Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH:23]2[C:31](=[O:32])[CH:30]3[CH:25]([CH:26]4[O:33][CH:29]3[CH:28]=[CH:27]4)[C:24]2=[O:34])=[C:18]([CH3:35])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:36][C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39]>ClCCl>[CH3:36][C:37]([CH3:42])([CH3:41])[C:38]([O:32][C:31]1[CH:30]2[CH:25]([C:24](=[O:34])[C:23]=1[C:19]1[C:18]([CH3:35])=[CH:17][C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:21][C:20]=1[CH3:22])[CH:26]1[O:33][CH:29]2[CH:28]=[CH:27]1)=[O:39]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1C(=O)C2C3C=CC(O3)C2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (5 ml, 35.9 mmol) is added, dropwise, to a solution of 4-(4-benzyloxy-2,6-dimethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (5.0 g, 13.4 mmol) and trimethylacetyl chloride (5 ml, 40.6 mmol) in dry dichloromethane (75 ml). The mixture is stirred for 2 hours at room temperature, then silica gel is added and the solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give rac-(1R,2S,6R,7S)-4-(4-benzyloxy-2,6-dimethylphenyl)-5-oxo-10-oxatricyclo[5.2.1.02,6]deca-3,8-dien-3-yl 2,2-dimethylpropionate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][CH:15]([C:17]1[S:18][CH2:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=1)[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][CH:15]([C:17]2[S:18][CH2:19][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=2)[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)[C@H]1CSC(C(C)N)=N1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: Cl
Product: CCOC(=O)[C@H]1CSC(C(C)NC(=O)Cc2cc(F)cc(F)c2)=N1

Procedure:
Following General Procedure A above and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(1-aminoethyl)-4-ethoxycarbonyl-2-thiazoline hydrochloride (Example G), the title compound was prepared as a semisolid. The reaction was monitored by tlc (Rf=0.2 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][C:6]([OH:9])=[N:5]1)([CH3:3])[CH3:2].[Cl:10]Cl>C(N(CC)CC)C>[CH:1]([N:4]1[C:8]([Cl:10])=[N:7][C:6]([OH:9])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnc(O)n1
Reactant: ClCl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(O)nc1Cl

Procedure:
127 g of 1-isopropyl-3-hydroxy-1,2,4-triazole and 276 ml of triethylamine are dissolved in 1200 ml of absolute alcohol. The solution turns cloudy yellow. While cooling (26° to 30°C), 106.5 g of chlorine (dried by concentrated sulphuric acid) are passed in within 30 minutes. In the process, the yellow solution initially becomes clear. Subsequently triethylamine hydrochloride precipitates as crystalline product, which is filtered off after stirring for 1 further hour. The filtrate is concentrated to dryness in a rotary evaporator. The brown residue is dissolved in 1 liter of water and 1 liter of ether. The mixture is extracted and separated in a separating funnel. The aqueous phase is extracted three times with 500 ml of ether on each occasion. The combined ether phases are dried over sodium sulphate, the drying agent is filtered off and the filtrate is concentrated to dryness. The light brown residue is dissolved in 500 ml of carbon tetrachloride containing activated charcoal, whereupon the mother liquor is concentrated to 1/3 of its volume and then cooled. The active substance crystallises out and is dried in vacuo for 15 hours at 60°C/15 mm Hg. Yield: 96.3 g (60 % of theory); m.p. : 103°-105°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH3:27][C@@:28]1([C:34]([OH:36])=[O:35])[CH2:33][O:32][CH2:31][CH2:30][NH:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:30][CH2:31][O:32][CH2:33][C@@:28]2([CH3:27])[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C[C@@]1(C(=O)O)COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC[C@@]2(C)C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 59.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.77 g, 1.53 mmol) was reacted with (S)-3-methylmorpholine-3-carboxylic acid (0.22 g, 1.53 mmol) according to the procedure as described in Example 46, Step F to give the title compound as a yellow solid (0.52 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH2:17].[H-].[Na+]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH3:13])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH2:17])(=[O:11])=[O:10])=[CH:7][CH:8]=1)#[N:2]
Reactant: C=C(CBr)c1ccccc1
Reactant: CNS(=O)(=O)c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(CN(C)S(=O)(=O)c1ccc(C#N)cc1)c1ccccc1
Yield: 46.4 %

