Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[C:10]([Br:38])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][C:17]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[CH2:16]2)=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(#N)C.[N+]([O-])([O-])=[O:44].[NH4+].[Ce]>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[C:10]([Br:38])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][C:17]([C:24]3[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=3)([C:20]([F:22])([F:23])[F:21])[CH:16]2[OH:44])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1Br
Reactant: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)nc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of t-butyl[(6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)-pyrrolidin-1-yl}-2-bromopyridin-3-yl)methyl]carbamate (0.5 g) and acetonitrile (30 ml), which had been stirred in ice water bath, a 1 M aqueous solution of cerium ammonium nitrate (IV) (1.6 ml) was added, stirred approximately for 10 minutes and the reaction mixture was diluted with ethyl acetate. After that, the mixture was washed with an aqueous solution of sodium thiosulfate and then an aqueous saturated brine solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography to obtain t-butyl[(6-{3-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl}-2-bromopyridin-3-yl)methyl]carbamate (0.35 g).
Reaction SMILES: N1(C([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:25][C@@H:24]([O:26][CH2:27][CH2:28][CH3:29])[C@H:23]([NH:30][C:31](=[O:46])[CH2:32][NH:33][C:34](=[O:45])[C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=5)[CH2:22]4)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=O)CCOCC1.N1(C(C2C=CC(N3CCC(=O)CC3)=CC=2)=O)CC[O:50][CH2:49]C1>>[CH3:49][O:50][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[CH2:25][C@@H:24]([O:26][CH2:27][CH2:28][CH3:29])[C@H:23]([NH:30][C:31](=[O:46])[CH2:32][NH:33][C:34](=[O:45])[C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=4)[CH2:22]3)[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: O=C1CCN(c2ccc(C(=O)N3CCOCC3)cc2)CC1
Reactant: CCCO[C@@H]1CN(C2CCN(c3ccc(C(=O)N4CCOCC4)cc3)CC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Product: CCCO[C@@H]1CN(C2CCN(c3ccc(OC)cc3)CC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was synthesized in similar fashion to rel-N-{2-[((3R,4R)-1-{1-[4-(morpholin-4-ylcarbonyl)phenyl]piperidin-4-yl}-4-propoxypyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide substituting 1-(4-methoxyphenyl)piperidin-4-one for 1-[4-(morpholin-4-ylcarbonyl)phenyl]piperidin-4-one and was isolated as a white solid. 1H-NMR (CDCl3) δ: 0.91 (m, J=7.2 Hz, 3H), 1.52-1.74 (m, 4H), 1.93-1.96 (m, 2H), 2.27-2.44 (m, 2H), 2.62-2.69 (m, 2H), 2.78-2.93 (m, 2H), 3.36-3.51 (m, 4H), 3.56-3.64 (m, 1H), 3.76 (s, 3H), 4.14 (d, J=4.8 Hz, 2H), 4.31-4.36 (m, 1H), 6.69-6.71 (m, 1H), 6.81-6.91 (m, 4H), 7.20-7.23 (m, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 8.11 (s, 1H). MS m/z: 563 (M+1).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:29][CH2:25][CH:26]([CH3:28])[CH3:27])=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC(C)CN
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(NCC(C)C)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 70 μL of isobutylamine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(isobutylamino)-2-methylnicotinamide. MS (Q1) 395.4 (M)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:12]([C:18]([OH:20])=O)[CH:11]=1)#[N:2].Cl.Cl.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:12]([C:18]([NH:32][C@@H:30]([C:27]2[CH:28]=[N:29][C:24]([CH3:23])=[CH:25][CH:26]=2)[CH3:31])=[O:20])[CH:11]=1)#[N:2]
Reactant: Cc1ccc(-c2cc(CO)cc(C(=O)O)c2)c(C#N)c1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CO)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2′-cyano-5-(hydroxymethyl)-4′-methylbiphenyl-3-carboxylic acid (40 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[NH:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[Br:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28](I)[CH3:29]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:25])[N:15]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[Br:24])[CH2:28][CH3:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Br)c(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)C1CCN(C(=O)OC(C)(C)C)CC1)c1cc(OC)ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-5-methoxy-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.21 mmol) was dissolved in dry N,N-dimethylformamide (5.