Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH:5]=O.[C:22]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH2:22])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21]
Reactant: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 100 °C
Yield: 79.5 %

Procedure:
To a stirred solution of 3-chloro-4-((1,3-dioxoisoindolin-2-yl)methyl)benzaldehyde (2.8 g, 8.2 mmol) in 1,4-dioxane (30 mL) were added K2CO3 (1.68 g, 12.24 mmol) and methyl triphenyl phosphonium bromide (4.37 g, 12.24 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 20% EtOAc in n-Hexane) to afford the title compound as a white solid (1.94 g, 70%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 2H), 7.70 (m, 2H), 7.41 (m, 1H), 7.21 (m, 2H), 6.71 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.23 (d, J=10.8 Hz, 1H), 4.92 (s, 2H); ESIMS m/z 298.10 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[C:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Into a solution of 14.6 g (52.6 mmol) of tert-butyl 4-[3-(amino)phenyl]-1-piperidinecarboxylate and 14.7 mL (105 mmol) of triethylamine in 120 mL THF at 0° C. was slowly added 4.5 mL (63.1 mmol) of acetyl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 16.6 g (52.1 mmol, 99%) of desired product: 1H NMR (400 MHz, CDCl3) δ 7.41–7.20 (m, 3H), 6.94 (d, 1H, J=7.5 Hz), 4.21 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 2.16 (s, 3H), 1.78 (m, 2H), 1.56 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10].[OH-:18].[Na+]>C(O)C>[OH:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10]
Reactant: [OH-]
Reactant: O=C(CCCCCCCBr)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCO
Product: O=C(CCCCCCCO)c1ccc(Cl)cc1

Procedure:
To 8-bromo-1-(4-chlorophenyl)octan-1-one (4.0 g) in ethanol (170 ml) was added 3% aqueous sodium hydroxide (70 ml). The mixture was heated at reflux for 3 h, cooled and evaporated to one third volume. Water (50 ml) and dichloromethane (100 ml) were added. The organic layer was separated and the aqueous layer was re-extracted with dichloromethane (2×50 ml). The combined extracts were washed with water (30 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was crystallised from 40-60° C. petroleum ether to give 8-hydroxy-1-(4-chlorophenyl)octan-1-one (1.0 g). 1H-NMR (CDCl3) δ 1.25-1.9 (10H, m), 2.94 (2H, t), 3.64 (2H, t), 7.43 (2H, m) and 7.89 (2H, m). (EI) Found M+=254. C14H19ClO2 requires 254.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>O1CCCC1>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline -2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.225 ml (1.63 mmol) dry triethylamine and 0.2 ml (1.58 mmol) phenyl chloroformate. The mixture was stirred at 25° C. for 30 min., and then filtered and evaporated in vacuo. The residue was stirred with ether to give 0.48 g (83%) of 7-cyano-1-phenoxycarbonyloxy-6-trifluoromethylquinoxaline-2,3-(1H,4H)-dione. M.p. 190° C. decomp. 1H-NMR (DMSO-d6): 8.43 (1H,s), 7.63 (1H, s), 7.3 (5H, broad s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Cl:30][C:31]1[N:36]=[C:35]2[S:37][C:38]([C:40](Cl)=[O:41])=[CH:39][C:34]2=[N:33][CH:32]=1>C(Cl)Cl>[Cl:30][C:31]1[N:36]=[C:35]2[S:37][C:38]([C:40]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=4)[CH:5]=[CH:6][C:7]=3[CH3:8])=[O:41])=[CH:39][C:34]2=[N:33][CH:32]=1
Reactant: O=C(Cl)c1cc2ncc(Cl)nc2s1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (2.56 mmol, 750 mg) and triethylamine (12.78 mmol, 1.782 mL) in CH2Cl21 ml at 0° C. was added 3-chlorothieno[2,3-b]pyrazine-6-carbonyl chloride 94 in 1 mL CH2Cl2 and stirred at rt for 1 h. The reaction mixture was quenched with water, extracted with CH2Cl2 (2×). The organic layer was dried and concentrated under reduced pressure. Purified with column chromatography (10-20% ethyl acetate in CH2Cl2) gave 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (1.04 g, 83%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.26 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.64 (dd, J=8.2 Hz and 2.0 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.57 (s, 1H), 8.98 (s, 1H), 10.37 (s, 1H), 10.56 (s, 1H). (m/z)=490 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2cccs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2cccs2)=NC1c1ccc(F)cc1Cl
Yield: 42.5 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.7 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.33 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][O:38][CH3:39])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][O:38][CH3:39])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COCCNS(=O)(=O)c1ccc(Br)cc1
Product: COCCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-bromo-N-(2-methoxy-ethyl)-benzenesulfonamide (example B.28) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (400 mg, 72%). MS (ISP) 551.3 [(M+H)+]; mp 184-186° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[C:20]1([C:26]2[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:26]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][C:29]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:30][CH:31]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccc(-c2ccccc2)cc1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(-c4ccccc4)cc3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-phenyl-thiophenol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>CNC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CNC
Product: COc1cc(C#C[Si](C)(C)C)ccc1F

