Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].CCN(CC)CC.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:35](=[O:36])[N:34]([CH3:38])[CH3:33]
Reactant: CN(C)C(=O)Cl
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 399.9 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added Et3N (0.141 mL, 1 mmol) and N,N-dimethylcarbamoyl chloride (0.08 g, 0.075 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a solid (0.15 g, 60%): 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 4H), 7.28 (m, 1H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 4.97 (br s, 1H), 4.38 (d, J=6.0 Hz, 2H), 4.10 (m, 1H), 2.9 (s, 3H), 2.7 (s, 3H); ESIMS m/z 497 ([M−H]−); IR (thin film) 3350, 1705, 1114, 808 cm−1.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][CH:22]=1)[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si]([N:35]=[C:36]=[N:37][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[O:1]([C:8]1[CH:9]=[C:10]2[C:20](=[CH:21][CH:22]=1)[O:19][C:13]1([CH2:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:12]/[C:11]/2=[N:37]\[C:36]#[N:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Oc3ccccc3)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#C/N=C1\CC2(CCCOC2)Oc2ccc(Oc3ccccc3)cc21
Temperature: 0 °C
Yield: 25.8 %

Procedure:
To a solution of 6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (500 mg, 1.27 mmol) and triethylamine (227 mg, 0.73 mmol) in dried CH2Cl2 (10 mL) was added TiCl4 (1 M solution in DCM, 1.47 mmol) dropwise within 15 minutes. The mixture was stirred forl h after addition. To this mixture was added bis-trimethylsilylcarbodiimide (300 mg, 1.16 mmol) dropwise. The resulting mixture was stirred for 18 h after addition. The reaction mixture was poured into ice-water (50 g) and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (E)-N-(6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyan amide (100 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][N:22]=[C:23]=[O:24]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][NH:22][C:23]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:12])[N:6]=[CH:7]2)=[O:24]
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Cl)cc3Cl)cccc2cn1
Temperature: 25 °C

Procedure:
5-Amino-3-methylisoquinoline (390 mg, 2.47 mmol) and the product from Example 195A (0.36 mL, 2.47 mmol) were heated in toluene (10 mL) at 80° for 2.5 hours. Upon cooling to room temperature, a precipitate formed, which was collected by filtration, washed with toluene, and air-dried. Remaining impurities were removed by slurrying the solid in 9:1 CH2Cl2:CH3OH and then filtering the mixture to provide the title compound. The corresponding hydrochloride salt was formed by treatment of the free base with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.78 (s, 1H), 8.21 (dd, 1H, J=7.4 Hz, 1.0 Hz), 7.77 (s, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.64 (m, 1H), 7.44-7.52 (m, 3H), 7.14 (t, 1H, J=6.1 Hz), 4.38 (d, 2H, J=6.0 Hz), 2.65 (s, 3H); MS (ESI+) m/z 360/362 (M+H, 35Cl/37Cl).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]([C:6]1[C:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[N:8][S:9][C:10]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17](OC)=[O:18])=[O:13])=[O:5].CO>O1CCCC1>[OH:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]([NH:11][C:10]1[S:9][N:8]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:6]=1[C:4]([NH2:3])=[O:5])=[O:13]
Reactant: COC(=O)CCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCO
Temperature: 25 °C
Yield: 80.9 %

Procedure:
Sodium borohydride (24.0 g 0.636 mol) was added to a solution of methyl 3-[({[4-(aminocarbonyl)-3-(4-nitrophenyl)isothiazol-5-yl]amino}carbonyl)amino]propanoate (25.0 g, 0.0636 mol) in tetrahydrofuran (1200 mL). The resulting suspension was heated to reflux. Methanol (200 mL) was added drop wise over 1 hr. and the reaction was refluxed for 1 hr. The reaction mixture was cooled to ambient temperature and solvent concentrated in vacuo. The residue taken in EtOAc (600 mL) and washed with water, 2 N HCl and brine then dried (sodium sulfate), filtered, solvent concentrated in vacuo to give the title compound as a yellow solid (18.8 g, 80%).
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl[CH:30]([S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:31](=O)[CH3:32]>>[CH:26]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:32]=[C:31]([CH2:30][S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[N:22]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:27][CH2:28]1
Reactant: CC(=O)C(Cl)S(=O)(=O)C(C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(CS(=O)(=O)C(C)C)cs3)nc21

Procedure:
Prepared from N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B) and 1-chloro-1-(isopropylsulfonyl)propan-2-one (example 5a) using same procedure as reported for 2.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=[N:41][O:42]C)[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:44]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:31]([I:44])=[C:32]([CH:33]2[CH2:36][CH:35]([CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:34]2)[O:42][N:41]=1)[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=C(C#CC1CC(CC(C)C)C1)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OC(C)(C)C
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(C)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2I)C1
Reaction time: 3 h
Yield: 60.1 %

