Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CC(C)=O.O>[N:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred solution of p-bromomethylbenzoic acid (13.607 g, 63.3 mmol) in acetone (300 ml) and H2O (15ml) was added dropwise at room temperature a solution of NaN3 (4.123 g, 63.4mmol) in H2O (40 ml). The reaction mixture was stirred at room temperature overnight (ca 20 h). After evaporation of the acetone, the residual solid was suspended in water and filtered, yielding 10.13 g (57.2 mmol, 90.3%) of p-azidomethylbenzoic acid as a white powder: 1Hmr (DMSO-d6 δ: 4.57 (2H, s, --CH3N3), 7.43-7.55-7.93-8.07 (4H, A2'B2', aromatic Hs) and 12.7 ppm (br, s, --CO2H): ir (nujol) νmax : (--N3) and 1670 cm-1 (--CO2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][C:3]=1[F:23].[CH3:24][O:25][C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:20])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:29]2[O:28][N:27]=[C:26]([O:25][CH3:24])[CH:30]=2)=[O:15])=[CH:4][C:3]=1[F:23]
Reactant: COc1cc(CN)on1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Product: COc1cc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)c(F)c3)c2)on1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-fluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinic acid (example BR) and 3-methoxy-5-isoxazolemethanamine (CAN 2763-94-2) as starting materials; LC-MS (UV peak area/ESI) 100%, 458.0537 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Br:16]Br.C(OCC)(=O)C.C(OCC)C>ClCCl>[Br:16][CH:8]([C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)s1
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)CC(Br)C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-(5-chlorothiophen-2-yl)-4-oxobutyrate (900 mg) in dichloromethane (9 ml) was added bromine (200 μl) under ice-cooling, and after stirring at the same temperature for 30 minutes, the reaction mixture was warmed to room temperature and the mixture was stirred for one hour. The reaction mixture was poured into ice-water, and ethyl acetate and diethyl ether were added thereto. The organic layer was collected, washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain ethyl 3-bromo-4-(5-chlorothiophen-2-yl)-4-oxo-butyrate (1.22 g) as pale brownish liquid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:7])=[C:4]([OH:21])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>CC(C)=O.C(OCC)(=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:21][C:4]1[CH:3]=[C:2]([F:1])[CH:20]=[CH:19][C:5]=1[C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 165 %

Procedure:
A solution of 4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide (5.00 g, 17.2 mmol) in acetone (86.0 mL) was treated with aq 2 N K2CO3 (13.0 mL, 25.8 mmol) and ethyl bromoacetate (1.50 mL, 9.66 mmol) and heated to 50° C. for 2 h. The solution was cooled to 0° C. and acidified to pH of 1 with 2 N HCl. The solution was diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Purification by MPLC(10-100% ethyl acetate in heptane, 23 mL/min, 75 min) to give [5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester as a pale yellow solid (6 g, 93%): mp 78-80° C.; Rf 0.26 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 9.01 (t, J=6 Hz, 1H), 8.19 (t, J=1.8 Hz, 1H), 8.10 (dd, J1=8.1 Hz, J2=1.5 Hz, 1H), 7.89 (dd, J1=8.7 Hz, J2=6.9 Hz, 1H),7.79 (d, J=7.5 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.11 (dd, J1=11.1 Hz, J2=2.4 Hz, 1H), 6.92 (dt, J1=8.4 Hz, J2=2.4 Hz, 1H), 5.0 (s, 2H), 4.63 (d, J=6.3 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H) 1.17 (t, J=6.5 Hz, 3H). ESI-LC/MS m/z calcd for C18H17FN2O6: 376.4. Found 377.0 (M+1)+. Anal. calcd for C18H17FN2O6: C, 57.45; H, 4.55; N, 7.44. Found : C, 57.47; H, 4.64; N, 7.28.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[C:44]3[CH:45]=[CH:46][S:47][C:43]=3[CH2:42][CH2:41][NH:40]2)=[CH:35][CH:34]=1>ClCCl.CN(C)C=O.O>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH:39]2[C:44]3[CH:45]=[CH:46][S:47][C:43]=3[CH2:42][CH2:41][N:40]2[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:37][CH:38]=1
Reactant: Clc1ccc(C2NCCc3sccc32)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCc2sccc2C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Benzoic acid (46 mg, 0.38 mmol) and 1-hydroxybenzotriazole (55 mg, 0.41 mmol) were dissolved in a mixture of dichloromethane (1 mL) and N,N-dimethylformamide (0.5 mL). N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol) was added and the mixture was shaken 0.5 hour at room temperature. 4-(4-Chlorophenyl)4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.38 mmol) dissolved in dichloromethane (0.5 ml) was added and the mixture was shaken at 1000 rpm for 3 hours. Water (1 mL) was added and the mixture was shaken at 1000 rpm overnight at room temperature. The organic phase was evaporated to give 129 mg (97%) of the title compound as an oil.
