Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20](Cl)=[O:21])=[CH:15][N:14]=1>C1COCC1>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([C:20](=[O:21])[NH:4][CH:1]([CH3:3])[CH3:2])=[CH:15][N:14]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cnc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A solution of isopropylamine (1.28 ml, 15.0 mmol) and triethylamine (2.10 ml, 15.1 mmol) in dry THF (5 ml) was added dropwise over 30 minutes to a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (obtained as described in J. Med. Chem., 1972, 15, 200; 3.18 g, 15.0 mmol) in dry THF (8 ml) at −10° C. The solution was stirred 0° C. for 2 hours, filtered and evaporated to dryness to yield the product (0.93 g), which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH3:20])[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[N:4]([CH3:20])[C:5]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: Cn1c(C=O)nc(-c2ccccc2)c1-c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(CO)nc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-formyl-1-methyl-4-phenyl-5-[4-pyridyl]imidazole (0.830 g, 3.15 mmol) in MeOH at 0° C. was added NaBH4 (0.143 g, 3.78 mmol). The mixture was stirred at rt for 0.5 h when the solvent was evaporated in vacuo and the residue was partitioned between CH2 Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with 25:1 CH2Cl2 /MeOH. The title compound was obtained as a white solid (0.608 g, 73%): mp 236°-238° C.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([O:21]C5CCCCO5)[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5].C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([OH:21])[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5]
Reactant: C[C@]12CCC3=C(CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CCC2=C(F)F
Yield: 68.9 %

Procedure:
A suspension of 927 mg of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),8-tetraene in 20 ml of methanol and 2.0 ml of water is refluxed with 950 mg of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed three times with water, once with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. After crystallization from hexane, 0.5 g of 17-difluoromethylene-estra-1,3,5(10),8-tetraen-3-ol is obtained as colorless crystals with a melting point of 127-128° C., [α]D22 =-1.5° (c=0.515% in pyridine).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.CN.C[CH2:27][N:28](C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:28][CH3:27])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: CN
Agent: Cl
Product: CNc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 100 °C
Yield: 16 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 67 mg, 0.226 mmol), methanamine hydrochloride (30.5 mg, 0.452 mmol; Sigma-Aldrich), and DIPEA (197 μl, 1.131 mmol), heating at 100° C. for 3 h. Purification by silica gel (100% DCM to 5% 2 M NH3 in MeOH/DCM) provided 2-(2-methyl-3-(methylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H) 2.88 (t, J=6.85 Hz, 2H) 3.05 (d, J=4.50 Hz, 3H) 3.43 (td, J=6.80, 2.25 Hz, 2H) 6.94-6.98 (m, 1H) 7.13 (d, J=1.96 Hz, 1H) 7.32 (t, J=7.73 Hz, 1H) 7.37-7.43 (m, 1H) 7.58 (d, J=6.85 Hz, 1H) 7.90 (d, J=6.46 Hz, 1H) 12.24 (br. s., 1H). MS (ESI, pos. ion) m/z: 308.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:3]1=2.[CH2:22]([OH:24])[CH3:23]>S(=O)(=O)(O)O>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([O:24][CH2:22][CH3:23])=[O:19])=[CH:16][C:3]1=2
Reactant: CCO
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1ccccc1O2
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc2c(c1)C(=O)Cc1ccccc1O2
Reaction time: 4 h

Procedure:
To 62 mg of 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-2-yl)-propionamide in 2 ml of ethanol were added three drops of conc. sulfuric acid and the mixture was reluxed with stirring for 4 hours. After the completion of the reaction, the solvent was distilled off to obtain the residue, to which was added ice and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogencarbonate solution, then saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain brown oil, which was chromatographed over silica gel, eluted with chloroform and there was obtained 58 mg of ethyl 2-(10,11-dihydro-11-oxo dibenzo[b,f]oxepin-2-yl)-propionate as pale yellow oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18]C(C(O)=O)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl.CN(C=O)C>[Cl:4][C:2]([CH:1]1[CH2:18][CH2:19][N:14]([C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])[CH2:15][CH2:16]1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of oxalyl chloride (8.72 ml, 17.45 mmol) in DCM (150 ml) was added 1-(tert-butoxy-carbonyl)piperidine-4-carboxylic acid (2 g, 8.72 mmol) at 0° C. Then a few drops of DMF were added. The mixture was stirred at room temperature for 2 h, washed with NH4Cl aqueous and brine. The organic layer was separated, dried (MgSO4) and concentrated. The resulting crude product was directly used in the next step.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12]N(C)C)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[C-]#N.[Na+].[CH3:21][N:22](C=O)C>CCOC(C)=O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][C:21]#[N:22])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: CN(C)Cc1c[nH]c2cc(C(F)(F)F)ccc12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#CCc1c[nH]c2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Yield: 60 %