Procedure:
To a mixture of 2.30 g of 4-cyano-N-methylbenzenesulfonamide, 2.40 g of α-(bromomethyl)styrene and 20 ml of N,N-dimethylformamide, 0.63 g of 50% sodium hydride (oil dispersed) was slowly added with stirring under ice cooling, then the mixture was stirred at room temperature for 6 hours. After evaporating the solvent under a reduced pressure, ethyl acetate was added to the residue. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate n-hexane) to obtain 1.70 g of the titled compound.
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[OH:25]>CN(C=O)C.O>[F:6][CH:2]([F:7])[O:25][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]=1[F:15]
Reactant: O=[N+]([O-])c1cccc(O)c1F
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OC(F)F)c1F
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To a mixture of sodium 2-chloro-2,2-difluoroacetate (7.14 g, 46.8 mmol) and potassium carbonate (3.50 g, 25.3 mmol) in DMF (10 mL) and water (2.5 mL) at 110° C. was added a solution of 2-fluoro-3-nitrophenol (2 g, 12.65 mmol) in DMF (10 mL) and the mixture was stirred at 110° C. for 6 h. After cooling down, the mixture was quenched with water and extracted with EtOAc. The organic layer was then washed with water, brine and dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.79 (td, 1H), 7.45 (t, 1H), 5.15 (m, 1H), 7.44 (m, 1H). tR (HPLC conditions f): 2.09 min.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].C(O[CH:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=O)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:26]1([CH:16]([C:5]2[C:3](=[O:4])[C:2]([CH3:1])=[C:8]([CH3:9])[C:7](=[O:10])[C:6]=2[CH3:11])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CC(=O)OC(CCCCCCC(=O)O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)C(C(CCCCCCC(=O)O)c2ccccc2)=C(C)C1=O
Yield: 78.7 %

Procedure:
2,3,5-Trimethylhydroquinone (3.1 g, 0.02 mole) and 8-acetoxy-8-phenyloctanoic acid (6.0 g, 0.021 mole) were added to toluene (80 ml), and boron trifluoride ethyl etherate (0.3 ml) was added dropwise to the mixture at room temperature, with stirring. The reaction solution was stirred at room temperature for 4 days, and then the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml), and a 10% aqueous solution of ferric chloride was added to the solution to conduct oxidation to the quinone derivative. The reaction product was extracted twice with ethyl acetate, and the organic layer was washed with water, dried and concentrated under reduced pressure. The resulting crude product was chromatographed on a silica gel column, followed by elution with isopropyl ether, and the quinone derivative was recrystallized from isopropyl ether to give 8-phenyl-8-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)octanoic acid (5.8 g, 78%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 10 to 19, 50 and 51 were prepared.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[S:10][CH3:11])[CH:5]=[O:6].[BH4-].[Na+].Cl.O>C1COCC1>[F:12][C:8]1[CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=[C:2]([F:1])[C:9]=1[S:10][CH3:11]
Reactant: CSc1c(F)cc(C=O)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1c(F)cc(CO)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of 3,5-difluoro-4-(methylthio)-benzaldehyde (31.3 g, 0.166 mol) in anhydrous THF (200 mL) cooled with a cold water bath was added sodium borohydride (1.6 g, 0.042 mol) in portions over 30 minutes. After stirring 1 hour at room temperature, excess dilute HCl was added, until gas evolution ceased. Water (600 mL) was added and the mixture extracted with dichloromethane (1×500 mL, 1×100 mL). The combined extracts were washed once with water, dried with magnesium sulfate, and concentrated. Purification by silica gel chromatography using 3% ethyl acetate/10% dichloromethane in hexanes initially, and eluting product with 60% ethyl acetate in hexanes gave [3,5-difluoro-4-(methylthio)-phenyl]methanol as a light yellow liquid (24.8 g, 78%). 1H NMR (CDCl3/400 MHz) 6.88-6.93 (m, 2H), 4.65 (s, 2H), 2.42 (s, 3H). HRMS m/z 190.0266 (M+H+, calcd 190.0264).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][C:15]=1[Cl:16]>CN(C=O)C>[NH2:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Br:1])=[C:12]([C:17]([F:20])([F:18])[F:19])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Solvent: CN(C)C=O
Product: Nc1cc(C(F)(F)F)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.7 %