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][C@@H:4]1[O:9][C@@H:8]([O:10][C@@H:11]2[C:16]3=[C:17]([OH:34])[C:18]4[C:30](=[O:31])[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][C:28]=5[O:32][CH3:33])[C:22](=[O:23])[C:19]=4[C:20]([OH:21])=[C:15]3[CH2:14][C@@:13]([OH:38])([C:35]([CH3:37])=[O:36])[CH2:12]2)[CH2:7][C@H:6]([NH2:39])[C@@H:5]1[OH:40]>>[CH3:3][C@@H:4]1[O:9][C@@H:8]([O:10][C@@H:11]2[C:16]3=[C:17]([OH:34])[C:18]4[C:30](=[O:31])[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][C:28]=5[O:32][CH3:33])[C:22](=[O:23])[C:19]=4[C:20]([OH:21])=[C:15]3[CH2:14][C@@:13]([OH:38])([C:35]([CH2:37][OH:2])=[O:36])[CH2:12]2)[CH2:7][C@H:6]([NH2:39])[C@@H:5]1[OH:40].[CH2:1]=[O:2]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(C)=O)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Agent: C=O
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reaction time: 72 h

Procedure:
Crystalline dimeric formaldehyde conjugate of doxorubicin was prepared in a similar manner as was crystalline dimeric formaldehyde conjugate of daunorubicin except for the crystallization step. For a procedure starting with 40 mg, the crude product was dissolved in 1.3 mL of chloroform diluted with 27 mL of 3:1 ethyl acetate:hexane. The resulting solution was dispensed in 3 mL aliquots into nine 5 mL vials and allowed to stand undisturbed and stoppered in the dark for 3 days. The resulting crystals grew as red hexagonal tubes on the glass. The crystals were washed with ethyl acetate, collected, and dried under vacuum (0.1 Torr) to yield 14.5 mg (37%) of pure dimeric formaldehyde conjugate of doxorubicin. Anal. (C57H58N2O22)C, H, N. The crystalline material showed the same 1H NMR spectral properties as the amorphous material. The positive ion ESI mass spectrum of a sample in chloroform/methanol supported the structure in Scheme III for the dimeric formaldehyde conjugate of doxorubicin.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH:13]([C:17](OC(C)(C)C)=O)[CH:12]2CN)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:33][C:34]1[C:42]2[CH2:41][CH2:40][O:39][C:38]=2[C:37]([C:43](O)=[O:44])=[CH:36][C:35]=1[Cl:46].O.C[N:49](C=O)C>C(Cl)Cl>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH:13]([CH2:17][NH:49][C:43]([C:37]3[C:38]4[O:39][CH2:40][CH2:41][C:42]=4[C:34]([NH2:33])=[C:35]([Cl:46])[CH:36]=3)=[O:44])[CH2:12]2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CN2CCOC(C(=O)OC(C)(C)C)C2CN)CC1
Reactant: CN(C)C=O
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCO2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(CN2CCOC(CNC(=O)c3cc(Cl)c(N)c4c3OCC4)C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(1-acetyl-4-piperidinylmethyl)-2-(tert -butoxycarbonyl)-aminomethylmorpholine (Reference Example 15) (0.70 g) in methylene chloride (5 ml) was added trifluoroacetic acid (5 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was dried under reduced pressure to be solidified, and the residue was dissolved in toluene, and then dried under reduced pressure to be solidified again. To the residue was added water, and the mixture was alkalified with 2N aqueous sodium hydroxide and extracted with chloroform. The extract was washed with water, then brine, and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. A solution of the oily residue in DMF (5 ml) containing 4-(1-acetyl-4-piperidinylmethyl)-2-aminomethylmorpholine was added to a reaction solution which was obtained by stirring a solution of 4-amino-5-chloro-2, 3-dihydrobenzo[b]furan-7-carboxylic acid (0.42 g) and N,N′-carbonyldiimidazole (0.35 g) in DMF (10 ml) at room temperature for 1 hour. The mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with chloroform, and then the extract was sequentially washed with saturated sodium bicarbonate, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1) to give the titled compound (0.85 g) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH2:4]O.S(Cl)([Cl:15])=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH2:4][Cl:15]
Reactant: COc1ccc(F)c(F)c1CO
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(F)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3-difluoro-6-methoxybenzyl alcohol (6.97 g) in toluene (100 mL) was added thionyl chloride (4.4 mL) in a dropwise manner at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine twice, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (7.65 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][C:2]1=[O:10].CO[CH2:13][Cl:14].Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[Cl:14][CH2:13][C:8]1[CH:7]=[CH:6][C:5]2[O:1][C:2](=[O:10])[CH2:3][C:4]=2[CH:9]=1
Reactant: COCCl