Procedure:
tert-Butyl 3-[2-(tert-butyldiphenylsilanyloxy)ethyl]-6-(3-isobutylcyclobutyl)-4-methoxyimino-5-hexynoate (53.6 g) and acetonitrile (320 mL) were mixed. To the mixture was added iodine (49.6 g) at ice temperature and the reaction mixture was stirred for 3 hr. After pouring the mixture into the solution of aqueous 20 w/v % sodium thiosulfate (380 mL) at ice temperature, the mixture was extracted with chloroform (1 L) and dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. After an addition of silica gel (80 g) and ethyl acetate/hexane=1/20 (600 mL) to the residue, the mixture was stirred at RT for 1 hr. The silica gel was filtered off and the filtrate was concentrated in vacuo. The residue was purified twice by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/60→1/50→1/45) to give the title compound (38.2 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.Cl.[CH2:12]([NH2:14])[CH3:13].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:14][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cccc(Br)n1
Yield: 92.2 %

Procedure:
By the reaction in the same manner as in Example 55-(i) using 6-bromopicolinic acid (3.06 g), ethylamine hydrochloride (2.49 g), triethylamine (6 ml), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.61 g) and 1-hydroxybenzotriazole (2.66 g), the title compound (3.20 g) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]1[C:14]2[C:10](=[N:11][O:12][N:13]=2)[CH:9]=[CH:8][CH:7]=1.[Na].[CH:20]([O:23][C:24](=[O:29])[CH2:25][C:26]([CH3:28])=[O:27])([CH3:22])[CH3:21].Cl>O1CCOCC1.CCOCC>[CH3:1][O:2][C:3](=[O:18])[CH:4]([N+:15]([O-:17])=[O:16])[CH:5]([C:6]1[C:14]2[C:10](=[N:11][O:12][N:13]=2)[CH:9]=[CH:8][CH:7]=1)[CH:25]([C:24]([O:23][CH:20]([CH3:22])[CH3:21])=[O:29])[C:26](=[O:27])[CH3:28]
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: COC(=O)C(=Cc1cccc2nonc12)[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C(C(c1cccc2nonc12)C(C(C)=O)C(=O)OC(C)C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.7 g of 3-(2,1,3-benzoxadiazol-4-yl)-2-nitro-propenoic acid methylester (IV,R1 =CH3) in 120 ml of dioxane is added to 4.2 g of the dry sodium salt of acetoacetic acid isopropylester. The suspension is stirred for 3 hours at room temperature. The mixture is poured into 120 ml of ice water and shaken with ether. The aqueous phase is acidified with hydrochloric acid whilst cooling, and extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulphate and the solvent is evaporated under vacuum, after which the substance is obtained.
Reaction SMILES: B([C:4]1[C:12]2[S:11][C:10]([NH:13][C:14](=[O:18])[NH:15][CH2:16][CH3:17])=[N:9][C:8]=2[CH:7]=[C:6]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][C:28]([CH2:34][CH3:35])([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)=[N:23][CH:24]=2)[CH:5]=1)(O)O.C(N(CC)CC)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:34]([C:28]1([C:31]([OH:33])=[O:32])[CH2:29][CH2:30][N:25]([C:22]2[N:21]=[CH:20][C:19]([C:6]3[CH:5]=[C:4]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[C:12]4[S:11][C:10]([NH:13][C:14](=[O:18])[NH:15][CH2:16][CH3:17])=[N:9][C:8]=4[CH:7]=3)=[CH:24][N:23]=2)[CH2:26][CH2:27]1)[CH3:35]
Reactant: C1COCCN1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(B(O)O)c2s1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(N3CCOCC3)c2s1
Temperature: 25 °C

Procedure:
1-[5-[7-borono-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-ethyl-piperidine-4-carboxylic acid (100 mg) was placed in DCM 5 ml and copper acetate 47 mg, triethylamine 122 mg, 4A molecular sieves (powdered) and morpholine 17 mg were added and the mixture stirred at rt over the weekend. LCMS showed that some desired product had formed and a close running 7-H impurity. The mixture was filtered and the solvent removed in vacuo to give a dark gum which was purified by preparative HPLC using a phenyl hexyl column eluting with 65-75% ACN to give Compound 114 as an off white solid (8 mg). 1H NMR (CDCl3) δ 8.52 (s, 2H), 7.38 (s, 1H), 6.84 (s, 1H), 4.50-4.42 (m, 2H), 3.89-3.85 (m, 4H), 3.35-3.29 (m, 4H), 3.21-3.17 (m, 4H), 2.22-2.14 (m, 2H), 1.61-1.54 (m, 2H), 1.45-1.35 (m, 2H), 1.19 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.5 Hz, 3H). MS: 540.13 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: CCOc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Product: CCOc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 77 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-ethoxy-N-phenyl-benzamide from Example 10 (0.335 g, 1.30 mmol) and 3,5-dichlorophenyl isothiocyanate (0.266 g, 1.30 mmol) to give the product (0.4609 g); m.p. 201-202° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CNCCNC.[I-:18].[Na+].O>O1CCOCC1>[I:18][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: [I-]
Reactant: Brc1cnc2ccccc2c1
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Ic1cnc2ccccc2c1
Reaction time: 18 h
Yield: 87.2 %

