1H, s), 7.24 (2H, d, J=8.24 Hz), 7.06 (2H, dd, J=8.54, 7.33 Hz), 4.63 (2H, d, J=6.41 Hz), 3.42 (3H, s). HRMS (ESI) calcd for C20H12F6N3O3 (M−H): 456.0783; found: 456.0793.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Si]([O:15][CH2:16][CH2:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[C:25]([NH:30][C:31]3[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=3)[CH:26]=[C:27]([CH3:29])[CH:28]=2)[CH:20]=[N:19]1)(C(C)(C)C)(C)C>ClCCl>[CH3:29][C:27]1[CH:28]=[C:23]([C:21]2[CH:20]=[N:19][N:18]([CH2:17][CH2:16][OH:15])[CH:22]=2)[CH:24]=[C:25]([NH:30][C:31]2[N:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][N:32]=2)[CH:26]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CCO)c2)c1
Reaction time: 0.5 h

Procedure:
TFA (24 μL, 0.31 mmol) was added to a solution of N-{3-[1-(2-{[tert-butyl(dimethyl)silyl]-oxy}ethyl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine in dichloromethane (2 mL), and the reaction was allowed to stir for 30 minutes. The competed reaction was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (ACN/water with 0.1% formic acid modifier to afford 2-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]ethanol. MS ESI calcd. for C17H17F3N5O [M+H]+ 364. found 364. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.79 (d, J=4.9, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.31 (s, 1H), 7.23 (d, J=4.9, 1H), 7.05 (s, 1H), 4.92 (t, J=5.2, 1H), 4.14 (t, J=5.6, 2H), 3.73 (q, J=5.6, 2H), 2.27 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:15]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: Brc1ccc(C2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCN1CCCC1c1ccc(Br)cc1
Yield: 62.4 %

Procedure:
2-(4-Bromo-phenyl)-pyrrolidine (640 mg, 2.83 mmol) and allyl bromide (343 mg, 2.83 mmol) is mixed in THF (15 mL) and K2CO3 (390 mg, 2.83 mmol) is then added. The mixture is heated at reflux for 2 h before THF is removed under reduced pressure and the residue is partitioned between EtOAc and H2O. The EtOAc layer is dried and concentrated and the residue is then subjected to chromatography to provide the desired product (470 mg, 62.4%).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].C([Li])CCC.C[O:22][B:23](OC)[O:24]C.[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[OH:10][C:8]([CH3:11])([CH3:9])[CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([B:23]([OH:24])[OH:22])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: CC(C)(O)COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)COc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
A solution of 1-(4-bromophenoxy)-2-methylpropan-2-ol (1.23 g) in tetrahydrofuran (25 ml) was added to oil-free sodium hydride (132 mg) under an atmosphere of argon. The mixture was stirred for 30 minutes and then cooled to −78° C. 1.6M Butyl lithium in hexane (6.9 ml) was added over 5 minutes and the solution was stirred at −78° C. for 30 minutes. Trimethylborate (1.14 g) was added over 1 minute and the mixture was stirred at −78° C. for 1 hour. Saturated ammonium chloride solution (25 ml) was added and the mixture was allowed to warm to room temperature. Water (25 ml) was added and the mixture was extracted with ether (2×25 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with ethyl acetate/hexane (7:3 v/v), to give 4-(2-hydroxy-2-methylpropoxy)phenylboronic acid (355 mg), 1H NMR (d6-DMSO): 1.2 (s, 6H), 3.7 (s, 2H), 4.5 (br s, 1H), 6.85 (d, 2H), 7.6-7.8 (m, 4H).
Reaction SMILES: Cl.[CH2:2]1O[C:5]([O:14]CC)([CH2:6][CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[O:4][CH2:3]1.C(=O)([O-])O.[Na+]>CC(C)=O>[O:13]=[C:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:5]([O:4][CH2:3][CH3:2])=[O:14])[CH2:8][CH2:9]1
Reactant: CCOC1(CC2CCC(=O)CC2)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.7 %