Procedure:
4-Bromo-2-methoxyfluorobenzene (obtainable from 5-bromo-2-fluorophenol by reaction with dimethyl sulfate under basic conditions) is reacted with trimethylsilylacetylene with catalysis by bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide in dimethylamine at 20° C. to give 1-(4-fluoro-3-methoxyphenyl)-2-(trimethylsilyl)ethyne; after filtration chromatography (SiO2/dichloromethane), the crude product is stirred in methanol for 1 hour at 20° C. with addition of 1 N aqueous NaOH solution. Removal of the solvent by distillation and chromatography (SiO2/dichloromethane) gives 4-ethynyl-3-methoxyfluorobenzene.
Reaction SMILES: [F:1][C:2]([F:12])([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4].[CH2:13]=[O:14]>CC(C)=O>[F:12][C:2]([F:1])([C:7]1[N:11]=[CH:10][N:9]([CH2:13][OH:14])[N:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(F)c1nc[nH]n1
Reactant: C=O
Solvent: CC(C)=O
Product: OCn1cnc(C(F)(F)C(F)(F)F)n1
Temperature: 150 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
The mixture of 1.45 g of 3-(pentafluoroethyl)-1H-1,2,4-triazole and 0.46 g of paraformaldehyde was stirred at 150° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added. The mixture was filtered. The filtrate was concentrated. Hexane was added to the residue, as a result, a crystal was formed. The crystal was collected to obtain 1.52 g of 3-(pentafluoroethyl)-1H-1,2,4-triazole 1-ylmethanol.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][NH:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[C:30]12([N:40]=[C:41]=[O:42])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>C(Cl)Cl>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[CH:6]([O:15][CH:16]1[CH2:19][N:18]([C:41]([NH:40][C:30]23[CH2:39][CH:34]4[CH2:33][CH:32]([CH2:38][CH:36]([CH2:35]4)[CH2:37]2)[CH2:31]3)=[O:42])[CH2:17]1)[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: CSc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CSc1ccc(C(OC2CN(C(=O)NC34CC5CC(CC(C5)C3)C4)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(methylthio)benzhydryloxy]azetidine hydrochloride (118) (100 mg, 0.26 mmol) in anhydrous DCM (5 mL) was added MP-carbonate (3.10 mmol/g; 250 mg, 0.84 mmol) and 1-adamantyl isocyanate (47 mg, 0.26 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (18 mL), then evaporated to afford the desired product as a white, crystalline solid (70 mg, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[N:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(C=O)c1
Reactant: Nc1ccccc1
Solvent: CCOCC
Product: COc1cccc(C=Nc2ccccc2)c1