Reactant: O=C1Cc2ccccc2O1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1Cc2cc(CCl)ccc2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3H-benzofuran-2-one (7.45 mmol) and chlormethyl methyl ether (9.31 mmol) in 15 ml of CH2Cl2 at 0° C. was slowly added SnCl4 (15 mmol). The reaction was slowly allowed to warm to ambient temperature and was stirred for 2 hours. The reaction was cooled to 0° C. and carefully quenched with saturated sodium bicarbonate. The mixture was extracted (2×EtOAc) and the organics were washed with brine. The combined organics were then dried over MgSO4, filtered and concentrated to dryness. The crude residue was chromatographed on silica gel using 20% EtOAc in hexanes as the eluant to obtain the title compound (55).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=O.[CH3:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of ethyl 3-fluorobenzoate (2.0 g, 11.9 mmol) and 4-methylpyridine (1.1 mL, 1.0 g, 10.8 mmol) in THF (9 mL) at 0° C. under nitrogen atmosphere was added dropwise lithium bis(trimethylsilyl)amide (23.8 mL, 1.0M in hexane, 23.8 mmol) During the addition a precipitate was formed and the suspension was stirred at room temperature overnight. The reaction was diluted with hexane (40 mL) and filtered. The solid was partitioned between ethyl acetate and a saturated solution of ammonium chloride. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give the title compound as a yellow solid (2.09 g, 82%).
Reaction SMILES: [Cl:1][C:2]([Cl:19])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[C:15]([Cl:17])[C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[C:8]([Cl:18])[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:53][C:54]([F:66])([F:65])[C:55]1[CH:56]=[C:57]([CH:62]=[CH:63][CH:64]=1)[C:58](=[N:60]O)[NH2:59]>CN(C=O)C.O.C1C=CC2N(O)N=NC=2C=1>[Cl:19][C:2]([Cl:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([Cl:18])[C:9]([O:10][CH2:11][C:12]2[O:14][N:60]=[C:58]([C:57]3[CH:62]=[CH:63][CH:64]=[C:55]([C:54]([F:53])([F:65])[F:66])[CH:56]=3)[N:59]=2)=[C:15]([Cl:17])[CH:16]=1
Reactant: NC(=NO)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(-c2noc(COc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)n2)c1
Temperature: 25 °C
Yield: 184 %

Procedure:
To a stirred solution of 0.129 gram (0.00037 mole) of 2-(4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy)acetic acid in 1.9 mL of DMF was added 0.141 gram (0.00037 mole) of HBTU, 0.008 gram (0.00006 mole) of HOBT and 0.24 gram (0.0019 mole) of DIEA. The reaction mixture stirred for 10 minutes at which time 0.075 gram (0.00037 mole) of 3-(trifluoromethyl)benzamidoxime was added. Upon completion of addition the reaction mixture was stirred at ambient temperature then heated to 112° C. where it stirred for four hours. After this time the reaction mixture was cooled to ambient temperature, diluted with water and extracted with a mixture of hexanes and ethyl acetate (70:30). The extract was washed in succession with two 5 mL portions of water, one 5 mL portion of an aqueous hydrochloric acid solution and one 5 mL portion of aqueous sodium bicarbonate, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using a mixture of hexanes and ethyl acetate as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.35 gram of the subject compound as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[C:10]([S:11](Cl)(=[O:13])=[O:12])[C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:16][CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])[OH:19]>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[CH:18]([OH:19])[CH2:17][NH:16][S:11]([C:10]1[C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=2[S:8][CH:9]=1)(=[O:13])=[O:12]
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Reactant: NCC(O)c1ccc(F)cc1F
Agent: Cl
Product: O=C1CCCc2c(S(=O)(=O)NCC(O)c3ccc(F)cc3F)csc21

Procedure:
From 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (280 mg) and 2-amino-1-(2,4-difluorophenyl)-ethanol hydrochloride (the compound of Preparation Example 20) (281 mg), the title compound (290 mg) was obtained as a colorless solid, in the same way as Preparation Example 41.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[N:3]=1
Reactant: Cc1ccn2c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cnc2n1
Reactant: Brc1ccccn1
Product: Cc1ccn2c(-c3cccc(-c4ccccn4)c3)cnc2n1
Yield: 36.1 %

Procedure:
7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)phenyl]-imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) was coupled to 2-bromopyridine (55 μl, 0.59 mmol) as described in Example 26 to give 7-methyl-3-[3-(pyridin-2-yl)phenyl]imidazo[1,2-a]pyrimidine as a white solid (30 mg): δH (400 MHz, CDCl3) 2.67 (3H, s), 6.79 (1H, d, J 7), 7.30 (1H, m 7.55-7.65 (2H, m), 7.77-7.81 (2H, m), 7.87 (1H, s), 8.00 (1H, dd, J 8 and 1.6), 8.19 (1H, d, J 1.5), 8.57 (1H, d, J 7), 8.71 (1H, d, J 1.6); m/z (ES+) 287 (M++H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([CH:11]([OH:13])[CH3:12])[CH:9]=[CH2:10].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCCCCC>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([C:11](=[O:13])[CH3:12])[CH:9]=[CH2:10]
