Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])([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.[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1](=[N:14][C:15]1[CH:22]=[C:21]([CH2:23][Br:24])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1N=C(c1ccccc1)c1ccccc1

Procedure:
To a solution of 2-(benzhydrylidene-amino)-4-methyl-benzonitrile (11.2 g, 37.8 mmol) in 500 mL of CCl4 is added N-bromosuccinimide (7.06 g, 39.7 mmol), and benzoyl peroxide (0.92 g, 3.8 mmol). The solution is heated to reflux for 16 hours. After this time, the solution is filtered and the organic solution is concentrated under vacuum. The residue is purified by column chromatography eluting with a gradient of 20% t-butyl ether/hexanes to 25% t-butyl ether/hexanes. The product is obtained as an oil containing a mixture of the desired monobromide, dibromide and unreacted starting material. The mixture is assayed by proton NMR and is found to have a purity between 60-75%. 1H NMR (CDCl3, 300 MHz) δ7.82 (m, 2H), 7.42 (m, 9H), 6.92 (d, 1H), 6.81 (s, 1H), 4.29 (s, 2H).
Reaction SMILES: CC(OC1CCCCO1)(C)C#C[C:5](=[O:11])[C:6]([O:8]CC)=[O:7].[C:20]1([CH:26]2[CH2:30][S:29][C:28](=[S:31])[S:27]2)[CH:25]=CC=C[CH:21]=1.C(Cl)Cl>C1(C)C(C)=CC=CC=1>[CH3:25][C:20]1([CH3:21])[C:26]2[S:27][C:28](=[S:31])[S:29][C:30]=2[C:5](=[O:11])[C:6](=[O:7])[O:8]1
Reactant: CCOC(=O)C(=O)C#CC(C)(C)OC1CCCCO1
Reactant: S=C1SCC(c2ccccc2)S1
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CC1(C)OC(=O)C(=O)c2sc(=S)sc21
Temperature: 130 °C

Procedure:
Ethyl 5-methyl-2-oxo-5-(tetrahydro-2H-pyran-2-yloxy)hex-3-ynoate (2) (1.0 g, 3.7 mmol) and 4-phenyl-1,3-dithiolane-thione (2.0 g, 9.3 mmol) were dissolved in xylene (15 mL). The deep yellow solution was heated to 130° C. for ca. 4 h under Ar (the reaction was followed by TLC, eluent: CH2Cl2). The solvent was removed under reduced pressure and purification of the residue by chromatography (silica gel, CH2Cl2) provided 4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-6,7-dione (4) as a yellow solid. Yield: 0.44 g (48%). 1H-NMR spectrum in CDCl3 (ppm): 1.88 (s, 6H). 13C-NMR spectrum in CDCl3 (ppm): 205.3, 167.7, 162.6, 157.8, 153.6, 83.2, 31.9. Selected IR (neat, cm−1): 1747, 1681, 1557, 1460. MS-ESI calculated for C7H8O4S2Na [M+Na]+ 268.96; found 268.79.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([NH:17][CH3:18])=[O:16])[N:14]=2)[N:11]=1.[CH3:22][N:23]1[C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]([CH3:31])=[N:24]1.O>CN(C)C(=O)C>[CH3:22][N:23]1[C:27]([C:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([NH:17][CH3:18])=[O:16])[N:14]=3)[N:11]=2)=[O:29])=[CH:26][C:25]([CH3:31])=[N:24]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: CNC(=O)c1cn2nc(Oc3cccc(N)c3)ccc2n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNC(=O)c1cn2nc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of 6-(3-aminophenoxy)-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (250 mg, 0.88 mmol) in N,N-dimethylacetamide (2.5 mL) was added 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (253 mg, 1.59 mmol). After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained residue was washed with water, acetonitrile and diethyl ether to give the title compound (262 mg, 73%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23](OC)=[O:24])(=[O:16])=[O:15])=[O:12])[N:4]=1.C[Al](C)C.C.[NH2:32][C:33]1[N:37]=[CH:36][NH:35][N:34]=1.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([NH:32][C:33]2[N:37]=[CH:36][NH:35][N:34]=2)=[O:24])(=[O:15])=[O:16])=[O:12])[N:4]=1
Reactant: Nc1nc[nH]n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Agent: C
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)Nc2nc[nH]n2)n1