Procedure:
A solution of 85.4 gm. of 3-methoxybenzaldhyde, 58.7 gm. of aniline, and 185 gm. of 3 A molecular sieves in 700 ml. of anhydrous ether was refluxed for 16 hours. The ether was dried (Na2SO4), filtered, and concentrated in vacuo to an oil which upon distillation provided 93.2 gm of oil. b.p. 141°-143°/0.5 Torr.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>C1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:5]([O:4][CH2:2][CH3:3])=[O:11])=[S:28])=[CH:22][C:21]=1[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: CC(C)OC(=O)c1cc(N=C=S)ccc1Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCN1C(=S)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
1.8 g (0.01 mol) of proline ethyl ester hydrochloride and 1.0 g of triethylamine were added dropwise to 30 ml of benzene and 2.6 g (0.01 mol) of 4-chloro-3-isopropoxycarbonylphenyl isothiocyanate were added thereto. The mixture was stirred at room temperature for an hour, washed with water, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by means of silica gel column chromatography to give 2.5 g (yield 63%) of the desired product as a yellow glassy substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](O)=[N:6][CH:7]=1.P(Br)(Br)[Br:11]>>[Br:11][C:5]1[C:4]([F:9])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: BrP(Br)Br
Reactant: Oc1ncc(Br)cc1F
Product: Fc1cc(Br)cnc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
97.6 g (508.0 mmol) of 5-bromo-3-fluoro-2-hydroxypyridine are stirred at 150° C. for 6 hours in 500 ml of phosphorus tribromide. The mixture is subsequently poured into ice water, stirred for 2 hours and extracted three times with dichloromethane, and the organic phase is washed with sodium hydrogencarbonate solution until neutral, dried over sodium sulfate and evaporated to dryness. Chromatographic purification (silica gel/dichloromethane) gives 76.53 g of 2,5-dibromo-3-fluoropyridine. ##STR22##
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[N:7]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[I:11][C:8]1[N:6]2[N:7]=[C:2]([NH:15][CH2:14][CH2:12][OH:13])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: NCCO
Reactant: Clc1ccc2ncc(I)n2n1
Product: OCCNc1ccc2ncc(I)n2n1
Yield: 36.8 %

Procedure:
562 mg (2.0 mmol) of 6-chloro-3-iodoimidazo[1,2-b]pyridazine and 2.35 ml (39.2 mmol) of ethanolamine were stirred at 90° C. for 16 h. After cooling, the mixture was concentrated. The resulting residue was purified by chromatography (DCM/EtOH 9:1). 224 mg of the product were obtained.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[S:18]1[CH2:22][CH2:21][N:20]=[CH:19]1>>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([CH2:2][CH:19]3[N:20]=[CH:21][CH2:22][S:18]3)[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Reactant: C1=NCCS1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CC1N=CCS1)C2
Temperature: 150 °C
Reaction time: 4 h
Yield: 38.4 %

Procedure:
A mixture of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (4.802 g) and thiazoline (5.815 g) was stirred at 150° C. in the stream of argon gas for 4 hours. The solvent was distilled off under reduced pressure. Chloroform was added to the residue, and extracted with 1N-HCl. After the extract was washed with chloroform, 1N-NaOH was added to bring the pH basic. Extraction was performed with chloroform, followed by washing with water. After dried, the residue was crystallized from methanol to obtain 1.885 g of a free base of the title compound as pale yellow powder (mp.: 196°-199° C.).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[CH:8][C:9]=2[F:10])[CH2:3][CH2:2]1.Cl[C:21]1[CH:22]=[C:23]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[N:24]=[N:25][CH:26]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:21]3[CH:22]=[C:23]([CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH3:33])[N:24]=[N:25][CH:26]=3)[CH:7]=[CH:8][C:9]=2[F:10])[CH2:2][CH2:3]1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2ccc(F)c(C3CC3)c2)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2ccc(F)c(C3CC3)c2)cnn1

