Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
Prepared from (3-amino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G49) (160 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) (130 mg, 0.5 mmol) according to the general procedure K. Obtained as an amorphous yellow substance (166 mg).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.Cl>C(#N)C.[Cu]Cl>[CH3:1][C:2]([O:6][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)([CH3:3])[C:4]#[CH:5]
Reactant: Oc1ccc2ncccc2c1
Reactant: C#CC(C)(C)O
Agent: Cl[Cu]
Agent: Cl
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C#CC(C)(C)Oc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-methyl-3-butyn-2-ol (2.45 mL, 25.1 mmol) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) in acetonitrile (15.5 mL) was stirred 0° C. for 30 minutes, and trifluoroacetic anhydride (3.55 mL, 25.1 mmol) was added dropwise. The resulting mixture was added dropwise to a mixed solution of 6-hydroxyquinoline (2.43 g, 16.7 mmol), copper (I) chloride (8.3 mg, 0.0835 mmol), acetonitrile (15.5 mL) and 1,8-diazabicyclo-[5.4.0]-7-undecene (4.25 mL, 28.4 mmol) at 0° C., and stirred at 0° C. for 3 hours. The resulting solution was acidified with 1 mol/L HCl and extracted with ethyl acetate, and the resulting aqueous phase was neutralized with aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/1 to 1/3) and the aimed product was obtained.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:13][CH2:14][CH3:15])=[N:9][C:8](=S)[N:7]([CH2:17][CH3:18])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[OH-].[Na+].[Ni]>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([N:12]=2)=[C:10]([NH:13][CH2:14][CH3:15])[N:9]=[CH:8][N:7]3[CH2:17][CH3:18])[CH2:3][CH2:2]1
Reactant: CCNc1nc(=S)n(CC)c2nc(C3CC3)[nH]c12
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: ClC(Cl)Cl
Product: CCNc1ncn(CC)c2nc(C3CC3)nc1-2
Temperature: 67.5 °C

Procedure:
The product of step (i) (11.85 g) was dissolved in 2N NaOH (270 ml) and 10N NaOH (27 ml) and heated to 65° C. Within 1.25 hours 50% Ni-Al alloy (518 mmoles. of Ni and 1125 mmols of Al) (60.8 g) was added under vigorous stirring at 65-70° C. After a further 0.75 hr at the same temperature the reaction mixture was cooled to room temperature and treated with chloroform (400 ml). The nickel was filtered off and washed with 350 ml of chloroform and 150 ml of water. The filtrate was separated and the chloroform layer evaporated to dryness. The residue (19.64 g) was dissolved in acetone (100 ml), treated with 2 portions of charcoal (0.15 g) filtered and evaporated. The residue was treated with diethylether (100 ml) and crystals collected (6.10 g), mp 80-9° C. A second , crop gave 1.25 g. A recrystallized sample from diisopropylether had mp 103-105° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:23])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[O:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:23])[CH2:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:17]([CH2:18][NH:30][CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH:16]=1
Reactant: O=Cc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Reactant: NC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OC(COc1cccc(CNC2CCOCC2)c1)CN1CCc2ccccc2C1
Temperature: 60 °C
Yield: 17 %

Procedure:
To a solution of 3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropoxy)benzaldehyde (200 mg, 0.64 mmol) in DCM (15 mL) was added tetrahydro-2H-pyran-4-amine (97 mg, 0.96 mmol). The solution was heated at 60° C. for 0.5 h. Then, NaBH(OAc)3 (204 mg, 0.96 mmol) was added into the reaction mixture and heated at 60° C. for another 1 h. The reaction mixture was quenched by adding 1N HCl aqueous solution and diluted with DCM then washed with NaHCO3 aqueous solution. The separated organic layer was concentrated and the crude product was purified by preparative HPLC purification. (40 mg, yield 17%) MS (ESI+) e/z: 397.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.36 (t, J=8.0 Hz, 1H), 7.19-7.15 (m, 3H), 7.11-7.02 (m, 4H), 4.39-4.33 (m, 1H), 4.16 (s, 2H), 4.08-4.00 (m, 6H), 3.49-3.40 (m, 3H), 3.25-3.20 (m, 2H), 3.15-3.03 (m, 4H), 2.12-2.02 (m, 2H), 1.71-1.60 (m, 2H).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C(=O)=O.[F:7][C:8]([F:33])([F:32])[S:9]([C:11]1[CH:12]=[CH:13][C:14]2[CH:20]=[CH:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[C:16](=[C:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:15]=2[CH:31]=1)=[O:10]>CO.C(Cl)(Cl)Cl>[OH:3][CH:1]([N:28]1[CH2:29][CH2:30][C:25](=[C:16]2[C:15]3[CH:31]=[C:11]([S:9]([C:8]([F:33])([F:7])[F:32])=[O:10])[CH:12]=[CH:13][C:14]=3[CH:20]=[CH:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]2=3)[CH2:26][CH2:27]1)[CH3:2]