Reactant: C=CC1(C(C)O)CCC(C)=CC1C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: C=CC1(C(C)=O)CCC(C)=CC1C
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of (2,4-dimethyl-1-vinylcyclohex-3-enyl)ethanol (20 mmol) in CH2Cl2 (40 ml) at room temperature was added PCC (40 mmol). The mixture was stirred at room temperature over night and was then diluted with hexane, filtered through a pad of celite and concentrated in vacuo. The residue was purified by chromatography to give 1-(2,4-dimethyl-1-vinylcyclohex-3-enyl)ethanone (83% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20]O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20][Cl:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1c(CO)nn(Cc2ccccc2)c2cccc(Cl)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c(CCl)nn(Cc2ccccc2)c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.2 %

Procedure:
To 0.42 g (1.4 mmol) of 1-benzyl-5-chloro-3-hydroxymethylcinnolin-4(1H)-one in 25 mL of dichloromethane at 0° C. was added 0.97 mL (7.0 mmol) of triethylamine and 0.33 mL (4.2 mmol) of methanesulfonyl chloride. The reaction was allowed to warm to room temperature and stirred for 5 h. The reaction was concentrated by rotary evaporation and was subsequently dissolved in dichloromethane and concentrated onto silica gel. The crude material was purified by flash chromatography eluting with a 33-50% ethyl acetate/hexanes gradient mixture to give 0.26 g (59%) of the title compound as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]1([CH2:14][NH2:15])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].S(Cl)([Cl:24])=O>>[Cl:24][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH2:14][CH:11]2[CH2:13][CH2:12]2)=[O:8])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: NCC1CC1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(NCC1CC1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated at reflux in thionyl chloride (2 ml) for 2.5 hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in acetone (4 ml), cyclopropylmethylamine (71 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to the solution. The reaction was stirred at room temperature for 4 hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-cyclopropylmethylnicotinamide as a cream solid. NMR: δH [2H6]-DMSO 8.82, (2H, m), 8.23, (1H, dd), 7.63, (1H, d), 3.14, (2H, t), 1.01, (1H, m), 0.44, (2H, m), 0.22, (2H, 10 m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:28]=[CH:27][C:13]([C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15])=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>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(O)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:28][CH:27]=1)[CH3:26]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccc(Br)cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCCCCCC(=O)c1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
To a mixture of 3-thiophene boronic acid (383 mg, 3 mmol) and bromoester 49d (1.03 g, 3 mmol) were added anhydrous toluene (30 mL) and ethanol (1.5 mL) (20:1, c=1.0M) followed by 2M K2CO3 aqueous solution (3 mL, 6 mmol). The reaction mixture was stirred under nitrogen for 30 minutes and then Pd(PPh3)4 (191 mg, 5 mol %, 0.16 mmol) was quickly added. After 24 hours of reflux, the mixture was cooled to room temperature, filtered through a pad of Celite and rinsed with ethyl acetate (50 mL). The organic solution was washed with brine (30 mL), dried (MgSO4), and concentrated. Purification by flash silica gel chromatography (10% methanol in dichloromethane) followed by crystallization from ethyl acetate afforded the corresponding ester 115 (210 mg, 20% yield) as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:7][N:6]([CH:8]2[CH2:14][CH:13]3[N:15](C(OC(C)(C)C)=O)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH2:5]1)#[N:2].[ClH:45]>C1COCC1.O1CCOCC1>[ClH:45].[ClH:45].[ClH:45].[CH:13]12[NH:15][CH:10]([CH2:11][CH2:12]1)[CH2:9][CH:8]([N:6]1[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:23]3[CH:27]=[C:26]([C:28]4[C:29]5[CH:36]=[CH:35][N:34]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[C:30]=5[N:31]=[CH:32][N:33]=4)[CH:25]=[N:24]3)[CH2:7]1)[CH2:14]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(N1CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C1)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CC6CCC(C5)N6)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate (123 mg, 0.2 mmol) in THF (3 mL) was added a 4 N solution of HCl in dioxane (3 mL). After being stirred at room temperature for 2 hours, the solution was concentrated. The residue obtained was used for the next reaction. LC-MS: 519.3 (M+H)+.