Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(N(CC)CC)C.[CH2:28]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=[S:32])[CH3:29]>C(Cl)Cl>[CH2:34]([NH:33][C:31]([S:32][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])=[N:30][CH2:28][CH3:29])[CH3:35]
Reactant: CCNC(=S)NCC
Reactant: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN=C(NCC)SCC(=O)NC1C(=O)N2C(c3nnn[nH]3)C(C)(C)S[C@H]12
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1.40 g (0.039 mole) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.54 ml (0.039 mole) of triethylamine, followed by 0.52 g (0.039 mole) of N,N'-diethylthiourea. Stirring is continued for a further 45 minutes, and then the solvent is decanted from the oil which has separated. The oil is triturated with ether, giving a white solid, which is filtered off. The yield is 1.28 g (76% of theory) of 6-(2-[N,N'-diethylamidinothio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum (KBr disc) of the product shows absorption bands at 1780 cm-1 (β-lactam) and 1670 cm-1 (amide I). The NMR spectrum (DMSO-d6) shows absorption bands at 5.65 ppm (multiplet, C-5 and C-6 hydrogens), 5.15 ppm (singlet, C-3 hydrogen), 4.10 ppm (singlet, methylene hydrogens), 3.45 ppm (quartet, ethyl hydrogens), 1.60 ppm (singlet, C-2 methyl hydrogens), 1.10 ppm (triplet, ethyl hydrogens) and 1.00 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])[CH2:34][CH2:33]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: Cc1nc2ccccc2cc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 84 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:67][NH:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>ClCCl>[CH2:69]([N:68]([CH3:67])[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12]2)[CH:17]=1)[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)C(=O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
The compound (0.10 g) prepared in step (c) was dissolved in dichloromethane (2 ml). A BOP reagent (0.10 g) and diisopropylethylamine (0.052 ml) were added to the solution. The mixture was stirred at room temperature for 30 min. N-Methylbenzylamine (0.039 ml) was then added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:1) to give 0.072 g (57.3%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:26][C@H:27]1[CH2:32][O:31][CH2:30][CH2:29][NH:28]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][C@@H:27]2[CH3:26])[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccc2)nc(Cl)n1
Temperature: -5 °C
Yield: 76.5 %

Procedure:
2,4-dichloro-6-[(phenylsulfonyl)methyl]pyrimidine (2.8 g, 9.24 mmol) was dissolved in DCM (20 mL) and stirred (under nitrogen) at −5° C. Triethylamine (1.42 mL, 10.17 mmol) was added to give a clear brown solution. (3S)-3-methylmorpholine (935 mg, 9.24 mmol) was dissolved in DCM and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM to give the desired material as a white solid (2.6 g).
Reaction SMILES: CN(C)C=O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:28](#[N:31])[CH:29]=[CH2:30].[NH2:32][C:33]1[C:42]2[N:43]=[C:44]([CH2:51][O:52][CH3:53])[N:45]([CH2:46][C:47]([CH3:50])([OH:49])[CH3:48])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37](Br)=[CH:36][C:35]=2[N:34]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:32][C:33]1[C:42]2[N:43]=[C:44]([CH2:51][O:52][CH3:53])[N:45]([CH2:46][C:47]([OH:49])([CH3:50])[CH3:48])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37]([CH:30]=[CH:29][C:28]#[N:31])=[CH:36][C:35]=2[N:34]=1
Reactant: C=CC#N
Reactant: COCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COCc1nc2c(N)nc3cc(C=CC#N)ccc3c2n1CC(C)(C)O
Temperature: 120 °C
Yield: 74.7 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (225 mg, 1.00 mmol), acetonitrile (50 mL), N,N-dimethylformamide (20 mL) triethylamine (8.25 mL, 59.3 mmol), tri-o-tolylphosphine (900 mg, 2.97 mmol), acrylonitrile (770 mg, 21.8 mmol) and 1-[4-amino-7-bromo-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (7.50 g, 19.8 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath for 18 hours. The reaction was cooled to ambient temperature and then concentrated under reduced pressure. The resulting solid was partitioned between chloroform (300 mL) and aqueous 1% sodium carbonate (100 mL). The fractions were separated and the aqueous fraction was extracted with chloroform (4×100 mL). The combined organic fractions were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-7% gradient of methanol in dichloromethane) to provide 5.2 g of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]([F:15])([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:12][C:25](=[O:26])[CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:28])([F:16])[F:29])[CH:19]=2)=[CH:9][CH:8]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: NCc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(C(F)(F)F)c1)NCc1ccc(C(F)(F)C(F)(F)F)cc1
Yield: 77.9 %