Procedure:
3-Bromoquinoline (64.00 g, 308 mmol), N,N′-dimethylethylenediamine (13.5 ml, 127 mmol), cuprous iodide (12.00 g, 63.0 mmol) and sodium iodide (112 g, 747 mmol) in dioxane (300 ml) was placed into a preheated oil bath at 100° C. After stirring for 18 h, the heterogeneous mixture was diluted water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with methylene chloride as the eluant to afford 68.47 g (87% yield) of 3-iodoquinoline as a yellow solid. Method [8] retention time 6.47 min by HPLC (M+=256).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:13]O)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](Br)(Br)(Br)[Br:35]>C(Cl)Cl>[Br:35][CH2:34][CH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]([Cl:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(Cl)cc1CCBr
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a solution of 169 mg (0.72 mmol) of the product of Step B in 3 mL of CH2Cl2 at 0° C. was added 283 mg (1.08 mmol, 1.5 eq) of triphenylphosphine and 360 mg (1.08 mmol, 1.5 eq) of carbon tetrabromide. The mixture was stirred for 16 hours and quenched with methanol. The reaction was concentrated in vacuo and the resultant oil was flash chromatographed with 2:1 hexane/ethyl acetate to afford the titled compound (107 mg, 50%) as a brownish orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12](Cl)=[C:11]([OH:17])[C:10]=2[N+:18]([O-:20])=[O:19])=[O:5])[CH3:2].[CH2:22](OC(C1C(=O)OC2C(C=1)=CC(CC)=C(O)C=2)=O)[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH2:22][CH3:23])=[C:11]([OH:17])[C:10]=2[N+:18]([O-:20])=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(CC)c(O)cc2oc1=O
Reactant: CCOC(=O)c1cc2cc(Cl)c(O)c([N+](=O)[O-])c2oc1=O
Product: CCOC(=O)c1cc2cc(CC)c(O)c([N+](=O)[O-])c2oc1=O

Procedure:
Compound 233 was prepared following the preparation of compound 241, except that 3-ethoxycarbonyl-6-ethyl-7-hydroxy-coumarin was nitrated to give the title compound 233.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4[CH:23]=[CH:24][S:25][C:19]=4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:29]([N:18]1[C:19]2[S:25][CH:24]=[CH:23][C:20]=2[C:21](=[O:22])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:9][CH2:10]2)[C:17]1=[O:26])(=[O:31])[CH3:30]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3sccc3c2=O)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2ccsc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
A mixture of 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[2,3-d]pyrimidine-2,4-dione of Example 2 (1.7 g, 4.2 mmol), acetyl chloride (0.33 ml, 4.6 mmol) and triethylamine (1.8 ml, 12.6 mmol) in methylene chloride (40 ml) was stirred at room temperature for two days. The resultant solution was washed with H2O (2×50 ml), and then dried over magnesium sulfate. The solvent was evaporated in vacuo, and the resultant residue was purified by flash chromatography on silica gel 60 (80 g) using 2% methanol in methylene chloride as the eluant to give the named compound (1.3 g, 69% yield) as a colorless solid, mp 137°-141° C. IR(KBr): 1630, 1700 and 1775 cm-1 ; MS (DCI), m/z 444 (MH+); 1H NMR (CDCl3): δ 1.76-1.85 (m, 4H), 2.19-2.25 (m, 2H), 2.70 (t, J=7 Hz, 2H), 2.86 (s, 3H), 3.12-3.25 (m, 3H), 4.22 (t, J=7 Hz, 2H), 7.07 (d, J=6 Hz, 1H), 7.13 (t, J=8 Hz, 2H), 7.40 (d, J=6 Hz, 1H), 7.94-7.97 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCCOCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)cc(OCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of methyl 3-hydroxy-5-methoxybenzoate (Chakraporty, T. K. and Reddy, G. V. J. Org. Chem., 57, 1992, 5462) (3.3 g, 18.1 mmol) in dry DMF (30 mL) was added K2CO3 (6.3 g, 45.3 mmol) at room temperature. The reaction was stirred at room temperature for 10 minutes then ((2-bromoethoxy)methyl)benzene (3.4 mL, 21.7 mmol) was added and the mixture stirred at 160° C. for 2 hrs. The reaction was cooled down to room temperature and diluted with EtOAc, washed with water and brine, and dried over MgSO4, filtered and concentrated to give the crude product (90%) which was used in the next step without further purification.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([OH:16])=[O:15])[CH:8]=[CH:7]2.[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>O>[C:17]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([OH:16])=[O:15])[CH:8]=[CH:7]2)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
In a 100 ml-reaction vessel, 16.7 g (2.53×10-1M) of potassium hydroxide and 85 ml of water were placed, followed by cooling to 0° C. To the mixture, 20.0 g (1.06×10-1M) of 6-hydroxy-2-naphthoic acid was added and dissolved therein. To the solution, 10.9 g (1.07×10-1M) of acetic anhydride was added dropwise in 40 minutes at 0° C. followed by stirring for 2 hours. After stirring, the reaction mixture was acidified with 6N-hydrochloric acid to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and drying to obtain 18.3 g of 6-acetoxy-2-naphthoic acid (Yield: 74.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.[N:15]#[C:16][NH2:17].[N+:18]([O-:21])([OH:20])=[O:19]>C(O)C>[N+:18]([O-:21])([OH:20])=[O:19].[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:16]([NH2:17])=[NH:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: N#CN
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reaction time: 24 h
Yield: 36.1 %