Procedure:
The title compound, MS: m/e=309.4 (M+H30), was prepared from 2-(3-cyclopropyl-4-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4]/[C:5](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:33])[C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:6]([O:8]C)=[O:7].C(O)(=O)C>O1CCCC1>[CH3:3][O:4]/[C:5](=[CH:10]\[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:33])[C:24]([NH:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:25])[CH:18]=2)=[CH:15][CH:16]=1)/[C:6]([OH:8])=[O:7]
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Nc3ccccc3)c2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CO/C(=C\c1ccc(-c2cccc(N(C)C(=O)Nc3ccccc3)c2)cc1)C(=O)O
Temperature: 68 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
2.5 mL (2.5 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 0.7 g (1.7 mmol) of methyl (Z)-2-methoxy-3-[3′-(1-methyl-3-phenylureido)biphenyl-4-yl]acrylate in 12 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 4 hours. The reaction medium is acidified with 2.6 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is filtered from hot ethanol. 410 mg (60%) of (Z)-2-methoxy-3-[3′-(1-methyl-3-phenylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white solid with a melting point of 223° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11]1>C1COCC1>[CH2:11]1[O:12][C:13]2([CH2:18][CH2:17][C:16]([OH:19])([C:3]3[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=3)[CH2:15][CH2:14]2)[O:20][CH2:10]1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Yield: 83.6 %

Procedure:
To a 500 ml round-bottom flask equipped with a mechanical stirrer, condenser and addition funnel were added magnesium turnings (3.50 g, 140 mmol) and enough THF to cover the Mg. A solution of 1-bromo-4-fluorobenzene (12.45 g, 70.43 mmol) in THF (90 ml) was added dropwise at such a rate that the reaction maintained a gentle reflux following reaction-initiation (the initiation may be accomplished by warming the flask). After the mixture was refluxed for an additional 2.5 h, a solution of 1,4-cylohexanedione monoethylene ketal (10.00 g, 64.03 mmol) in THF (75 ml) was added dropwise. The mixture was kept at refluxing for an additional 2 h before being quenched with saturated ammonium chloride solution (7 ml). After removal of the magnesium salts by filtration, the filtrate was concentrated to dryness. The residue was dissolved in CHCl3 and washed with water and brine. The organic layer was separated, dried over MgSO3, and concentrated. The residue was purified by flash chromatography (30% ether in petroleum ether) to afford the desired alcohol (13.50 g, 87%) as a colorless solid. mp 133-134° C. 1H NMR (500 MHz, CDCl3) δ1.69 (d, J=11.7 Hz, 2H), 1.79 (d, J=12.2 Hz, 2H), 2.05-2.18 (m, 4H), (m, 4H), 7.02 (t, J=8.3, 2H), 7.47-7.50 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:38](Cl)(=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(CCCC)nn(-c3ccccc3C(F)(F)F)c2=O)cc1
Yield: 37 %

Procedure:
By the procedure of Example 13, Step C, 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C) was reacted with octanoyl chloride. Flash chromatography of the crude product twice on silica gel (gradient elution with 0.3-3% and 0.5-2% MeOH in CH2Cl2) gave a 37% yield of the title compound as a gum, homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 657 (M+1)+. 400 MHz NMR CDCl3) δ0.81 (t, 3H), 0.89 (t, 3H), 1.1-1.3 (m, 8H), 1.39 (m, 4H), 1.66 (m, 2H), 1.88 (t, 2H), 2.55 (t, 2H), 4.92 (s, 2H), 7.26, (d, 2H), 7.35 (d, 2H), 7.5-7.7 (m, 6H), 7.78 (d, 1H), 8.20 (br s, 1H), 8.28 (d, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:32]([CH2:34][O:35]C(=O)C)=[O:33]>>[OH:35][CH2:34][C:32]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:33]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Product: O=C(CO)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.