Procedure:
To a slurry of 4.0 g of N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide in 100 ml of methylene chloride was added by syringe 10 ml of a 2M solution of trimethylaluminum in toluene (1.44 g of Al(CH3)3). Evolution of methane gas was seen. 3-Amino-1,2,4-triazole (1.7 g) was then added and the mixture was heated at reflux for 18 hours. The reaction mixture was then treated with aqueous hydrochloric acid and the precipitated product was purified by trituration in methylene chloride, 0.63 g, m.p. 176°-179° C. NMR in TFA 2.9 ppm s, CH3 on triazine, 4.4 ppm s, OCH3 on triazine, 7.8-8.0 ppm and 8.2-8.5 ppm M, aromatic.
Reaction SMILES: O=[C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:40][C:39]([C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3C(OC(C)(C)C)=O)=[N:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][C:16]([C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3C(OC(C)(C)C)=O)=[N:15][CH:14]=2)=[CH:9][CH:8]=1)=O.Cl.Cl.[N:55]1([C:61]2[N:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=2)[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[C:16]1[NH:15][CH:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([C:5]3[N:67]([C:64]4[CH:63]=[CH:62][C:61]([N:55]5[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]5)=[N:66][CH:65]=4)[C:2]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[N:40]=[C:39]([C@@H:41]6[CH2:45][CH2:44][CH2:43][NH:42]6)[NH:38][CH:37]=5)=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)[N:17]=1
Reactant: Nc1ccc(N2CCCCC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(C(=O)CCC(=O)c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1cc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5)n4)cc3)n2-c2ccc(N3CCCCC3)nc2)ccc1-c1c[nH]c([C@@H]2CCCN2)n1
Temperature: 110 °C
Reaction time: 3 h
Yield: 170.4 %

Procedure:
To a solution of the product from Example 138B (0.20 g, 0.28 mmol) and the product from Example 144C (0.11 g, 0.42 mmol) in toluene (2.8 mL) was added TFA (22 μL, 0.28 mmol). The mixture was stirred at 110° C. for 3 hours. To the cooled mixture was added TFA (0.5 mL) and the mixture was stirred for 1 h at rt. The solvent was then removed under reduced pressure and triturated with diethylether and dried to provide 0.31 g of the desired compound as a TFA salt. 1HNMR (DMSO-d6; 400 MHz): δ 9.78 (br s, 2H), 7.84 (d, J=2.71 Hz, 1H), 7.75 (s, 2H), 7.67 (AA′XX′, J=8.34 Hz, 4H), 7.35 (dd, J=9.11, 2.71 Hz, 1H), 7.18 (AA′XX′, J=8.46 Hz, 4H), 6.79 (d, J=9.11 Hz, 1H), 6.53 (s, 2H), 4.79 (app t, J=7.81 Hz, 2H), 3.4-3.2 (m, 4H), 2.44-2.36 (m, 2H), 2.25-1.98 (m, 6H), 1.65-1.45 (m, 6H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)(O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.ClCCCl>C(O)CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1(c2cccc(F)c2)CCC(C2CCC3(CC2)OCCO3)CC1
Solvent: ClCCCl
Solvent: OCCO
Product: Fc1cccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)c1
Yield: 75.3 %