Procedure:
A suspension of 3-fluoro-4-(4-methyl-imidazol-1-yl)-phenylamine (500 mg, 2.62 mmol), of 50% aqueous cyanamide solution (249 mg, 2.96 mmol) and of 65% aqueous nitric acid (253 mg, 2.62 mmol) in ethanol (2.6 mL) was heated for 5 days to reflux under an atmosphere of nitrogen. Twice the same amounts of cyanamide and nitric acid were added to the reaction mixture after 2 and 4 days, respectively. The mixture was cooled and let stand at 20° C. for 1 d. The precipitated solid was filtered off (Caution: the filtrate may contain the ethyl ester of nitric acid) and washed with ethanol to yield the title compound (280 mg, 36%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:12][CH:13]([CH2:15]O)O>>[CH2:9]([C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:15][CH:13]=[CH:12]2)[CH3:10]
Reactant: OCC(O)CO
Reactant: CCc1ccc(N)c(Br)c1
Product: CCc1cc(Br)c2ncccc2c1

Procedure:
2-bromo-4-ethylaniline and glycerol can be combined to form 6-ethyl-8-bromoquinoline,
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[C:3]([OH:9])([C:2]([F:10])([F:11])[F:1])[CH:12]=[CH2:13])[CH3:8]
Reactant: C=C[Mg]Br
Reactant: CCOC(=O)C(=O)C(F)(F)F
Solvent: C1CCOC1
Product: C=CC(O)(C(=O)OCC)C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of ethyl 3,3,3-trifluoropyruvate (14.2 g) in THF (200 mL) at −78° C. was added vinyl magnesium bromide (84 mL of 1M in THF) dropwise via addition funnel. The resulting mixture was then warmed to ambient temperature over 2 h. The reaction was quenched by pouring the mixture over ice. To the resulting mixture was then added 2 N HCl, the mixture was extracted with EtOAc, and dried over Na2SO4. After concentration, the resulting crude material was filtered through a plug of silica gel and rinsed with 50% Et2O/hexanes. The resulting mixture was concentrated to yield the title compound as a golden oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:22]#[CH:23].C1(C)C=CC(S(O)(=O)=[O:31])=CC=1>C(#N)C>[C:22]([C:3]1[C:4]([C:20]#[N:21])=[N:5][N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:17])([F:16])[F:18])=[CH:9][C:8]=2[Cl:19])[C:2]=1[NH2:1])(=[O:31])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N
Solvent: CC#N
Product: CC(=O)c1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-4-ethynylpyrazole (0.318 g) in acetonitrile (10 ml) was added p-toluenesulphonic acid (0.455 g) and the mixture was stirred at room temperature for 1.5 hours and then evaporated to dryness. The residue was taken up in ether and washed with saturated aqueous sodium hydrogen carbonate solution (5 ml). The aqueous layer was twice extracted with ether. The combined organic layers were dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with hexane:ether (1:1). Combination and evaporation of suitable fractions gave a yellow solid which was further purified by reverse phase high performance chromatography on C18 silica eluted with acetonitrile:water:methanol (60:30:10). Appropriate fractions were combined and evaporated to give, after recrystallisation from propan-2-ol, the title compound as a white solid, m.p. 192.3-192.7° C.