Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH2:13])=[N:2]1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([C:27](O)=[O:28])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:27]([CH:23]2[CH2:24][CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22]2)=[O:28])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: NCCNc1nsc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NCCNc2nsc3ccccc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine (600 mg, 3.11 mmol), 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (854 mg, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (585 mg, 3.7 mmol) and triethylamine (577 μL, 3.7 mmol) in dichloromethane (40 mL) was allowed to stir at room temperature overnight. The reaction mixture was washed successively with 1N aqueous hydrochloric acid, saturated sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by flash column chromatography, on silica gel, eluting with a mixture of 25% ethyl acetate in hexanes gave fractions that were combined and concentrated under reduced pressure to yield tert-butyl 3-(2-(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)piperidine-1-carboxylate as a white solid, (325 mg). 1H NMR (300 MHz, DMSO-d6): 8.1 (m, 2H), 7.92 (m, 3H), 7.9 (d, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 3.9 (m, 2H), 3.5 (m, 2H), 3.3 (m, 2H), 2.8 (m, 2H), 2.2 (m, 1H), 1.8 (m, 1H), 1.6 (m, 3H), 1.3 ppm (s, 9H). MW=405 confirmed by LC-MS, tr=3.81 min (Method B) MH+=406.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([CH3:16])[O:9][CH:6]1OC)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[C:22]([OH:25])(=[O:24])[CH3:23]>C(OC(=O)C)(=O)C>[C:22]([O:25][CH:6]1[O:9][C@@H:10]([CH3:16])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:5]1[O:4][C:1](=[O:3])[CH3:2])(=[O:24])[CH3:23]
Reactant: CC(=O)O
Reactant: COC1O[C@@H](C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1O[C@@H](C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 96 h
Yield: 58 %

Procedure:
Methyl 5-deoxy-2,3-di-O-acetyl-L-ribofuranoside (33 g, 15.2 mmol) was dissolved in acetic acid (20 mL) and acetic anhydride (5 mL). The solution was cooled to ice bath temperatures and concentrated sulfuric acid was added dropwise (1 mL). The solution was kept at 5° C. for 4 days, then it was poured into ice water (50 mL) and extracted with 3:1 ethyl acetate hexanes (200 mL and 75 mL). The combined organics were washed with 10% sodium biarbonate (2×50 mL) and water (50 mL). The organic layers were dried, and concentrated and the residue purified on a silica gel column (5×15 cm, 230-400 mesh) with ethyl acetate:hexanes (1:3). Both anomers were observed but were isolated together as a clear oil (2.2 g, 8.8 mmol, 58%); 1H NMR (DMSO-d6) δ5.96 (d, 1H J=1 Hz), 5.23 (d, 1H, H-2, J=5 Hz), 4.96 (t, 1H, H-3, J=5.7 Hz), 4.24-4.16 (m, 1H, H-4), 2.07 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.27 (d, 3H, H-5, J=6.3 Hz).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][CH:13]([NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][CH3:26])[CH2:12][CH2:11]2.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O.[N+](C)([O-])=O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([N+:1]([O-:4])=[O:2])=[C:10]2[C:15]=1[CH2:14][CH:13]([NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][CH3:26])[CH2:12][CH2:11]2
Reactant: O=[N+]([O-])O
Reactant: CCCc1ccccc1C(=O)NC1CCc2cccc(Cl)c2C1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: CCCc1ccccc1C(=O)NC1CCc2c([N+](=O)[O-])ccc(Cl)c2C1

Procedure:
Fuming nitric acid (100 ml), 33% in concentrated sulphuric acid was added dropwise to a solution of 72 g (0.22 mol) 8-chloro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene in 300 ml nitromethane at 0° C. The mixture was allowed to reach ambient temperature and was stirred over night. After pouring on ice water/diethyl ether the mixture was basified (sodium carbonate solution) and the phases separated. The organic phase was dried (magnesium sulphate), filtered and evaporated to a residue of 65.5 g of an isomeric mixture. Elution of the mixture on a silica column (isooctane/diethyl ether, 1:1) gave 19 g of 8-chloro-5-nitro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene and 12 g of the desired isomer; 8-chloro-7-nitro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene. MS m/e 372 (M+, 3), 374 (M++2, isotope, 1), 105 (100), 164 (72), 77 (35), 134 (16), 165 (9).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2([C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH2:11][O:10]2)=[CH:3][CH:2]=1.[Na].[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1>C(O)CC>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:10])([CH2:11][N:27]2[CH:26]=[N:25][N:24]=[CH:28]2)[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])=[CH:3][CH:2]=1
Reactant: C=CC(C)(C)C1(COc2ccc(-c3ccccc3)cc2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCCO
Product: C=CC(C)(C)C(O)(COc1ccc(-c2ccccc2)cc1)Cn1cnnc1
Yield: 15.1 %