Reactant: C1CO1
Reactant: O=S(c1ccc2c(c1)C(=C1CCNCC1)c1ccccc1C=C2)C(F)(F)F
Agent: O=C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(O)N1CCC(=C2c3ccccc3C=Cc3ccc(S(=O)C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.244 g. of ethylene oxide in 30 ml. of methanol at dry-ice temperature is added to an ice cold solution of 2.25 g. of 4-(3-trifluoromethylsulfinyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine in 15 ml. of chloroform and 75 ml. of methanol. The solution is stirred at ambient temperature overnight. A second quantity (0.25 g.) of ethylene oxide is added as before and the mixture is again stirred overnight. The mixture is concentrated to dryness and the residue is coevaporated in vacuo several times with acetonitrile. The product is recrystallized several times from acetonitrile to give 1-hydroxyethyl-4-(3-trifluoromethylsulfinyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][CH:19]=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.Br[C:22]1[CH:26]=[CH:25][S:24][CH:23]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Brc1ccsc1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC=O)cc1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2ccsc2)cc1

Procedure:
Prepared from (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridine-3-yl)-acetaldehyde 6b and 3-bromo-thiophene using the procedure of Method B described above. 1H NMR (400 MHz, CDCl3) 2.33 (s, 3H), 2.41 (s, 3H), 4.60 (s, 2H), 7.05 (dd, J=1.4 Hz, 9.1 Hz, 1H), 7.30 (m, 4H), 7.53 (d, J=1.4 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.59 (s, 1H), 7.99 (d, J=1.1, 2.5 Hz, 1H). Mass spectrum (m/e) 347 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[CH3:19][O:20][C:21](=[O:27])[CH2:22][CH2:23][C:24](Cl)=[O:25]>O1CCCC1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:21]([O:20][CH3:19])=[O:27])=[N:7][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(=O)CCC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1ccc(C#N)cn1
Yield: 71 %

Procedure:
The 6-amino-3-pyridinecarbonitrile (commercially available, 0.470 g, 1.0 eq.) was dissolved in tetrahydrofuran (10 mL) then N,N-dimethylaniline (0.5 mL, 1.0 eq.) and methyl-4-chloro-4-oxo-butanoate (0.54 mL, 1.1 eq.) were successively added. The mixture was reflux for 12 h. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate to give methyl 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoate A1 (71%). M.p.=161-164° C. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.20 (m, 2H), 3.58 (s, 3H), 2.74 (t, 2H), 2.61 (t, 2H) ppm. LC-MS (Method B): RT 1.19, 234 (M+H+) The following compounds from table A or B were prepared by the same method using commercial or described starting aminopyridine:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[C:36]=1[F:53])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:53][C:36]1[C:37]([O:43][CH2:44][CH2:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=1[C:21](=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCOC2CCCCO2)c1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OCCOC2CCCCO2)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
After adding 13 mg of 2-hydrazinopyrimidine and 0.016 ml of triethylamine to a solution of 69 mg of (2-{2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester in 1 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated to give a crude product of 5-({2-fluoro-5-methoxy-3-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]methyl)-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][C:4]=1[CH:10]1[C:16](=[O:17])[CH:15]2[CH2:18][CH:12]([CH2:13][CH2:14]2)[C:11]1=[O:19])[CH3:2].[Cl-].[Li+].C([Mg]Cl)(C)C.[B:27](OC)([O:30]C)[O:28]C>O1CCCC1.ClCCl>[O:17]=[C:16]1[CH:10]([C:4]2[CH:5]=[C:6]([B:27]([OH:30])[OH:28])[CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2])[C:11](=[O:19])[CH:12]2[CH2:18][CH:15]1[CH2:14][CH2:13]2
Reactant: CCc1ccc(I)cc1C1C(=O)C2CCC(C2)C1=O
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccc(B(O)O)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