Procedure:
6-Trifluoromethyl-N,N-dimethyl-1H-indole-3-methanamine (1.2 g, 4.95 mmol) and NaCN (0.72 g, 14.86 mmol, 3.0 eq.) were combined with DMF (10 mL) and EtOAc (2 mL). The mixture was heated to reflux for 6 hours, then cooled to rt. The product was extracted with EtOAc and the organic layer was washed with water and dried (MgSO4). The solvent was removed in vacuo to give 0.66 g (60%) of the title compound after column chromatography (Hex:EtOAc 1:1).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C@@H:13]([CH2:18][OH:19])[CH2:14][CH:15]([CH3:17])[CH3:16].O>C1COCC1>[OH:19][CH2:18][C@H:13]([N:12]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)C[C@@H](N)CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](CO)N1C(=O)c2ccccc2C1=O
Temperature: 85 °C
Yield: 47.1 %

Procedure:
Phthalic anhydride (10.30 g, 69.55 mmol) and D-Leucinol (8.15 g, 69.55 mmol) were mixed in THF (100 mL), the reaction mixture was heated at 85° C. and refluxed for 18 hours. After cooling to room temperature, water was added and the solution was extracted with EtOAC, the extracts were washed with 1 N HCl, water, aq. NaHCO3, water and brine, dried over MgSO4, filtered and evaporated to give 8.1 g of (R)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (47%). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 6H); 1.54 (m, 2H); 1.99 (m, 1H); 3.86 (m, 1H); 4.04 (m, 1H); 4.47 (m, 1H); 7.72 (m, 2H); 7.83 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>CN(C=O)C>[CH2:22]([O:13][C:12]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Br:1])[CH:7]=[CH:8][CH:9]=1)=[O:14])[CH3:23]
Reactant: O=C(O)c1cccc2cccc(Br)c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8-bromo-naphthalene-1-carboxylic acid (1.6 g) in DMF (15 ml) was treated with potassium carbonate (2.2 g) and iodoethane (1.03 ml). The reaction mixture was stirred overnight at r.t., then quenched with water and extracted with ethyl acetate. The organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient:cyclohexane→cyclohexane/EtOAc 1:1) to give 8-bromo-naphthalene-1-carboxylic acid ethyl ester (1.57 g) as colorless liquid. MS (ISP): 279.1 ((M+H)+).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([O:23]C)=[O:22])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10]>CO.O>[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[CH2:20][C:21]([OH:23])=[O:22])(=[O:12])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COC(=O)CC1CCCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 16 h

Procedure:
Lithium hydroxide (0.75 mg, 18 mmol) was added to a cooled solution of methyl 2-(1-(3,4-dichlorophenylsulfonyl)piperidin-2-yl)acetate (2.1 g, 6 mmol) in methanol (20 ml) and water (20 ml), and stirring was carried out for 16 h at room temperature (TLC monitoring). The solvent was removed using a rotary evaporator and the residue was taken up in water. The aqueous phase was washed with ethyl acetate and then acidified with 1 M HCl, and the product was extracted with ethyl acetate, and the organic phase was then washed with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated to dryness. Yield: 2.9 g (98%)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10].[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[N:21]=1>C(#N)C>[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])[N:21]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: Cc1nc(-c2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(Oc1cccc(-c2noc(C)n2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
11.5 g (33.5 mmol) of caesium carbonate and 7.67 g (35.2 mmol) of methyl 2-bromo-2-phenylacetate are added to a solution of 5.90 g (33.5 mmol) of 3-(5-methyl-1,2,4-oxadiazol-3-yl)phenol in 50 ml of acetonitrile. The reaction mixture is stirred at room temperature for 24 hours, then filtered, and the filtrate is evaporated, giving methyl [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-phenylacetate as a yellowish oil; ESI 325.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].[CH3:11]O>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CO
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Product: COC(=O)[C@@H]1CCCC[C@@H]1N
Reaction time: 1 h