Procedure:
35.3 g (0.120 mol) of 2-(biphenyl-4-yloxymethyl)-2-(3,3-dimethylprop-1-en-3-yl)-oxirane, dissolved in 80 ml of n-propanol, were added to a boiling solution of 1 g (0.012 mol) of sodium propylate and 9.1 g (0.132 mol) of 1,2,4-triazole in 50 ml of n-propanol. After the solution had been boiled under reflux for two days, it was evaporated down under reduced pressure, the oily residue was taken up in 200 ml of ethyl acetate, and the solution was washed with three times 50 ml of water. After the organic phase had been dried over anhydrous sodium sulphate, the solution was concentrated under reduced pressure. After the residue had been triturated with 150 ml of ethyl acetate, 6.6 g (15.1% of theory) of 4-(biphenyl-4-yloxymethyl)-3,3-dimethyl-4-hydroxy-5-(1,2,4-triazol-4-yl)-pent-1-ene were obtained as colorless crystals of melting point 171° to 173° C. The oil (37.1 g) which remained after the filtrate had been evaporated down was taken up in 200 ml of acetone, and a solution of 34.6 g of naphthalene-1,5-disulphonic acid in 100 ml of acetone was added. The salt which crystallized out was filtered off under suction, washed with acetone, and taken up in a mixture of 250 ml of water and 250 ml of dichloromethane. The solution was rendered alkaline by stirring in 10% strength sodium carbonate solution. After the organic phase had been concentrated, 24 g of an oil were obtained, which was dissolved in ethyl acetate and the solution then filtered over silica gel. After the filtrate had been concentrated, 17.8 g (40.8% of theory) of 4-(biphenyl-4-yloxymethyl)-3,3-dimethyl-4-hydroxy-5-(1,2,4-triazol-1-yl)-pent-1-ene were obtained in the form of colorless crystals of melting point 85° to 87° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:9][NH:8][C:7]=12.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:25]2[CH2:33][CH2:32][NH:31][CH2:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]([C:11](=[O:15])[C:12]([N:31]3[CH2:32][CH2:33][C:25]4[C:24]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=5)=[N:29][CH:28]=[N:27][C:26]=4[CH2:30]3)=[O:14])=[CH:9][NH:8][C:7]=12
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
To a flask containing 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.264 g, 0.884 mmol) was added a solution of 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, TFA (0.5 g, 1.149 mmol) in DMF (8 mL) followed by Hunig's Base (0.772 mL, 4.42 mmol) and finally TBTU (0.369 g, 1.149 mmol). After stirring the mixture at rt for 4 h, it was quenched with 10 mL of water and concentrated under reduced pressure. The residue was diluted with water (25 mL) and sat. aq. ammonium chloride (25 mL) added to the mixture. The mixture was extracted with dichloromethane (3×40 mL). The combined organic layers were washed with sat. aq. NaHCO3, dried with MgSO4, filtered and concentrated under reduced pressure. The residue was purified by BIOTAGE® flash chromatography using a 0-6% MeOH in dichloromethane gradient. The expected product, 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione (0.333 g, 0.675 mmol, 76% yield), was isolated as a brown solid. LC/MS: m/z 493 (M+H)+, 495.13 (M+3H)+, 2.177 min (method 3). 1H NMR (500 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1H) 9.05-9.19 (m, 1H) 8.66-8.78 (m, 1H) 8.33-8.44 (m, 1H) 7.99-8.12 (m, 2H) 7.82 (s, 1H) 7.50-7.60 (m, 1H) 4.66-4.91 (m, 2H) 3.63-3.92 (m, 5H) 3.11-3.32 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].CC(C)([O-])C.[K+].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=1>CN(C)C=O.C(OCC)(=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=3)=[CH:16][CH:17]=2)=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (35 g, 0.1060 mol) was dissolved in dry N,N-dimethyl formamide (100 ml) and potassium tert-butoxide (14.28 g, 0.1272 mol) was added in one lot at room temperature. The reaction mass was stirred at ambient temperature for 2-3 hours and 4-chloro-N-methyl picolinamide (18.09 g, 0.1060 mol) was added in one lot. The reaction mass was maintained at 60-70° C. for 2-3 hours and cooled to room temperature. It was then diluted with ethyl acetate and the organic layer was washed with water followed by 1N HCl and finally with brine. The organic layer was separated, dried over sodium sulfate and degassed to obtain solid. The obtained solid was stripped with ethyl acetate, finally slurried in acetonitrile (350 ml) at room temperature, filtered and vacuum dried to give 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide (sorafenib) (32 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])=[N:6][CH:7]=1.C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1cnc(NC(=O)c2ccc3ccccc3c2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Nc1cnc(CBr)cn1)c1ccc2ccccc2c1