Procedure:
A mixture of 174.3 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(3-fluorophenyl)cyclohexanol, 1000 ml of 1,2-dichloroethane, 25 ml of ethylene glycol and 25 g of Amberlyst 15 was boiled under reflux for 22 hrs., the condensate being dried over a dropping funnel filled with 175 g of neutral aluminiumoxide. Then, the reaction mixture was cooled, filtered, washed with water and the organic phase was dried over sodium sulphate. Subsequent chromatography on 1000 g of silica gel with hexane/ethyl acetate (90:1) gave 124.2 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(3-fluorophenyl)-cyclohexene as colorless crystals. M.p. of a sample recrystallized from methylene chloride/hexane: 133.7°-135.3° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13](Br)=[CH:12][N:11]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH:28]1([Zn+])[CH2:30][CH2:29]1>C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:28]2[CH2:30][CH2:29]2)=[CH:12][N:11]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Zn+]C1CC1
Reactant: CCCCc1ccc(-n2cc(Br)c(=O)c(OCc3ccccc3)c2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1ccc(-n2cc(OCc3ccccc3)c(=O)c(C3CC3)c2)cc1
Temperature: 60 °C

Procedure:
3-(Benzyloxy)-5-bromo-1-(4-butylphenyl)pyridin-4(1H)-one (37 mg, 0.09 mmol) was treated with 1,1′-bis(diphenylphosphino)ferrocene dichloro palladium(II) dichloromethane complex (6.6 mg, 0.009 mmol) and cyclopropylzinc bromide (0.54 mL of a 0.5 M solution in THF, 0.27 mmol). The reaction vessel was purged with N2, sealed, and heated at 60° C. for 1 h, after which it was concentrated under a stream of N2 and purified by flash chromatography (4 g SiO2, 0-55% ethyl acetate/hexanes) to provide 3-(benzyloxy)-1-(4-butylphenyl)-5-cyclopropylpyridin-4(1H)-one. LC/MS (M+H)+ 374.
Reaction SMILES: [SH2:1].[C:2]([C:4]1[CH:8]=[N:7][N:6]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[N:5]=1)#[N:3].C(N(CC)CC)C>C(O)C>[C:12]([O:11][C@@H:10]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:21][C@H:9]1[N:6]1[N:5]=[C:4]([C:2](=[S:1])[NH2:3])[CH:8]=[N:7]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ncc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: S
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2ncc(C(N)=S)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 98 %

Procedure:
Hydrogen sulfide was passed through a suspension of 2.0 g of 7 in ethanol (60 ml) to which 3.5 ml of triethylamine had been added. After 2 1/2 hr passage of hydrogen sulfide was ceased and the solvent was removed. The resultant syrup was dissolved in a minimum of chloroform and added to a silica gel column (2 × 38 cm) packed in chloroform. The column was eluted with chloroform (0.25 liter) and chloroform-ethyl acetate (9:1, 0.5 liter); 20 ml fractions were collected. Fractions 19-34 provided 2.6 g (98%) of 9 as a syrup; nmr (DMSO-d6) δ 6.36 (d, 1, J1',2' 2.0 Hz, 1'--H), 8.39 (s, 1,5--H); (CDCl3) δ 6.24 (d, 1, J1'2' 3.0 Hz, 1'--H), 8.32 (s, 1, 5--H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH:15]([CH3:19])[C:16]([OH:18])=O)[C:13](=[O:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]3[CH2:31][CH2:32][C:33](=[O:34])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[CH2:64]([CH2:66][NH2:67])[OH:65]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH:15]([CH3:19])[C:16]([NH:67][CH2:66][CH2:64][OH:65])=[O:18])[C:13](=[O:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[C:11]3[CH2:31][CH2:32][C:33](=[O:34])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C(=O)O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C(=O)NCCO)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)propanoic acid (intermediate 28, 40 mg, 85 μmol) and triethylamine (45 μL, 0.32 mmol) in N,N-dimethylformamide (1.5 mL) is treated with N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (27 mg, 85 μmol) and stirred at room temperature for 15 min Ethanolamine (12 μL, 0.21 mmol) is added and the mixture is stirred at room temperature for 1 h. The mixture is diluted with N,N-dimethylformamide and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 37 mg; ESI mass spectrum [M+H]+=513; Retention time HPLC: 0.81 min (Z018_S04).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:18])[CH2:8][N:9]2[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:18])[CH2:8][N:9]3[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)OC(=O)N1CC(=O)Nc2ccc(Br)cc21
Product: CC(C)OC(=O)N1CC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
The title compound was prepared according to the procedure for Example 5 from isopropyl 7-bromo-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate (6.3 g, 20 mmol), and 3-chlorophenyl boronic acid (3.2 g, 20 mmol). Off-white crystals (3.7 g, 49%): m.p. 174-176° C. 1H-NMR (DMSO-d6) δ 1.27 (d, J=6.4 Hz, 6H), 4.30 (s, 2H), 4.94 (sep, J=6.2 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 7.50 ( m, 4H ), 7.61 (t, J=1.9 Hz, 1H), 7.86 (s, 1H), 10.79 (s, 1H), MS (APCI) m/z 345/347 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCCC1>[C:21]([NH:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 7-amino-1-phenyl-5-trifluoromethylbenzimidazole (300 mg, 1 mmol), benzoylchloride (0.23 ml, 2 mmol) and triethyl amine (0.3 ml, 2 mmol) in tetrahydrofurane (10 ml) was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and hydro chloric acid (4M). The aqueous phase was rendered alkaline with saturated, aqueous sodium carbonate and extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure and the resultant gum was triturated with a mixture of diethyl ether and petroleum ether to leave the solid, off-white product (145 mg, 38%), m/z, 382.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:18]([CH3:20])[CH3:19])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)I
Reactant: N#Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Oc1ccc(Br)c(C#N)c1
Temperature: 60 °C
Yield: 78.4 %