To a solution of 3-(2-ethyl-5-iodophenyl)bicyclo[3.2.1]octane-2,4-dione (0.65 g, 1.77 mmol) in anhydrous tetrahydrofuran (15 ml) at −10° C. is added iso-propyl magnesium chloride lithium chloride complex (10.6 ml, 10.6 mmol, 1M in tetrahydrofuran) dropwise over 10 minutes. The reaction mixture is stirred at this temperature for 1.5 hours, then cooled to −78° C., at which point trimethyl borate (1.39 ml, 12.4 mmol) is added dropwise to maintain a temperature below −60° C. After re-cooling to −78° C. the mixture is further stirred for 5 minutes, then additionally at room temperature for 1 hour. The solution is quenched with 2M hydrochloric acid and extracted with ethyl acetate (×3). All organic fractions are combined, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo to give an orange-coloured gum. This crude product is dissolved in a minimum amount of dichloromethane then precipitated with iso-hexane to afford 3-(2,4-dioxo-bicyclo[3.2.1]oct-3-yl)-4-ethylphenylboronic acid (0.46 g, 90%) as a cream-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH:6]=[CH:5]2.[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1.C(Cl)Cl>>[C:20]([O:15][CH2:14][C@H:13]([N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[N+:17]([O-:19])=[O:18])[C:8]1=[O:12])[CH3:16])(=[O:22])[CH3:21]
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 45 °C

Procedure:
A mixture of (R)-6-chloro-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (750.0 mg, 0.002653 mol), acetic anhydride (0.325 mL, 0.00345 mol), pyridine (0.322 mL, 0.00398 mol) and methylene chloride (20 mL, 0.3 mol) was heated at 45° C. over night. The solvent was removed under reduced pressure and dried to get pure product as thick yellow oil. MS m/z=325.4 (M+H). 1H NMR (400 MHz; DMSO) δ 8.42 (d, J=8.61 Hz, 1H), 7.47 (d, J=8.61 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 6.29 (d, J=8.03 Hz, 1H), 5.34-5.29 (m, 1H), 4.28-4.20 (m, 2H), 1.94 (s, 3H), 1.40 (d, J=6.96 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[CH:7]([C:9](=[O:18])[C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[O:8][C:4]=2[CH:3]=1.S(OC)(O[CH3:26])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([O:19][CH3:26])=[C:7]([C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])=[O:18])[O:8][C:4]=2[CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1Cl)C1Oc2cc(Br)ccc2C1=O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Yield: 27.8 %

Procedure:
To a solution of 6-Bromo-2-(2,4-dichloro-benzoyl)-benzofuran-3-one (3.30 g, 8.55 mmol) in acetone (50 mL) was added dimethyl sulfate (1.19 g, 9.40 mmol) and cesium carbonate (4.18 g, 12.82 mmol). The resulting mixture was heated at 50 deg for 6 hours is at which time the reaction mixture was concentrated via rotary evaporation. The resulting mixture was taken up in EtOAc and washed twice with water and one time with a saturated sodium carbonate solution. The organic portion was dried over MgSO4 and then filtered and concentrated. The resultant oil was purified via column chromatography (10% MeOH/Dichloromethane) to provide the title compound (950 mg, 28%). 1H-NMR (CDCl3): δ 8.03 (d, 1H), 7.65 (d, 1H), 7.46 (m, 2H), 7.35 (m, 2H), 2.46 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[C:17]([CH2:19]O)[CH:16]=[CH:15][N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>>[Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[C:17]([CH2:19][Cl:23])[CH:16]=[CH:15][N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccnc(OCc2cn3c(Cl)cccc3n2)c1
Reactant: O=S(Cl)Cl
Product: ClCc1ccnc(OCc2cn3c(Cl)cccc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of 2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethanol (2.90 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-chloro-2-(4-chloromethyl-2-pyridyloxymethyl)imidazo[1,2-a]pyridine (2.63 g, yield 85%) as colorless crystals from the fraction eluted with tetrahydrofuran. This was recrystallized from tetrahydrofuran-hexane. Melting point: 118–119° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccccc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 30.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g. 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, phenyl isocyanate (0.33 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 7:3) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(phenylamino)carboxamide (0.23 g, 31%) as a white solid: mp 212–214° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 8.78 (s, 1H), 7.88–7.76 (m, 3H), 7.37 (d, J=7.7 Hz, 2H), 7.21 (t, J=7.7 Hz, 2H), 6.89 (t, J=7.3 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 5.20–5.13 (dd, J=5.3 and 12.5 Hz, 1H), 4.72 (d, J=5.9 Hz, 2H), 2.97–2.84 (m, 1H), 2.65–2.49 (m, 2H), 2.09–2.05 (m, 1H); 13C NMR (DMSO-d6) δ 172.72, 169.79, 167.58, 166.99, 155.22, 140.25, 134.69, 133.63, 131.59, 128.60, 127.18, 121.83, 121.18, 117.70, 48.86, 38.71, 30.92, 21.97; Anal. Calcd. For C21H18N4O5: C, 62.07; H, 4.46; N, 13.79. Found: C, 62.14; H, 4.49; N, 13.49.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:12])[N:3]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1OC1C.CCOCC>C(COC)OC>[Cl:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]1[N:3]2[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:1]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc2c(Cl)cccc2n1