Procedure:
50 ml of a 1N aqueous solution of hydrochloric acid was added to a solution of 5.0 g of ethyl 4-oxocyclohexylacetate ethylene acetal, as obtained in Example 58, in 50 ml of acetone. The reaction mixture was stirred for 10 minutes at room temperature, neutralized by the addition of a saturated aqueous solution of sodium hydrogencarbonate, and then concentrated by evaporation under reduced pressure. The resulting residue was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 100 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 3.9 g of the title compound as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: COC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 45.9 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.94 g, 6.6 mmol) (The compound was synthesized according to the procedure as described in WO2010069147A) was reacted with morpholine-3-carboxylic acid hydrochloride (1.1 g, 6.6 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (1.5 g, 46%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].Br[CH2:13][CH2:14][CH3:15].O>C1COCC1>[CH2:13]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1])[CH2:14][CH3:15]
Reactant: CCCBr
Reactant: OCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCOCc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a solution of 2-bromobenzyl alcohol (10.0 g) in THF (100 ml) was added at 0° C. sodium hydride (60%, 2.35 g), and the resulting mixture was stirred at room temperature for 2 hours. 1-Bromopropane (5.8 ml) was added to the reaction mixture, which was stirred at 60° C. for 20 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate:hexane 1:9) to obtain 2-bromobenzyl propyl ether (7.88 g) as a colorless oily substance.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]=[O:15])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.C1(C)C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O>[C:29]([O:15][N:14]=[C:11]1[CH:12]=[CH:13][C:8](=[N:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:9]=[CH:10]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: O=Nc1ccc(Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)ON=C1C=CC(=Nc2ccccc2)C=C1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution was prepared by mixing 4-nitrosodiphenylamine, 19.8 grams, (0.10 mole), pyridine, 8.6 grams, (0.11 mole), and toluene, 10 mL, in a suitable reaction flask. The solution was cooled to 5° C. and acetic anhydride, 11.22 grams, (0.11 mole) was added slowly. The mixture was stirred for 2 hours and allowed to come to room temperature. The reaction mixture was mixed with a quantity of water, allowed to stand until the water layer separated, and the water layer was discarded. The toluene solution was evaporated to leave 21.4 grams of a solid residue, 96% of theory. The material melted at 63-65° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][N:10]=2)[N:7]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:13]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][OH:12])=[N:9][N:10]=3)[N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: OCc1nnc2ccc(Cl)nn12
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1nnc2ccc(-c3ccccc3)nn12
Temperature: 85 °C

Procedure:
A suspension of (6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanol (0.289 mmol, 1 eq), phenylboronic acid (0.665 mmol, 2.3 eq), Pd(PPh3)4 (45.9 mg, 0.0405 mmol, 14 mol %), and K2CO3 (132 mg, 0.955 mmol, 3.3 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated conventionally at 85° C. for 1 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by pTLC [Silicycle, 1000 μM, 20×20 plate], which required two developments in a 3% MeOH in EtOAc solvent system. 1H NMR (400 MHz, CDCl3): δ=1.69 (br s, 1H), 5.35 (s, 2H), 7.56-7.60 (m, 3H), 7.64 (d, J=9.6 Hz, 1H), 7.97-8.02 (m, 2H), 8.22 (d, J=9.6 Hz, 1H). MS (ES+): m/z 227.08 (100) [MH+]. HPLC: tR=2.42 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27]([N+:31]([O-:33])=[O:32])=[CH:26][N:25]=1>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][N:10]([C:26]2[C:27]([N+:31]([O-:33])=[O:32])=[CH:28][N:29]=[C:24]([Cl:23])[N:25]=2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C1(CNC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
To a solution of ethyl1-[(cyclohexylamino)methyl]cyclopropane-1-carboxylate (Intermediate 273; 7.175 g, 34 mmol) in acetone (200 mL) was added potassium carbonate 7.05 g, 51 mmol) followed by 2,4-dichloro-5-nitropyrimidine (Aldrich; 9.235 g, 47.6 mmol). The reaction mixture was stirred at room temperature for 5 hours. A further addition of 2,4-dichloro-5-nitropyrimidine (4.62 g, 23.8 mmol) and potassium carbonate (3.5 g, 25.5 mmol) was made and the reaction stirred overnight at room temperature. The reaction mixture was then concentrated in vacuo and partitioned between EtOAc and water. The EtOAc layer was separated, dried over sodium sulphate and purified on a silica column eluting with EtOAc/isohexane 10:90, to yield the title compound as a yellow oil (12 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.Br[C:15]1[S:16][C:17]([C:20](O)=O)=[CH:18][N:19]=1>>[CH2:8]([NH:9][C:15]1[S:16][C:17]([CH2:20][NH:13][C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[CH:18][N:19]=1)[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Product: Clc1ccc(-c2csc(NCc3cnc(NCc4ccccc4)s3)n2)cc1
Reaction time: 2 h