Procedure:
A solution of 4-pentafluoroethyl-benzylamine (485 mg, 2.16 mmol), 3-(trifluoromethyl)-phenylacetic acid (484 mg, 2.37 mmol), 4-methylmorpholine (654 mg, 6.46 mmol), and HBTU (1.23 g, 3.23 mmol) in DMF (30 mL) was stirred at RT for 16 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (692 mg, 78%). Light yellow solid, MS (ISP) 412.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])[CH:2]=1.C(Cl)(=O)C([Cl:20])=O>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([Cl:20])=[O:11])[CH:2]=1
Reactant: O=C(O)c1cccnc1Oc1cccnc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=C(Cl)c1cccnc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(pyridin-3-yloxy)-nicotinic acid (0.432 g, 2.0 mmol) in THF (15 mL) at 0° C. was added oxalylchloride (2 mL, 2M in CH2Cl2, 4.0 mmol) dropwise. The solution was stirred at room temperature for 3 h. The solvent was evaporated in vacuo to yield 2-(pyridin-3-yloxy)-nicotinoyl chloride as a solid. To a solution of 2-(pyridin-3-yloxy)-nicotinoyl chloride in 15 mL THF was added 3-trifluoromethyl-benzylidene-hydrazine (0.376 g, 2.0 mmol) in 5 mL THF and 1 mL Et3N at 0° C. The reaction mixture was refluxed for 6 h and the solvent was evaporated. The residue was purified by chromatography with EtOAc:hexanes, 1:2, yielding (0.425 g, 55%) of the title compound. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.90 (m, 2H), 7.78 (t, J=7.8 Hz, 1H), 7.41 (m, 2H), 6.43 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH2:15](O)[CH3:16].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]2
Reactant: CCO
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-2-naphthalenecarboxylic acid (Compound M) 3.1 g, (12.43 mmol) in ethanol (30 ml, 23.55 g, 511.0 mmol) was added 18M sulfuric acid (2 ml). The solution was refluxed for 30 minutes, cooled to room temperature, and the reaction mixture partitioned between pentane (100 ml) and water (100 ml). The aqueous, phase was extracted with pentane (100 ml) and the combined organic layers washed with saturated aqueous NaCl (100 ml), dried (MgSO4), and concentrated to yield an off-white solid. Purification by flash chromatography (silica, 10% EtOAc-hexane) afforded the title compound as a white solid. 1H NMR (CDCl3): δ8.58 (1H, br s), 8.10 (1H, dd, J=1.7, 9 Hz), 8.06 (1H, d, J=2 Hz), 7.83 (1H, d, J=9 Hz), 7.80 (1H, d, J=9 Hz), 7.62 (1H, dd, J=2, 9 Hz).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:9]([O:11]C)Cl>>[SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]=[O:11])=[CH:4][CH:3]=1
Reactant: Sc1ccccc1
Reactant: COC(Cl)Cl
Product: O=Cc1ccc(S)cc1