Agent: CC1CO1
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)c1cn2c(ccc3c(Cl)cccc32)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
140 mg of 2-amino-5-chloroquinoline were dissolved in 2.5 ml of dimethoxyethane and then a mixture of 170 mg of ethyl bromopyruvate and 30 mg of propylene oxide was added. The mixture was stirred at room temperature for 2 hours and 2 ml of ether were added. Then, the mixture was cooled in ice and the precipitated quaternary salt was filtered off, was dissolved in 5 ml of ethanol and the solution was heated at reflux for 2 hours. Then, the solvent was removed under vacuum and the residue was partitioned between sodium bicarbonate solution and chloroform. The chloroform solution was dried over magnesium sulfate and was evaporated to dryness. The residue was chromatographed over silica with chloroform as eluent and the purified product was recrystallized from ethyl acetate/petroleum ether to obtain colorless needles of ethyl 6-chloroimidazo-[1,2-a]-quinoline-2-carboxylate melting at 193°-194° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[Ca+2].C(COC)OC.[C:29](Cl)(Cl)=[S:30]>O>[N:1]([C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:7][C:6]=2[CH:16]=1)=[C:29]=[S:30]
Reactant: Cc1cc2oc(-c3ccccn3)nc2cc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2oc(-c3ccccn3)nc2cc1N=C=S
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A mixture of 5-amino-6-methyl-2-(2-pyridinyl)benzoxazole (8.7 g, 0.044 mole), calcium carbonate (4.44 g, 0.044 mole), glyme (150 ml) and water (50 ml) is cooled to 5° C in an ice-bath, and thiophosgene (5.11 g, 0.044 mole) is added. The mixture is stirred for 0.5 hour at 5° C and then allowed to warm to room temperature and stirred for about 16 hours. The precipitated material is collected, washed with water and crystallized from glyme/water (3:1) yielding 8.1 g of the title compound, melting point 192°-194° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:3]=1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O.O>C1COCC1>[NH2:1][C:2]1[C:7]([N:8]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:9](=[O:12])[O:10][CH3:11])=[C:6]([NH2:13])[N:5]=[C:4]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:15]=2)[N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(CC(F)(F)F)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A quantity of 3.470 g (8.138 mmol) of the compound from Example 1 was suspended in 35 ml of THF, admixed at 0° C. with 358 mg (8.952 mmol) of sodium hydride (60% suspension in mineral oil) and stirred at 0° C. for 90 min, in the course of which a solution was formed. A quantity of 2.519 g (8.952 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate was added and the mixture was stirred at RT for 48 h. It was then stirred with water and concentrated on a rotary evaporator. The residue was taken up in ethyl acetate, and the organic phase was washed twice with water and dried over sodium sulphate. This gave 5.005 g of the target compound (79% of theory, purity by HPLC 65%). A quantity of 250 mg of the residue was purified by means of preparative HPLC (mobile phase: methanol/water, gradient 30:70→90:10).
Reaction SMILES: [Cl:1][SiH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>>[Cl:1][Si:2]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:19][CH2:18][CH2:17][CH2:16][C:15]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: Cl[SiH](c1ccccc1)c1ccccc1
Reactant: C=CCCC(=O)OCc1ccccc1
Product: O=C(CCCC[Si](Cl)(c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a mixture of chlorodiphenylsilane (0.49 g; 2.58 mmol) and benzyl pent-4-enoate (0.50 g; 2.58 mmol) under argon was added two drops of Karstedt's catalyst solution (in xylenes; ˜2% Pt). The reaction vessel was sealed and the mixture was heated to 60° C. for 15 hours. The crude liquid was used without purification.