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 60.0 mg, 1.45 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C., ethyl iodide (0.226 g, 1.45 mmol). The reaction mixture was stirred at 0° C. for one hour, then at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was then added into an excess of water-ice and a solid precipitated. The solid was filtered by suction, washed with water and dried to yield a crude solid. The crude solid was purified via flash chromatography (25% ethyl acetate/hexanes) to yield the title compound as a solid.
Reaction SMILES: [C:1]([O:7]C)(=O)[C:2]([O:4][CH3:5])=[O:3].C[O-].[Na+].[I:12][C:13]1[CH:14]=[C:15]([N+:24]([O-:26])=[O:25])[C:16]([CH3:23])=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.Cl>CO>[N+:24]([C:15]1[CH:14]=[C:13]([I:12])[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[C:16]=1[CH2:23][C:1](=[O:7])[C:2]([O:4][CH3:5])=[O:3])([O-:26])=[O:25]
Reactant: COC(=O)C(=O)OC
Reactant: Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dimethyl oxalate (127.79 g, 5.0 eq) was added to sodium methylate (216.4 mL, 28%, 5.0 eq). The resulting mixture was stirred at room temperature for 1.5 hours. To the mixture was then added 5-iodo-2-methyl-3-nitrobenzotrifluoride (71.64 g, 216.4 mmol), dissolved in MeOH (216 mL). The dark red mixture was then stirred at room temperature for 6 hours and left over night. The solvent was removed in vacuo to give a red solid which was subsequently added to aqueous 2.5N HCl (800 mL). The mixture was extracted with EtOAc (500 mL and 2×300 mL). The extracts were combined and dried (anhydrous MgSO4). After filtration, the solvent was removed in vacuo to give a yellow solid of the crude product (161.41 g). A fraction of this was purified by column chromatography (silica gel, eluting 15:1 to 10:1 hexane:EtOAc) to give the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].[CH:13]([O-])([O-])[O:14][CH3:15].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>COCCOC>[CH3:13][O:14][CH:15]1[O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=2[CH2:9][O:10]1
Reactant: OCc1ccc(CO)c(CO)c1
Reactant: COC([O-])[O-]
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: COCCOC
Product: COC1OCc2ccc(CO)cc2CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4 g of (3,4-bis-hydroxymethylphenyl)methanol (23.8 mmol), 40 ml of 1,2-dimethoxyethane, 2.78 g of methyl orthoformate (26.2 mmol) and 0.24 g of Montmorillonite KSF (10 mg/mmol) are introduced into a flask. The reaction medium is stirred at room temperature for 4 hours 30 minutes and then the montmorillonite is filtered off and the 1,2-dimethoxyethane is evaporated under vacuum at 30° C. The residue is chromatographed on silica gel (dichloromethane/methanol=98/2) to give 3.2 g of (7-methoxy)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl)methanol in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:4]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[C:5]([C:10]([F:11])([F:12])[F:13])[CH:4]=1
Reactant: COc1ccc(O)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Oc2ccc(C#N)cc2)c(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A solution of 4 g (20.82 mmol) of 4-methoxy-2-trifluoromethyl-phenol and 2.52 g (20.82 mmol) of 4-fluorobenzonitrile in 60 mL DMSO was combined with 5.75 g (41.64 mmol) of potassium carbonate and stirred for 3 h at 120° C. The reaction mixture was diluted with water, and extracted three times with dichloromethane. The organic phase was washed twice with water, dried on sodium sulphate and evaporated down. The residue was purified by chromatography (reversed phase).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11]C(=O)C)[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:30])[CH2:26][N:27]=[N+]=[N-])[N:17]=[CH:16]2)[C@@H:6]1[F:31])(=O)C.[H][H]>CO.[Pd]>[NH2:27][CH2:26][C:25]([C:18]1[N:17]=[CH:16][N:15]([C@@H:7]2[O:8][C@H:9]([CH2:10][OH:11])[C@@H:5]([OH:4])[C@H:6]2[F:31])[C:19]=1[N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[O:30]
Reactant: [H][H]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CN=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CN(C)C=Nc1c(C(=O)CN)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F