Procedure:
The above reaction of Example 68(A) is repeated except that the starting materials are mercaptobenzene and dichloromethyl methylether. Using the same reaction conditions and techniques, there is obtained 4-mercaptobenzaldehyde.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:21]([O-])=O)=[C:11]([CH:20]=2)[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:3][CH2:2]1.[H][H]>C1COCC1.[Ni]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:20]=[C:11]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:10]([NH2:21])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(C2=CCOCC2)cc1NCc1ccccn1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(C2CCOCC2)cc1NCc1ccccn1

Procedure:
5-(3,6-dihydro-2H-pyran-4-yl)-2-nitro-N-(pyridin-2-ylmethyl)aniline E-1.9′ (82 mg; 0.26 mmol) is dissolved in THF (25 ml) and filled into a Büchi autoclave. RaNi is added and the reaction is hydrogenated with 5 bar hydrogen pressure overnight. The reaction mixture is filtered on a plug of celite. The filtrate is then concentrated under reduced pressure. The product is used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9](O)[CH2:10][OH:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1csc(C2OCCO2)c1
Reaction time: 1.5 h

Procedure:
4-Bromo-thiophene-2-carbaldehyde (9.24 g, 48.4 mmol), ethane-1,2-diol (13.5 mL, 242 mmol), toluene-4-sulfonic acid monohydrate (416 mg, 2.42 mmol) were dissolved in toluene (100 mL), and the solution was stirred for 1.5 hours under reflux. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (11.8 g, quantitatively) was obtained as a white solid.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:16][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(O)c1ccccc1
Yield: 91 %

Procedure:
Under nitrogen atmosphere, 30 mL of THF was added to 3.96 g (6.50 mmol, 0.65 equivalent (equivalent relative to a carbonyl compound as a starting raw material; the same, hereinafter)) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.06 g (10 mmol) of benzaldehyde in 5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 25 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 10 mL (×2) of 1N hydrochloric acid, 20 mL of an aqueous saturated sodium chloride solution, 20 mL (×2) of an aqueous saturated sodium bicarbonate solution and 20 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.76 g of the desired product (yield 91%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](Cl)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20].[CH:21]1[C:26]([NH2:27])=[CH:25][C:24]2[NH:28][N:29]=[CH:30][C:23]=2[CH:22]=1.Cl.N1C=CC=CC=1.C(OC(O)C)C>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:27][C:26]3[CH:25]=[C:24]4[C:23]([CH:30]=[N:29][NH:28]4)=[CH:22][CH:21]=3)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Reactant: Nc1ccc2cn[nH]c2c1
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCCl
Yield: 90 %

Procedure:
The title compound was prepared by the procedure of Example 166 using 0.311 g of 7-(3-chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.147 g of 6-aminoimidazole, 0.128 g of pyridine hydrochloride and 12 ml of ethoxyethanol to give 0.367 g (90%) of the desired product. MP 280-285° C. mass spectrum (electrospray m/e): M+H=407.9.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[F:16])[CH3:6])=[O:4].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:16][C:8]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[C:12]2[C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2]2
Reactant: CN(C(=O)CCl)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 80 °C

Procedure:
Following the method described by Hennessy and Buchwald in J. Am. Chem. Soc., 2003, 125, 12084-12085, 2-chloro-N-(2-fluoro-4-nitro-phenyl)-N-methyl-acetamide (15, 1.00 g, 4.05 mol), palladium acetate (27.3 mg, 0.122 mmol) and 2-(di-tert-butylphosphino)biphenyl (72.5 mg, 0.243 mmol) are placed under a nitrogen atmosphere, and toluene (20 ml) and triethylamine (0.85 ml, 6.08 mmol) are added via syringe. The reaction is heated at 80° C. for 4 hours and then evaporated to dryness. The dark residue is purified by PTLC (dichloromethane) to give the title compound as a light brownish-orange solid. HPLC r.t. 4.4 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:7][S:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:6])[CH3:2].C(N(CC)CC)C.[Br:36][CH2:37][C:38](Br)=[O:39]>C1COCC1>[CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:7][S:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:6][C:38](=[O:39])[CH2:37][Br:36])[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of S-triphenylmethyl-L-cysteine ethyl ester (18 g, 46 mmol.) and triethylamine (6.4 mL, 46 mmol.) in dry THF (250 mL) under nitrogen was cooled to 0° C. A solution of bromoacetyl bromide (9.28 g, 46 mmol.) in dry THF (60 mL) was added dropwise during which time the solution turned cloudy. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give an oil. The oil was partitioned between methylene chloride and water (60 mL each), the organic layer washed with 5% HCl, NaHCO3, dried (magnesium sulfate), filtered, and the volatiles removed to give the desired product (69%).
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)(=[O:3])[CH3:2].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[Br:14][C:15]1[CH:16]=[C:17]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][C:6]=2[N+:11]([O-:13])=[O:12])[CH:18]=[CH:19][CH:20]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Temperature: 180 °C
Reaction time: 48 h

