Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CS(C)=O.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>[OH-].[Na+]>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of p-hydroxybenzoic acid (19.2 g, 150 moles) in 10% aqueous sodium hydroxide (120 ml) is added to dimethyl sulfoxide (DMSO) (480 ml) previously heated to 80° C. n-Octyl bromide (28.95 g, 150 moles) is added dropwise to the solution. The reaction mixture is stirred for 4 hours at room temperature after which it is poured into ice water (1200 ml). Conc. hydrochloric acid (30 ml) is added, and the mixture is allowed to stand until precipitation is complete. The precipitate is collected, dried, and crystallized from acetonitrile-water. mp 97°-99° C.
Reaction SMILES: [O:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:31]O>>[CH3:31][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:9]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:10]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
36.2 g of 4-phenoxy-3-(1-pyrrolidinyl)-5-sulphamoylbenzoic acid are dissolved in 200 ml of methanol and 7 ml of concentrated H2SO4 and heated for 4 to 6 hours under reflux. Upon cooling, the ester crystallises. Recrystallisation from methanol; M.p. 191° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[CH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C[O-].[Na+].Br[C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:30]2[CH:31]=[N:32][C:33]3[C:38]([CH:39]=2)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Brc1cnc2ccccc2c1
Agent: B1C2CCCC1CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCc2cnc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A solution of 260 mg (1.15 mmol) of 1-(t-butoxycarbonyl)-4-(prop-2-enyl)piperidine (from EXAMPLE 33, Step B) in 3 mL of THF under argon was treated with 2.30 mL of 0.5 M 9-BBN solution in THF. The resulting mixture was stirred at rt for 2 h, then treated with 68 mg (1.25 mmol) of NaOMe. The resulting mixture was stirred until it was homogeneous (˜15 min) and then was treated with 0.155 mL (1.15 mmol) of 3-(bromo)quinoline and 41 mg (0.05 mmol) of [1,1′-bis(triphenyl-phosphino)ferrocene]dichloropalladium.CH2Cl2. The resulting mixture was heated at reflux for 30 min, cooled and quenched with 20 mL of 1.0 N NaOH. The quenched reaction was extracted with 2×50 mL of ether; the extracts were dried over MgSO4, combined and concentrated. Flash chromatography on 15 g of silica gel using 4:1 v/v hexanes/EtOAc as the eluant afforded 240 mg (59%) of the title compound: 1H NMR (300 MHz) B 1.00-1.16 (m, 2H), 1.25-1.40 (m, 2H), 1.45 (s, 9H), 1.60-1.80 (5H), 2.62-2.72 (m, 2H), 2.79 (t, J=7.8,22H), 4.06 (br s, 2H), 7.52 (m, 1H), 7.66 (m, 1H), 7.76 (dd, J=8.0, 1.6, 1H), 7.91 (d, J=1.6, 1H), 8.77 (d, J=2.2, 1H).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[S:17]([C:20]3[CH:25]=[CH:24][C:23](C=O)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl.[OH:39][NH2:40].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[S:17]([C:20]3[CH:21]=[CH:22][C:23](=[N:40][OH:39])[CH2:24][CH:25]=3)(=[O:19])=[O:18])[CH2:12][CH2:13]2)=[O:7])=[CH:36][CH:37]=1
Reactant: NO
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)C1=CCC(=NO)C=C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.7 %

Procedure:
N-{2-[4-(4-Fluorobenzoyl)piperidino]ethyl}-4-formyl-N-(2-methoxyphenyl)benzenesulfonamide (63 mg, 0.12 mmol) and hydroxyamine hydrochloride (9.5 mg, 0.132 mmol) were dissolved in ethanol (2 ml) to which were subsequently added anhydrous sodium carbonate (14 mg, 0.132 mmol) and water (1 ml). After 1.5 hours of stirring at room temperature, ethanol was removed by evaporation, and the resulting residue was mixed with water (10 ml) to collect crystals by filtration. The thus collected crystals were washed with water and hexane, dissolved in methylene chloride (50 ml) and then dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation to obtain 65 mg (100%) of the title compound in the form of colorless powder.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][CH:20]=[CH2:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)C=[O:26]>O.[Pd](Cl)Cl>[CH2:1]([C@H:8]([CH2:19][C:20](=[O:26])[CH3:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: C=CC[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: O
Product: CC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 86 %