Procedure:
N-(5-methylpyrazin-2-yl)-2-naphthamide (2.63 g, 10.0 mmol) was weighed and dissolved in 30 mL carbon tetrachloride. NBS (1.96 g, 11.0 mmol), BPO (242 mg, 1.0 mmol) were added and heated to reflux and reacted in dark for 12 hours. It was rotate evaporated to dryness to remove the solvent, and was used for the next step directly.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:16][S:17]([O:1][CH:2]1[CH2:3][CH:4]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:5][O:6][CH2:7]1)(=[O:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NC1COCC(O)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1COCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A solution of tert-butyl 5-hydroxy-tetrahydro-2H-pyran-3-ylcarbamate (109 mg, 0.5 mmol) and N,N-dimethylpyridin-4-amine (80 mg, 0.65 mmol) in 10 mL of dichloromethane was cooled in an ice bath, methanesulfonyl chloride (0.05 mL, 0.6 mmol) was added drop-wise. The reaction mixture was stirred overnight at room temperature, then was washed with 50 mL of water, organic phase dried with sodium sulfate filtered and concentrated. The residue was purified by column chromatography (silica gel. 200-300 mesh, eluting with ethyl acetate/petroleum ether=1/1) to afford 5-(tert-butoxycarbonylamino)-tetrahydro-2H-pyran-3-yl methanesulfonate (100 mg, 67%) as white solid. LCMS: (M+H)+=318; 1H NMR (300 MHz, CDCl3): δ 4.89-4.83 (m, 1H), 3.99-3.62 (m, 5H), 3.06 (s, 3H), 2.26-2.20 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:38])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][O:18]CC1C=CC=CC=1)[N:10]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](=[O:36])(=[O:35])[NH:33][CH3:34])[C:9]2=[O:37])=[O:5])[CH3:2].[CH2:39](OC(=O)C1C(C)=CC(NC(=O)COCC2C=CC=CC=2)=C(C(O)=O)C=1C)[CH3:40].NC1C=CC=CC=1S(NC)(=O)=O.P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:38])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][OH:18])[N:10]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](=[O:35])(=[O:36])[NH:33][CH3:34])[C:9]2=[O:37])=[O:5])[CH2:2][CH2:39][CH3:40]
Reactant: CCOC(=O)c1c(C)cc2nc(COCc3ccccc3)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Reactant: CCOC(=O)c1c(C)cc(NC(=O)COCc2ccccc2)c(C(=O)O)c1C
Agent: CNS(=O)(=O)c1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCOC(=O)c1c(C)cc2nc(CO)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Preparation of 2-Benzyloxymethyl-5,7-dimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: To a mechanically-stirred suspension of 4-(Benzyloxyacetyl)amino-2,6-dimethyl-isophthalic acid 1-ethyl ester (27 g, 0.07 mol), 2-amino-N-methyl-benzenesulfonamide (13 g, 0.07 mol) and anhydrous toluene (500 mL) in a three-necked round bottom flask is added phosphorus trichloride (51 mL, 0.56 mol) via an addition funnel. The reaction mixture is stirred at room temperature for 5 minutes and then heated to reflux. After 45 minutes LCMS analysis indicates that the reaction is complete. The suspension is cooled to room temperature and the solution phase is decanted from the solid material. The solution and solid material are worked-up separately. The toluene solution is partitioned between ethyl acetate and saturated aqueous NaHCO3 solution with vigorous stirring to give a clear biphasic solution. The organic and aqueous phases are separated and the aqueous phase is extracted (×2) with ethyl acetate. The organic phases are combined, dried over anhydrous Na2SO4, and evaporated in vacuo to give an orange oil. Similarly, the solid material is stirred, vigorously with ethyl acetate and saturated aqueous NaHCO3 solution to give a clear biphasic solution. The organic and aqueous phases are separated and the aqueous phase is extracted (×2) with ethyl acetate. The organic phases are combined, dried over anhydrous Na2SO4, and evaporated in vacuo to give an orange oil. Trituration of the orange oil with diethyl ether provides a yellow solid, which is removed by filtration, washed with diethyl ether and air-dried to provide the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:29])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>C(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:29])[C:26]=1[O:27][CH3:28])[C:21]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:22]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(Cl)cc(C(=O)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (50 mL), and triethylamine (17.4 mL) and 3,5-dichloro-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (d).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:18]([F:21])=[CH:19][CH:20]=3)[C:15]([NH2:17])=[O:16])=[N:7][C:6]=2[CH:23]=1.O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:7][C:6]1[CH:23]=[CH:2][CH:3]=[CH:4][C:5]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:18]([F:21])=[CH:19][CH:20]=3)[C:15]([NH2:17])=[O:16])=[N:7][C:6]=2[CH:23]=1
Reactant: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(-c4ccccc4N)ccc3s2)c1F
Temperature: 120 °C
Yield: 16.1 %