Procedure:
cis-2-Amino-1-cyclohexane carboxylic acid (2500 mg, 17.5 mmol) was suspended in methanol (30 ml) at 0° C. Gaseous hydrochloric acid was bubbled through the suspension for 10 minutes. The reaction was allowed to reach room temperature then stirred under nitrogen for 1 h and the solvent removed under reduced pressure. The residue was azeotroped with diethyl ether (2×20 ml) and dried to give the title compound as a solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]=[CH:16]3)=[CH:11][CH:10]=2)O1.[CH3:25][O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31](Br)=[N:32][CH:33]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C.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>[CH3:25][O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[N:17]=[CH:16]3)=[CH:13][CH:14]=2)=[N:32][CH:33]=1)=[O:28]
Reactant: COC(=O)c1cnc(Br)n1C
Reactant: CC1(C)OB(c2ccc(-n3cnc4ccccc43)cc2)OC1(C)C
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: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-c2ccc(-n3cnc4ccccc43)cc2)n1C
Temperature: 90 °C
Yield: 36 %

Procedure:
To a solution of 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-benzoimidazole (0.43 g, 1.5 mmol) and 2-bromo-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (0.25 g, 1.15 mmol) in DME (9 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.057 mmol) and 2 M aqueous potassium carbonate (1.4 mL) and the reaction mixture was heated at 90° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The reaction mixture was filtered and the filtrate washed with water, dried (Na2SO4), and the solvent removed under reduced pressure. Purification by flash column chromatography (silica, petroleum ether:ethyl acetate 7:3→1:1 then dichloromethane:methanol 99:1→97:3) provided the title compound (36%). LCMS (ESI+) 332.2 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:10])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>CS(C)=O.O>[O:11]([CH2:2][C:3]1([CH3:10])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(CCl)COC(C)(C)O1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(COc2ccccc2)COC(C)(C)O1

Procedure:
4-Chloromethyl-2,2,4-trimethyl-1,3-dioxolane (5.0g) and sodium phenoxide (3.7g, prepared from phenol and sodium hydride) in dimethyl sulphoxide (90 ml) were heated together at 140° C for 4 hours. The reaction mixture was diluted with water and the aqueous solution extracted with ether. The ether extracts were dried and the solvent was removed under reduced pressure to yield a liquid which, on distillation, gave the desired product having a b.p. 83.5° C at 0.3 mm Hg.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:15][C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:19]([OH:21])[N:20]=1.P(Cl)(Cl)Cl>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH:18]2[S:17][C:16]([NH:15][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])=[N:20][C:19]2=[O:21])=[CH:27][CH:26]=1
Reactant: Nc1nc(O)c(-c2ccc(Cl)cc2)s1
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(NC1=NC(=O)C(c2ccc(Cl)cc2)S1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.280 g) of Preparation 1 and 2-amino-5-(4-chlorophenyl)-4-hydroxy-1,3-thiazole (0.340 g) in 50 mL xylenes is heated to reflux. To this is added dropwise PCl3 (0.103 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is triturated with HOAc to yield 0.236 g of the title product as a gold solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[NH:12][C:13](=[O:22])[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:25][N:26]1[C:30]([CH2:31]Cl)=[N:29][CH:28]=[N:27]1.O>CN(C=O)C>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([O:22][CH2:31][C:30]4[N:26]([CH3:25])[N:27]=[CH:28][N:29]=4)=[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=[C:10]3[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1ncnc1CCl
Reactant: O=c1[nH]c2c(cc1-c1ccccc1)nnn2-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1nc2c(cc1-c1ccccc1)nnn2-c1ccccc1
Temperature: 25 °C
Yield: 10.4 %