Procedure:
A suspension of 500 mg (5 mmoles) of cuprous chloride and 180 mg (1 mmole) of palladium chloride in a mixture of 5 ml of dimethylformamide and 0.6 ml of water was stirred for 1 hour under an atmosphere of oxygen. At the end of this time, 1.41 g(5.03 mmoles) of benzyl 2(S)-benzyl-4-pentenoate (prepared as described in Preparation 18) was added to the mixture. The mixture was then stirred for an additional 5 hours at room temperature and under an atmosphere of oxygen, after which the reaction mixture was poured into 100 ml of 1N aqueous hydrochloric acid, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (using a 5:1 by volume mixture of hexane and ethyl acetate as eluent), to give 1.28 g (yield 86%) of the title compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:28][CH3:29])[C:4]1=[O:5])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:36])(=O)=O>O.CO>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:36])[C:9](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[N:8][C:7]=2[N:6]([CH2:28][CH3:29])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3ccc(-c4ccccc4)cc3)nc2n(CC)c1=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(-c4ccccc4)cc3)n2C)n(CC)c1=O
Reaction time: 4 h
Yield: 30.8 %

Procedure:
Compound 163 (1.50 g, 3.89 mmol) obtained in Reference Example 104 was suspended in a mixed solvent of 13 ml of water, 3.9 ml of a 2N aqueous solution of sodium hydroxide, and 7 ml of methanol. To the suspension was dropwise added 0.55 ml (5.83 mmol) of dimethyl sulfate, and the resultant mixture was stirred at 60° C.; for 4 hours. Water (10 ml) was added thereto, and the deposited crystals were collected by filtration and dried. The obtained crude crystals were purified by silica gel column chromatography, followed by recrystallization from ethyl acetate to give 480 mg (yield 28%) of Compound 164 as yellow columns.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13]=[CH2:14]>>[CH:13]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[CH2:14]
Reactant: C=C
Reactant: COC(=O)Cc1cccc(Br)c1
Product: C=Cc1cccc(CC(=O)OC)c1

Procedure:
Methyl 3-bromophenylacetate (8.0 g, 34.9 mmol) was reacted with ethylene using the procedure described in Example 6, step 1. The crude reaction product was purified by column chromatography (SiO2, 5% EtOAc in petroleum ether) to give 3,3′-bis-[(carbo-methoxy)methyl]stilbene and methyl 3-(ethenyl)phenyl-acetate as a white solid mixture.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C([O-])=O.[NH4+]>O1CCCC1.[Zn]>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:6]1[C:7]2[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=2[C:4]2[CH:3]=[CH:2][CH:24]=[N:23][C:5]1=2
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cccnc21
Temperature: 75 °C
Yield: 79.3 %

Procedure:
A mixture of 3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (5.6 g, 14 mmol), ammonium formate (8.8 g, 139 mmol), and zinc (9.1 g, 139 mmol) in tetrahydrofuran (85 mL) was heated at 75° C. for 10 h. The reaction was allowed to cool, filtered over a pad of celite, and washed with DCM (200 mL). The filtrate was concentrated in vacuo and then purified by flash chromatography (silica, 120 g, ISCO, 5-45% ethyl acetate in heptane) to afford the title compound as a white solid (3.6 g, 80%). 1H NMR (CDCl3, 400 MHz): 9.17 (s, 1H), 8.73 (dd, J=4.8 Hz, 1.5 Hz, 1H), 8.46 (dd, J=7.8 Hz, 1.5 Hz, 1H), 8.39 (s, 1H), 7.39 (dd, J=7.8 Hz, 4.8 Hz, 1H), 6.01 (s, 2H), 3.60 (t, J=8.0 Hz, 2H), 0.93 (t, J=8.0 Hz, 2H), −0.09 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:16]=[CH2:17].O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[CH2:8][C:9](=[O:10])[CH2:17][CH2:16]2
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C1CCc2cc(F)ccc2C1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
p-Fluorophenylacetyl chloride (17.25 g) in dichloromethane (100 ml) was added dropwise to aluminium chloride (26.7 g) suspended in dichloromethane (400 ml) maintained at -10° C. by cooling in a solid carbon dioxide/acetone bath. Ethylene gas was then passed through the mixture for 15 minutes while maintaining the temperature at -10° C. The mixture was then allowed to warm to room temperature and stirred for 3 hours. The mixture was then cooled to 5°-10° C. and ice and water (160 ml) added cautiously with stirring over a period of 45 minutes. The dichloromethane was then separated and washed successively with dilute hydrochloric acid, (150 ml×2), sodium bicarbonate solution (150 ml×2) and brine. The dichloromethane was then dried and evaporated. The residue was distilled to give 6-fluoro-2-tetralone (12.81 g) with a boiling range of 68°-76° C./0.05 Torr. The distillatte crystallised on standing.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[Br:18][CH2:19][C:20]([N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: c1ccc(NC2CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)N(c1ccccc1)C1CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a stirred solution of 908 mg (6.83 mmol) Cyclopropyl-phenyl-amine (Kang, Sung, Kim, J. Chem. Soc., Chem. Commun., 1987, 897-898) and 690 mg (6.83 mmol, 1 equiv) Et3N in 10 mL DCM is added 1.38 g (6.83 mmol, 1 equiv) Bromoacetyl bromide in 4 mL DCM dropwise over 15 minutes at 0° C. The reaction mixture is stirred 3 h at 0° C., diluted with 30 mL DCM, washed with 1N HCl (30 mL), dried (MgSO4), and concentrated in vacuo. The crude product is purified by flash chromatography on 30 g silica gel eluted successively with EtOAc/Hexanes (1:9, 100 mL), (3:17, 300 mL). Appropriate fractions were combined and concentrated in vacuo to give 948 mg (3.73 mmol) of 2-Bromo-N-cyclopropyl-N-phenyl-acetamide as an amber oil: 1H NMR (CDCl3, 300 MHz) δ7.39 (m, 3H), 7.15 (m, 2H), 3.62 (s, br, 2H), 3.24 (m, 1H), 0.83 (m, 2H), 0.52 (m, 2H); TLC Rf =0.18 (EtOAc/Hexanes, 3:17).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][CH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+].O.CN(C)C=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:13]([O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: CC(C)(C)OCc1cccc(B(O)O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2ccc(-c3cccc(COC(C)(C)C)c3)n2n1
Temperature: 60 °C