Procedure:
2-Bromo-5-hydroxy-benzonitrile (20.0 g, 10.1 mmol) and K2CO3 (5.60 g, 40.4 mmol) were taken-up in dry DMF (12.5 mL). 2-Iodopropane (2.00 mL, 20.2 mmol) was added and the reaction mixture was heated at 60° C. for 2 h. The mixture was diluted with ether (100 mL), filtered over celite and the filtrate was washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, evaporated and purified by column chromatography (5-45% EtOAc/hexanes) to give 1.9 g (81%) of 2-bromo-5-isopropoxybenzonitrile as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=9.0 Hz, 1H), 7.15 (d, J=2.9 Hz, 1H), 6.99 (dd, J=9.0, 3.0 Hz, 1H), 4.58-4.49 (m, 1H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 239.0. found 240.1 (M+1)+. Retention time: 1.81 minutes (3 min run).
Reaction SMILES: BrP(C)(C1C=CC=CC=1)(C1C=CC=CC=1)[C:3]1C=CC=CC=1.CC([O-])(C)C.[K+].[F:28][C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][C:44]=1[F:45])[O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][C:34]=1[F:41]>>[F:28][C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][C:44]=1[F:45])[O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH2:3])=[CH:35][C:34]=1[F:41]
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)c(F)c1
Reactant: CP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=Cc1ccc(Oc2ccc(F)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D162 starting from bromo(methyl)triphenylphosphorane, potassium 2-methylpropan-2-olate and 4-(3,4-difluorophenoxy)-3-fluorobenzaldehyde.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].O.[N:18]1[C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:20][C:19]=1[C:27]1[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](=O)[C:31]=2[CH:30]=[CH:29][CH:28]=1>CO>[CH2:3]([NH:10][N:11]=[C:32]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:19]3[NH:18][C:26]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[N:20]=3)[C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Reactant: NNCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(CNN=C2c3ccccc3-c3c2cccc3-c2nc3cnccc3[nH]2)cc1
Temperature: 52.5 °C
Yield: 27.4 %