Procedure:
In step 17, compound (22) is subjected to catalytic reduction with hydrogen in the presence of a hydrogenation catalyst, e.g. palladium black in methanol at room temperature for converting the azido group of compound (22) into amino group. Thereby, 4-aminoacetyl-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)-5-(dimethylaminomethyleneamino)imidazole [compound (24)] is produced.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:16][N:15]([C:17](OC(C)(C)C)=O)[CH2:14]1.ClC1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>>[Cl:35][C:32]1[CH:33]=[N:34][C:17]([N:15]2[CH2:14][CH:13]([NH:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[CH3:1])[CH2:16]2)=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: Cc1cc(C(F)(F)F)ccc1NC1CN(C(=O)OC(C)(C)C)C1
Product: COC(=O)c1cc(Cl)cnc1N1CC(Nc2ccc(C(F)(F)F)cc2C)C1
Yield: 30.3 %

Procedure:
The title compound (D86) (44 mg) was prepared according to the experimental procedure described in Description 85 starting from tert-butyl 3-((2-methyl-4-(trifluoromethyl)phenyl)amino)azetidine-1-carboxylate (D32) (150 mg, 0.454 mmol) and methyl 2,5-dichloronicotinate (74.92 mg, 0.363 mmol)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]O.C(N(S(F)(F)[F:17])CC)C.C(=O)(O)[O-].[Na+].CCOCC>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][F:17]
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: FCCCCCCCCBr
Temperature: -78 °C
Yield: 61.3 %

Procedure:
A solution of 8-bromooctan-1-ol (Hendry et al., J. Chem. Ecol., 1, 317, 1975), (2.50 g, 11.9 mmol) in methylene chloride (about 3 ml) is slowly added to a stirred solution of diethylaminosulfur trifluoride (DAST) (Middleton, J. Org. Chem, 40, 574, 1975) (1.5 mL, 11.9 mmol) in methylene chloride (10 mL), cooled to -78° C. After the addition is completed, the reaction mixture is warmed to 25° C. and saturated aqueous sodium bicarbonate (about 5 mL) is added, followed by dilution with ether (about 200 mL). The organic layer is then separated, and washed with water (20 mL), saturated sodium bicarbonate (20 mL) and then dried (MgSO4). The volatiles are removed in vacuo and the crude product is purified by flash chromatography using hexane/ethyl acetate, (95.5, v/v) to afford 8-bromo-fluoro-octane (1.54 g, 61%) as a clear colorless liquid: Rf=0.70, hexane/ethyl acetate (7:3, v/v); IR (film) ν2850-3000 (alkane CH) and 1H-NMR (CDCl3) δ1.15-2.0 (m, 12H), 3.39 (t, J=6 Hz, 2H), 4.42 (dt, J=48 Hz, 6 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:19][S:26]([C:24]3[S:25][C:21]([Cl:20])=[CH:22][CH:23]=3)(=[O:28])=[O:27])[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)c4ccc(Cl)s4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(5-Methyl-furan-2-ylmethyl)-quinoline-2,5-diamine (200 mg, 0.791 mmol) was dissolved in 2 mL pyridine and 5-chlorothiophene-2-sulfonylchloride (175 mg, 0.806 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of 50 mL water and 1.2 mL acetic acid. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a brown solid (192 mg, 56%), MS: m/e=434.3 (M+H+).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:12]([CH2:13][CH2:14]Cl)=[C:11](Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>C(O)C>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([N:23]2[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[C:3]([CH3:2])[C:12]=3[CH2:13][CH2:14]2)=[C:21]([CH3:26])[CH:20]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: Cc1nc2ccccc2c(Cl)c1CCCl
Agent: Cl
Solvent: CCO
Product: COc1ccc(N2CCc3c(C)nc4ccccc4c32)c(C)c1
Yield: 33.5 %

Procedure:
2-Methyl-3-(2-chloroethyl)-4-chloroquinoline hydrochloride (5.53 g, 20 mmol) and 4-methoxy-2-methylaniline (5.15 ml, 40 mmol) in ethanol (100 ml)were heated at 170° C. in a pressure vessel for 24 hours, then the solvent evaporated, the crude product taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Chromatography (silica gel, 2% methanolic ammonia in dichloromethane) and recrystallisation from aqueous methanol gave 1-(4-methoxy-2-methylphenyl)-4-methyl-2,3-dihydropyrrolo[3,2-c]quinoline (2.04 g, 22 %), m.p. 115°-117°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:15](=O)([O:22]C1C=CC([N+]([O-])=O)=CC=1)[O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:16][CH2:17][C:18]([NH:20][CH3:21])=[O:19])=[O:22])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(N2CCCNCC2)nc1
Reactant: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Product: CNC(=O)COC(=O)N1CCCN(c2ccc(Br)cn2)CC1
Yield: 70.6 %

Procedure:
The process is performed as described in Example 1 (step 1.2.). Starting with 0.95 g (3.70 mmol) of 1-(5-bromo-2-pyridyl)-1,4-diazepane, obtained in step 11.2., and 0.94 g (3.70 mmol) of 2-(methylamino)-2-oxoethyl 4-nitrophenyl carbonate, prepared in step 2.2. of Example 2, and after chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane and then with a 95/5 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether, 0.97 g of product is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Br[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.Br>C(#N)C>[Br-:10].[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:19][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[CH:4]1)([OH:17])=[O:16]
Reactant: O=C(O)CCCCBr
Reactant: BrCCc1cccc2ccccc12
Reactant: Clc1nc[nH]c1Cl
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)CCCCn1c[n+](CCc2cccc3ccccc23)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of 5-bromopentanoic acid (1.33 g, 7.36 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and placed back onto reflux. An equivalent of 1-(2-bromoethyl)naphthalene (1.73 g, 7.36 mmol) was added to solution and refluxed for 2.5 h. The solution was neutralized with 6M HBr, volatiles removed in vacuo, and the resulting product will be collected and analyzed.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH2:26].[C:31]([OH:40])(=[O:39])[C@@H:32]([C@H:34]([C:36]([OH:38])=[O:37])[OH:35])[OH:33]>CC(O)C>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[O:23][CH2:24][CH2:25][NH:26][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]=12.[C:31]([O-:40])(=[O:39])[CH:32]([CH:34]([C:36]([O-:38])=[O:37])[OH:35])[OH:33]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Reactant: COc1ccccc1OCCN
Solvent: CC(C)O
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Yield: 56.9 %