Procedure:
7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.370 g, 1.52 mmol), 3-(tert-Butoxymethyl)phenylboronic acid (0.564 g, 2.71 mmol), Bis(tri-tert-butylphosphine)palladium (47 mg, 0.092 mmol), 2.00 M of Sodium Carbonate in Water (3.0 mL, 6.0 mmol), and N,N-Dimethylformamide (12.0 mL, 155 mmol) were combined in a reaction vial, partially degassed and backfilled with Nitrogen, and the mixture was heated at 60° C. overnight under an atmosphere of Nitrogen. The reaction mixture was diluted with water (25 mL) and DCM (25 mL). The aqueous was extracted with DCM (2×, 10 mL) and combined organics diluted with 1:1 EtOAc:hexane (50 mL), followed by washes with water (2×, 25 mL) and brine (25 mL). The organics were dried over sodium sulfate and conc. in vacuo to afford 7-(3-tert-Butoxymethyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine which was then oxidized, analogous to Example 1504a, to afford 7-(3-tert-Butoxymethyl-phenyl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (398 mg, 73%). 1H-NMR (DMSO-d6): 9.37 (s, 1H), 8.22 (s, 1H), 8.10 (d, 1H, J=7.77 Hz), 7.81 (d, 1H, J=4.97 Hz), 7.53 (t, 1H, J=7.77 Hz), 7.44 (d, 1H, J=4.97 Hz), 7.41 (d, 1H, J=7.77 Hz), 4.50 (s, 2H), 3.46 (s, 3H), 1.26 (s, 9H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[C:11]([C:24]3[CH:25]=[C:26]([NH:30][S:31]([C:34]4[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=4[F:41])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=3)=[N:12][N:13](CC3C=CC(OC)=CC=3)[CH:14]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[C:11]([C:24]3[CH:25]=[C:26]([NH:30][S:31]([C:34]4[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=4[F:41])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=3)=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)n1
Solvent: O=C(O)C(F)(F)F
Product: CCNc1nccc(-c2c[nH]nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)n1
Temperature: 70 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
450 mg (0.78 mmol) of N-(3-{4-[2-(ethylamino)pyrimidin-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}phenyl)-2,5-difluorobenzenesulfonamide were dissolved in 10 ml of trifluoroacetic acid and the resulting solution heated at 70° C. under stirring for 4 hours. After this time the solvent was evaporated and the residue taken up with dichloromethane and washed with aqueous sodium hydrogenocarbonate. The organic phase was then dried over sodium sulphate and evaporated again. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3; from 9/1 to 8/2), giving 80 mg (22%) of the title compound.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:13]([C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>CCO>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)=[O:24])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCNC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.35 g (19.2 mmol) of N-boc-1,3-diaminopropane in 50 ml of EtOH is mixed at 0° C. in portions with 3.15 g (19.2 mmol) of 3-nitrophenyl isocyanate. The batch is stirred overnight at room temperature and then concentrated by evaporation in a rotary evaporator. It is mixed with DCM and washed with water. The organic phase is filtered through a Whatman filter and concentrated by evaporation. 6.4 g (18.9 mmol, corresponding to 98% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[C:2]=1[N:1]=[CH:17][N:18]([CH3:20])[CH3:19])=[O:8]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc2ccccc2c1N
Product: COC(=O)c1sc2ccccc2c1N=CN(C)C
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of 3.38 g (16.32 mmol) of methyl 3-aminobenzo[b]thiophene-2-carboxylate (J. Org. Chem. 37, 3224 (1972)) in 8 mL of N,N,-dimethylformamide dimethyl acetal is heated at reflux temperature for 2 hours, then cooled to room temperature. The solid is collected by filtration, washing with hexane and ethyl acetate to provide 3.96 g (93%) of a white solid, mp 73–74° C.
Reaction SMILES: [CH2:1]([CH2:16][C:17]([OH:19])=O)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:40]>>[CH2:1]([CH2:16][C:17]([Cl:40])=[O:19])[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(=O)Cl