Procedure:
In a 10-ml round-bottomed flask, dissolve 100 mg of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, obtained in Example 1, in 3 ml of methanol, then add successively 197 mg of benzylhydrazine dihydrochloride and 138 mg of dry sodium acetate and heat at 50-55° C. for 5 hours. Pour the cooled reaction mixture into 10 ml of water, extract with ethyl acetate then twice with dichloromethane. Combine the organic phases, wash with a saturated aqueous solution of sodium chloride, dry over sodium sulphate then concentrate under reduced pressure. After purification by chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (93-7 by volume), we obtain 37 mg of N-benzyl-N′-[4-(1H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-ylidene]-hydrazine, in the form of a yellow foam with the following characteristics:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1.[CH3:11][S:12]([O-])(=[O:14])=[O:13].[Na+]>CS(C)=O.CCOC(C)=O.[Cu]I>[CH3:11][S:12]([C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)[O-]
Reactant: CCC(=O)c1cnc(Br)s1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC(=O)c1cnc(S(C)(=O)=O)s1
Temperature: 120 °C

Procedure:
To a solution of 1-(2-bromo-thiazol-5-yl)-propan-1-one (75 mg, 0.34 mmol) in dimethyl sulfoxide (3 mL) was added the sodium methanesulfonate (41 mg, 0.34 mmol) followed by copper (I) iodide (65 mg, 0.34 mmol). The mixture was heated in a microwave at 120° C. for 1 hour. The reaction was diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to afford 1-(2-methanesulfonyl-thiazol-5-yl)-propan-1-one which was used without further purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[S:3][C:4]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: COc1ccc2nc(Cl)sc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 160 °C

Procedure:
A mixture of 1.50 mmol 2-chloro-6-methoxybenzothiazole (CA=[2605-14-3]), 4.51 mmol of piperazine and 4.51 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 5 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27])=[CH:20]2.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:8][CH:9]=3)[CH2:31][CH2:30]1)(=[O:28])=[O:27])=[CH:20]2
Reactant: O=C(O)c1ccc(-c2ccncc2)nc1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccncc2)nc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A stirred suspension of 6-(4-pyridyl)nicotinic acid (400 mg, 2 mmol) in dimethylformamide, DMF, (10 ml) was treated with 1-(5-chloroindol-2-ylsulphonyl)piperazine (600 mg, 2 mmol, 1 mol eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (EDAC, 460 mg, 2.4 mmol, 1.2 mol eq.). After stirring overnight the solvent was removed in vacuo and the residue chromatographed (Isolute 20 g silica cartridge, eluting with dichloromethane containing 2.5%-5% v/v of methanol) to yield 1-(5-chloroindol-2-ylsulphonyl)-4-[6-(4-pyridyl)nicotinoyl]piperazine as a colourless foam (680 mg). This was dissolved in dichloromethane/methanol mixture (40 ml of 1:1) and treated with a saturated solution of HCI in methanol until acid to indicator paper (slight excess). The resulting solution of hydrochloride salt was evaporated to dryness and the residue boiled in 2-propanol (100 ml, incomplete solution). Filtration and cooling gave 1-(5-chloroindol-2-ylsulphonyl)-4-[6-(4-pyridyl)nicotinoyl]piperazine hydrochloride as a colourless solid, (220 mg), 1H NMR (d6-DMSO) 3.0-3.3 (broad d, 4H), 3.6-4.0 (broad d, 4H), 7.05 (s, 1H), 7.35 (dd, 1H), 7.5 (d, 1H), 7.8 (d, 1H), 8.1 (dd, 1H), 8.35 (d, 1H), 8.5 (m, 2H), 8.8 (d, 1H), 8.95 (d, 2H), 12.4 (s, 1H), signals were also present due to 2-propanol (0.5 mol equiv.); MS (M+H)+ 481/483; mp 186-190° C. (not sharp).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][Cl:34]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COCOc1ccc(F)cc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCOc1ccc(F)cc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
4.15 g of 5-fluoro-2-methoxymethoxybenzyl alcohol [prepared as described in step (b) above] were dissolved in 70 ml of tetrahydrof tiran, and then 6.86 g of carbon tetrachloride and 11.69 g of triphenylphosphine were added to the resulting solution, in that order. The resulting mixture was then stirred at room temperature for 1 hour, and then heated under reflux for 5 hours. At the end of this time, insoluble substances were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and purified by silica gel column chromatography, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.27 g (yield 71%) of the title compound as an oily substance.