Procedure:
A mixture of 4-(oxiran-2-ylmethoxy)-9H-carbazole (II) (25.0 g, 104.60 mmole) and 62.5 ml 2-propanol is heated to 70° C. to 80° C. To this 2-(2-methoxyphenoxy)ethylamine (III) (25.33 g, 151.67 mmole) is added in one lot. The temperature of reaction mass is raised to reflux (80° C. to 85° C.) and maintained at this temperature for 2 hour. After that, this reaction mass is added to the pre-heated (80° C. to 85° C.) solution of L(+) tartaric acid (24.32 g) (162.1 mmole) in 2-propanol (287.5 ml) and continued the reflux for next 1 hour, cooled to 50° C. to 55° C. and maintained for 1 hour. The product is filtered at the same temperature (50° C. to 55° C.) followed by three 33.5 ml wash with hot (50° C. to 55° C.) 2-Propanol. The wet product dried at 60° C. to 65° C. for 6-8 hours or till constant weight gave 33.0 g of Carvedilol tartarate (Yield 56.89%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.Cl>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:3][C:4]=1[CH3:9]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1cc(Br)ccc1F
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CCC(=O)O)ccc1F
Temperature: 62 °C
Reaction time: 0.5 h

Procedure:
To an oven dried three neck flask was added Mg turnings (355 mg, 14.6 mg-at.) catalytic amount of iodine, and 20 mL THF. To the resulting mixture was added dropwise 4-bromo-1-fluoro-2-methyl-benzene (1.0 g, 0.005 mol) with heating to ˜62° C. After completing the addition of the aryl bromide, the mixture was stirred for an additional 30 min at 62° C. The THF solution of the prepared aryl magnesium bromide was cooled to −70° C. and succinic anhydride (1.0 g, 0.01 mmol) added as a solution in 10 mL THF. The mixture was vigorously stirred with warming to rt over 3 h and then hydrolyzed by the addition of 30 mL of 1M HCl. The resulting mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were extracted with 5% aqueous K2CO3 (3×10 mL) and the combined aqueous layers acidified with 1M HCl to pH3. A milky colloidal suspension was extracted with ethyl acetate (3×30 mL) and the combined organic layers washed with brine (2×20 mL). The solvent was evaporated under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH3:16][C:17]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[Cl:26])=O.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C>C(O)C>[Cl:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[C:17]1[CH:16]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]=1
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Solvent: O
Product: Clc1ccc(Cl)c(-c2cc(-c3ccccc3)c3ccccc3n2)c1
Reaction time: 24 h
Yield: 65 %

Procedure:
2-Aminobenzophenone (33 g) and 2,5-dichloroacetophenone (32 g) were placed in a flask together with 2.5 g of toluenesulfonic acid monohydrate. The mixture was heated and stirred at 160°-170° C. for 24 hours. The resulting mixture was diluted with ethanol (300 ml). The crystals was filtered to give 63 g crude product, which was treated with charcoal and recrystallized first from ethanol, followed by recrystallization from hexane and ethyl acetate to give monomer as white crystals (65%).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:3]=1[C:4](=[O:16])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=O)[O:7]1.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:3]=1[C:4]([CH:5]=[CH:6][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:8]([Cl:24])=[O:7])=[O:16]
Reactant: Cc1ccc(C)c(C(=O)CC2OC(=O)c3ccccc32)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc(C)c(C(=O)C=Cc2ccccc2C(=O)Cl)c1

Procedure:
A 1 liter flask was charged with 32.2 grams (115 mmol) of 3-(2',5'-dimethylphenacyl)phthalide, 200 ml of benzene and 50 ml of thionyl chloride. After heating at reflux on a steambath for 30 minutes, the solution was concentrated. The residue was triturated with ligroin to give 32.5 grams of o-(2',5'-dimethylbenzoylvinyl)benzoyl chloride, m.p. 96°-98° C. Analysis shows 72.29% carbon, 5.07% hydrogen and 11.80% chlorine as against calculated values of 72.36%, 5.06% and 11.87% for C18H15ClO2.