Procedure:
A three-necked flask equipped with a stirrer, a reflux condenser and a thermometer was charged with 132 g of farnesylacetic acid, 140 g of triphenylphosphine and 500 ml of carbon tetrachloride, and the contents were heated under reflux of carbon tetrachloride for 4 hours. The reaction mixture was filtered to remove a formed solid matter, the carbon tetrachloride distilled off, 500 ml of n-hexane added, the mixture ice-cooled and the crystalline precipitate filtered off. The n-hexane was then distilled off, leaving 146 g of crude farnesylacetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:16][N:17]1[CH:21]([CH2:22][CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:20][N:19]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[C:18]1=[O:46].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[C:4]([CH3:13])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:23][CH2:22][CH:21]2[CH2:20][N:19]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:45])[F:43])=[CH:38][CH:37]=3)[C:18](=[O:46])[N:17]2[CH3:16])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Reactant: COC(=O)C(C)(C)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Temperature: 60 °C
Yield: 93.4 %

Procedure:
To a solution of 3-(4-Hydroxy-phenyl)-2,2-dimethyl-propionic acid methyl ester (31 mg, 0.15 mmol) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (75 mg, 0.16 mmol) in DMF (1 ml) is added Cs2CO3 (64 mg, 0.19 mmol), and the mixture heated at 60° C. for 15 hours. The mixture is cooled, diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with brine (25 ml), dried (Na2SO4), and concentrated to an oil. Purification by flash chromatography on a Biotage silica cartridge (gradient elution, 2:1 hexanes:ethyl acetate to 1:4 hexanes:ethyl acetate) produced an oil (69 mg, 94%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C([O-])([O-])=O.[K+].[K+].[CH3:39][NH2:40].O>CS(C)=O>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([NH:40][CH3:39])=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
A mixture of 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide, 1 g of K2CO3 and 10 ml of a 40% solution of monomethylamine is heated in 25 ml of dimethylsulfoxide for 8 hours at 100° C. The reaction mixture is poured over water and the pale yellow solid separated. The reaction mixture is filtered and the collected solid washed well with water. After drying the solid is purified by column chromatography on silica gel by elution with 9:1 ethyl acetate:methanol to give 850 mg of the desired product as a pale yellow solid: M+ =437.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:13]3[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: O=Cc1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c(Sc3ccc(C=O)s3)nc2c1
Temperature: 110 °C
Yield: 47.4 %

Procedure:
a mixture of 0.82 g of 2-mercapto-5-methyl-benzimidazole (5 mmoles), 0.6 ml of 5-bromo-2-thiophenecarboxaldehyde (5 mmoles) and 1.4 g of potassium carbonate in 10 ml of DMF is heated at 110° C. for 2 hours. The mixture is cooled down to room temperature, then poured into 200 ml of water and extracted twice with 50 ml of ethyl acetate. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated. The crude product is purified on silica gel using DCM/MeOH as eluent to give 0.65 g of 5-(5-methyl-1H-benzimidazol-2-ylsulfanyl)-thiophene-2-carbaldehyde. (Yield=47%). Analytical LC/MS method A: ([M+H]+): 275). RT: 3.42 min (gradient 5 to 85% acetonitrile in 7 min).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22](S(C)(=O)=O)[N:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5][CH:4]=1)[CH3:2].[CH3:31][NH:32][CH3:33]>CN(C=O)C>[CH3:31][N:32]([CH3:33])[C:22]1[N:21]=[C:20]([C:16]2[S:15][C:14]([NH:13][C:11]([NH:10][CH2:9][CH2:8][C:6]3[O:7][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=3)=[O:12])=[N:18][C:17]=2[CH3:19])[CH:25]=[C:24]([CH3:26])[N:23]=1
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)(=O)=O)n3)s2)o1
Reactant: CNC
Solvent: CN(C)C=O
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(N(C)C)n3)s2)o1

Procedure:
A solution of 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfonyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (0.22 g, 0.049 mmol) and dimethylamine (2M in THF, 0.073 ml, 0.15 mmol) in DMF (1 ml) is heated at 70° C. for 18 hours. The solvent is removed and the product is purified by chromatography on silica eluting with ethyl acetate to give the titled compound.