Procedure:
A mixture of 4-acetyl-2-nitroaniline (3.41 g, 18.94 mmol), 1,3-dibromobenzene (4.6 ml, 38.06 mmol), potassium carbonate (2.62 g, 19 mmol) and a catalytic amount of copper bronze is heated with stirring to 180° C. under a stream of nitrogen for 2 days. After cooling the solid reaction cake is extracted with a mixture of dichloromethane and methanol (9:1). The extract is concentrated under reduced pressure. The residue is extracted with ethyl acetate. This extract is concentrated under reduced pressure and the residue is eluted through silica gel with a mixture of petroleum ether and ethyl acetate (4:1) to afford the pure product. Yield 0.67 g (10.6%). M.p. 142-144° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:36]([NH2:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:38])[CH3:37]>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:45][C:36]([CH3:38])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Yield: 73.1 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-acetoxybenzoic acid (7.92 g, 44.0 mmol) was dissolved in DMF (45 mL), and the solution was treated with EDCI (12.7 g, 66.0 mmol), HOBT monohydrate (3.37 g, 22.0 mmol) and cumylamine (14.2 mL, 96.8 mmol), followed by purification by slurry using diisopropylether to obtain 3-acetoxy-N-(1-methyl-1-phenylethyl)benzamide (9.57 g, yield 73%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[CH2:12]([NH:11][C:9](=[O:10])[CH2:8][N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCN1CCNCC1
Reactant: CCCCCCCNC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCNC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
Potassium carbonate (1.52 g, 11 mmol) was added to a solution of this amide (2.36 g, 10 mmol) and 1-(2-hydroxyethyl)piperazine (1.30 g, 10 mmol) in acetonitrile (40 ml) and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated and the residue was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the residue obtained by evaporation of the solvent was purified by a silica gel column chromatography (75 g of silica gel; developing solvent, ammonia-saturated methanol:chloroform=1:20) to provide 2.39 g (yield 83%) of N-heptyl-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide as colorless oil.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([C:20]3[S:21][C:22]([CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:23][CH:24]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[NH:10][CH:11]=[C:12]2[C:20]1[S:21][C:22]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:23][CH:24]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccc(CN3CCCC3)s2)c2cccc(F)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Fc1cccc2c(-c3ccc(CN4CCCC4)s3)c[nH]c12
Yield: 76.1 %

Procedure:
1-benzenesulfonyl-7-fluoro-3-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-indole (0.20 g, 0.46 mmol) and potassium carbonate (0.25 g, 1.82 mmol) were treated with a mixture of methanol and water (3:1 v/v; 4 ml) and subjected to microwave irradiation at 100° C. for 600 s. The resulting suspension was then concentrated under reduced pressure and partitioned between dichloromethane (10 ml) and water (10 ml). The organic phase was separated and the aqueous phase washed with dichloromethane (10 ml). The combined organic layers were dried with sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 0-10% (v/v) methanol in dichloromethane to afford 7-fluoro-3-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-indole as a colourless solid (0.10 g, 0.35 mmol).