Procedure:
A mixture of 3,6-diphenyl-5-oxo-4H-1,2,3-triazolo[4,5-b]pyridine (0.03 g, 0.10 mmol) and sodium hydride (55% in oil, 0.006 g, 0.12 mmol) in dry DMF (2 ml) was stirred at room temperature under nitrogen until all effervescence had ceased. A solution of 2-methyl-3-chloromethyl-1,2,4-triazole (0.025 g, 0.20 mmol) in dry DMF (0.5 ml) was added and the mixture was stirred for 4 days. Water (20 ml) was added and the aqueous solution was extracted with 10% methanol-dichloromethane (20 ml). The extract was dried (Na2SO4), filtered and concentrated. Preparative thin-layer chromatography on silica gel, eluting with 5% methanol-dichloromethane, gave the alkylation product which was recrystallised from ethyl acetate-hexane to give 3,6-diphenyl-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,3-triazolo[4,5-b]pyridine (0.004 g, 10%) as a white, crystalline solid, m.p. 153-156° C. δH (360 MHz; CDCl3) 3.71 (3H, s), 5.69 (2H, s), 7.42-7.54 (6H, m), 7.63 (2H, dd, J=8 and 8), 7.86 (1H, s), 8.24 (2H, d, J=8) and 8.32 (1H, s); m/z (ES+) 383 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([O:20][C:21](=O)[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:29](=[O:32])(=[O:31])[NH2:30])[CH:24]=2)C=CC=CC=1>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:21](=[O:20])[NH:22][C:23]2[CH:24]=[C:25]([S:29]([NH2:30])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: NS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CO
Product: NS(=O)(=O)c1cccc(NC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)c1
Temperature: 80 °C

Procedure:
A solution of (R)—N-benzyl-3-aminopyrrolidine (14.9 g, 0.084 mol) in methanol (100 mL) is added to a suspension of (3-sulfamoyl-phenyl)-carbamic acid phenyl ester (25 g, 0.084 mol). The resulting pale orange solution is stirred at mild reflux (DrySyn @ 80° C.) for two hours, then allowed to cool to room temperature, before the volatile components are removed under reduced pressure. The orange syrup is purified by flash column chromatography (silica; DCM/methanol 10:1) to give a beige foamed solid.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:5][O:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:4][O:3]1.[ClH:18]>>[Cl:18][CH2:4][C@@:2]([OH:3])([CH3:1])[CH2:5][O:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17]
Reactant: Cl
Reactant: C[C@@]1(CON2C(=O)c3ccccc3C2=O)CO1
Product: C[C@](O)(CCl)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[[(2S)-2-Methyloxiranyl]methoxy]-1H-isoindole-1,3(2H)-dione (3.0 g, 12.9 mmol) was treated with concentrated hydrochloric acid (12 ml) and stirred at ambient temperature for 2 h. The mixture was partitioned between water and dichloromethane, the organics were dried and purified by chromatography (EtOAc) to give the sub-title compound as a colourless solid (3.3 g).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:21](=[O:39])[N:22]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=2)[C:23](=[O:26])[C:24]=1[CH3:25]>O1CCCC1.C(OCC)(=O)C>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([N:22]2[C:23](=[O:26])[C:24]([CH3:25])=[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[C:21]2=[O:39])=[CH:28][C:29]=1[C:35]([F:38])([F:37])[F:36])#[N:32]
Reactant: CC1=C(CCCCCI)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(CCCCCN2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 98 %

Procedure:
1.56 g of 1,1-dimethylethyl piperazine-1-carboxylate was added under a nitrogen atmosphere to a solution of 2.0 g of 4-[2,5-dihydro-3-(5-iodopentyl)-4-methyl-2,5-dioxo-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile in 53 ml of tetrahydrofuran, and this mixture was stirred for 7 days at room temperature. For working-up, it was diluted with ethyl acetate and washed with semi-saturated sodium bicarbonate solution. After drying on sodium sulfate and concentration by evaporation, it was chromatographed with methanol/dichloromethane on silica gel, and thus 2.2 g of the title compound was obtained as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([O:31]C1C=CC=CC=1)=O)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:41][CH:38]1[CH2:40][CH2:39]1)=[O:31])[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: NC1CC1
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)c2cc1C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C(=O)OC

Procedure:
Methyl 4-[3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-7-(2-methoxyethoxy)-6-quinolinecarboxylate (3.2 g), cyclopropylamine (1.3 ml) and dimethylformamide (20 ml) were stirred together at 60° C. for 10 minutes. The mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. Silica gel was added to the extract solution and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=50:1, 20:1) to obtain 2.26 g of the target substance as a white powder.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[C:17]([C:7]2[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=2)[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 550.4 %

Procedure:
4.08 g (30.0 mmol) of 3-trifluoromethylpyrazol, 4.75 mmol (30.0 mmol) of 2-chloro-4-fluorobenzaldehyde and 4.14 g (30.0 mmol) of potassium carbonate in 30 ml of N,N-dimethylformamide were stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into 100 ml of water, and the organic matters were extracted with 50 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. The residue afforded 7.18 g of 2-chloro-4-(3-trifluoromethylpyrazolyl)benzaldehyde (yield 87.2%) as a pale yellow powder, after washed with n-hexane.