Procedure:
To the solution of compound 3-(5-bromo-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide (0.3 g 0.755 mmol) in dry DMF:H2O (5 mL: 2.5 mL), phenylamine-2-boronic acid (0.260 g, 1.5 mmol), and K2CO3 (0.125 g, 0.9 mmol) was added under nitrogen atmosphere at room temperature. After that reaction mixture was degassed for half an hour. Dichlorobis[(triphenylphosphine)-palladium (II) was added to the reaction mixture (0.080 g, 0.113 mmol) and again degassed for half an hour and the reaction mixture was heated at 120° C. for 2 hrs under nitrogen atmosphere. DMF was distilled off, after cooling to r.t. water was added into reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50 as the eluent to provide the title compound as yellow solid (0.025 g, 8%). 1H NMR (DMSO-d6, 400 MHz); δ 4.86 (broad s, 2H), 5.71 (s, 2H), 6.66 (dt, 1H, J=8.4 Hz (o-coupling), 6.78 (d, 1H, J=7.2 Hz (o-coupling), 7.04-7.13 (m, 3H), 7.37-7.44 (m, 1H), 7.51 (dd, 1H, J=8.4 Hz (o-coupling), J=1.6 Hz (m-coupling), 7.89 (broad s, 1H), 8.00 (broad s, 1H), 8.18 (d, 2H, J=4.0 Hz); MS ES+ (412.16), HPLC (method 5) Rt=15.33 min.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH:10]=1.C(O)(=O)C>C(O)C.O.[Fe]>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2ccccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1ccccc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Yield: 80.5 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-nitrophenyl)isonicotinamide (350 mg, 0.87 mmol, 1.00 equiv) in ethanol/H2O (1/1) (30 mL), iron (489 mg, 8.73 mmol, 10.00 equiv), and acetic acid (0.1 mL). The resulting solution was heated to reflux for 0.5 h. The solids were filtered out. The resulting solution was extracted with of ethyl acetate and the organic layers combined and dried over magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The product was obtained as 260 mg (80%) of a yellow solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:25][Si:26]([CH3:43])([CH3:42])[C:27]#[C:28][Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.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>[C:19]1([C:8]2[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[N:10][C:5]3[N:6]([C:2]([C:28]#[C:27][Si:26]([CH3:43])([CH3:42])[CH3:25])=[CH:3][N:4]=3)[CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(-c2nc3ncc(Br)n3cc2-c2ccccc2)cc1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12

Procedure:
400 mg 4-(3-bromo-6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde, 820 mg trimethyl[(tributylstannyl)ethynyl]silane and 60 mg Pd(PPh3)4 were suspended in 8 mL toluene under a nitrogen atmosphere. The mixture was heated (microwave) to 130 for 1 h. The solvent was evaporated and the crude product was purified by column chromatography (dichloromethane/methanol)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:10]([CH3:14])[C:11]=2[CH:12]=[O:13])=[CH:3][CH:2]=1.[BH4-].[Na+].P([O-])([O-])([O-])=O>CO>[OH:13][CH2:12][C:11]1[C:10]([CH3:14])=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[S:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1C=O
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.4 %

Procedure:
To a stirred solution of 2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde (0.145 g) in methanol (10 mL) was added sodium borohydride (0.11 g) at 0° C. The mixture was stirred at room temperature for 30 minutes. Phosphate buffer was added to the reaction mixture and MeOH was removed by evaporation. The residue was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with ethyl acetate-CH2Cl2-MeOH (1:1:0.04) to give the subtitle compound (0.170 g).