Procedure:
Compound 2ak was prepared as described for 2 h starting from 4-(4-chlorophenyl)thiazol-2-amine and 2-bromothiazole-5-carboxylic acid (31 mg, 49%). Mp. 105-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(O)=O.C([NH2:16])=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:16])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NC=O
Reactant: CC(=O)c1cccc(Cl)c1
Solvent: O
Solvent: O=CO
Product: CC(N)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
1-(3-Chlorophenyl)ethanone (11.9 g, 77.5 mmol) and formic acid (3.72 g, 77.5 mmol) were heated in formamide (10 mL) at 170-180° C. for 20 h. The mixture was cooled to room temperature, diluted with water and extracted with benzene. After removal of benzene by rotary evaporation the crude mixture was heated under reflux conditions in 3M HCl for 30 h. After cooling, the reaction was added to ether and extracted. The aqueous layer was basified with NaOH to pH 9 and extracted with dichloromethane. The dichloromethane was evaporated to collect the title compound (3.93 g, 33%). 1H NMR (400 MHz, CDCl3): δ 7.34 (s, 1H), 7.21 (m, 3H), 4.07 (m, 1H), 1.35 (d, 3H); MS (ESI) m/z: Calculated for C8H11ClN: 156.06; Observed: 156.0 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[NH:20][CH2:19][CH2:18]2>>[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[N:20]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH2:19][CH2:18]2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(Br)ccc21
Product: CC1c2ccc(Br)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]([O-])=O.[NH4+].Cl[C:6]1[CH:7]=[C:8]([C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=1)[C:9]([OH:11])=[O:10]>CO.[C].[Pd]>[F:16][C:15]([F:18])([F:17])[C:12]1[CH:13]=[N:14][CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH3:1])=[O:10]
Reactant: O=C(O)c1cc(Cl)ncc1C(F)(F)F
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 13 h
Yield: 49 %

Procedure:
Ammonium formate (500 mg) and 10% palladium carbon (270 mg) were added to a solution of 2-chloro-5-(trifluoromethyl)isonicotinic acid (1.04 g) in methanol (10 ml), followed by stirring at room temperature for 13 hours. An insoluble substance was removed by celite filtration and the filtrate was concentrated. Thionyl chloride (5 ml) was added to a solution of the resulting residue in methanol (30 ml), followed by heating to reflux for 15 hours. The reaction solution was concentrated, an aqueous saturated sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain methyl 3-(trifluoromethyl)isonicotinate (463 mg) as an orange solid.
Reaction SMILES: C(Cl)Cl.[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:12]2=[O:22])=[CH:7][CH:6]=1.[C:23](Cl)(=[O:25])[CH3:24].[Cl-].[Na+]>C(N(CC)CC)C>[C:23]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:12]2=[O:22])=[CH:9][CH:10]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(N2CCN(c3cccnc3)C2=O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(N2CCN(c3cccnc3)C2=O)cc1
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a 10 ml dried methylene chloride solution of 0.57 g (2.24 mmol) of 1-(4-aminophenyl)-3-(3-pyridyl)-2-imidazolidinone in a 100 ml round-bottomed flask were added 0.34 ml (1.1 eg.) of triethylamine, and, after stirred for 15 minutes, 0.17 ml (1.1 eg.) of acetyl chloride were added dropwise under cooling with ice. After dropwise addition, the mixture was stirred for 8 hours at room temperature. To this reaction mixture were added 10 ml of saturated aqueous solution of sodium chloride, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then solvent was distilled off under reduced pressure to obtain 0.16 g (yield 24%) of 1-(4-acetylaminophenyl)-3-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:44])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:24])[OH:23])[C@H:18]1[C:25]([O:27][C@H:28]([C:42]#[N:43])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[O:26].[C:45]([CH:47](O)[C:48](Cl)([Cl:50])[Cl:49])#[N:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:44])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:23])[O:24][C:47]([C:45]#[N:46])=[C:48]([Cl:50])[Cl:49])[C@H:18]1[C:25]([O:27][C@H:28]([C:42]#[N:43])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[O:26]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: N#CC(O)C(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC(C#N)=C(Cl)Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
140 mg of 4-dimethylaminopyridine and then 1.76 g of dicyclohexylcarbodiimide were added at 0° C. to a mixture of 3.36 g (S)α-cyano-3-phenoxy-benzyl (IR,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate, 1.7 g of chloral cyanohydrin and 16 ml of methylene chloride and the mixture was stirred at 20° C. for 21/2 hours and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with an 85-15 cyclohexane-ethyl acetate mixture to obtain 1.65 g of (S)α-cyano -3-phenoxy-benzyl (IR,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2,2-dichloro-1-cyanovinyloxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+40° (c=0.3% in chloroform).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)([O-])=O>CO.[Pd]>[ClH:1].[NH2:2][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[NH:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(NCc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)C(NCc1ccccc1)CC2
Reaction time: 1 h

Procedure:
To 6-nitro-1-(phenylmethyl)aminoindane hydrochloride (1.34 g, 4.40 mmol) in MeOH (100 ml) was added a catalytic amount of 10% Pd/C. The mixture was hydrogenated at 50 psi for 1 hr, filtered through celite, and concentrated to give 6-amino-1-(phenylmethyl)aminoindane hydrochloride which was homogeneous by TLC and used immediately in the next step.