Procedure:
A solution of N-bromosuccinimide (1.0 g, 5.6 mmol) dissolved in DMF (3 mL) was slowly added to a mixture of 3-amino-4-chlorobenzotrifluoride (1 g, 5 mmol) dissolved in DMF (2 mL) and the reaction mixture was stirred at RT for 20 min, concentrated, and extracted with ethyl acetate/water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by flash chromatography (eluted with 100% hexanes) to produce the title intermediate as a reddish colored oil (970 mg, 70% yield). (m/z): [M+H]+ calcd for C7H4BrClF3N, 273.92, 275.92 found 276.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]1[N:21]=[C:20]([C:22]#[N:23])[C:19]([C:24](OC)=[O:25])=[C:18]([NH:28][C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>[Pd].CCO>[O:25]=[C:24]1[C:19]2[C:18]([NH:28][C:29]3[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=3)=[N:17][C:16]([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:21][C:20]=2[CH2:22][NH:23]1
Reactant: COC(=O)c1c(C#N)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cccc(Nc2nc(N3CCCCC3CNC(=O)OC(C)(C)C)nc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
A mixture of methyl 2-(2-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)-4-cyano-6-(m-tolylamino)pyrimidine-5-carboxylate (310.1 mg, 0.645 mmol), palladium on carbon (72.4 mg, 0.680 mmol) in EtOH (8 mL), and 1N HCl (4 mL) was stirred at RT for 16 h. The mixture was filtered to remove the catalyst. The filtrate was treated with saturated aq NaHCO3 (20 mL) for 3 h. The mixture was concentrated under reduced pressure and the residue was extracted with EtOAc (2×40 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL), were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (213.4 mg, 73%). 1H-NMR (DMSO-d6) δ ppm 1.28 (s, 9H), 1.35 (br s, 1H), 1.49-1.56 (m, 2H), 1.67-1.69 (m, 3H), 2.31 (s, 3H), 3.06 (br s, 1H), 3.24 (br s, 2H), 4.16 (s, 2H), 4.67 (br s, 1H), 5.08 (br s, 1H), 6.77 (br s, 1H), 6.87 (d, 1H, J=7.0 Hz), 7.23-7.25 (m, 1H), 7.53 (br s, 2 h), 8.07 (s, 1H), 8.55 (s, 1H). [M+H] calc'd for C24H33N6O3, 453. found, 453.5.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:7][CH2:1][C:2]4[O:6][CH:5]=[CH:4][CH:3]=4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:31])(=[O:32])[C:16]=2[CH:33]=1)=[O:11]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: NCc1ccco1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCc3ccco3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Freshly distilled furfurylamine (0.58 g, 0.60 mmol) and tetrabutylammonium iodide (0.010 g, 0.027 mmol) were sequentially added with stirring to a solution of Example 56k (0.5 g, 1.20 mmol) in dry methanol (10 mL). The reaction mixture was stirred at 110° C. for 5 h in an atmosphere of nitrogen. It was concentrated, treated with methanolic HCl solution (15 mL), refluxed overnight, concentrated, treated with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.438 g, (84.88%); 1H NMR (DMSO-d6): δ 1.70 (s, 2H, CH2), 2.30 (m, 6H, 3CH2), 2.65 (s, 3H, CH3), 3.05 (q, 2H, CH2), 3.60 (t, 2H, CH2), 3.90 (s, 3H, OCH3), 5.10 (s, 2H, CH2), 6.25 (t, 1H, NH), 6.70 (s, 1H, Ar), 6.70 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar); MS (CI+): m/e (ES+) 490 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>>[CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:29](=[O:30])[C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC1)O2
Yield: 51 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 4-nitrobenzoic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 51%.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[N:16]=[C:15]([Cl:17])C=C[C:9]=1[C:10](O)=O.CN(C)C=O>C(Cl)Cl>[Cl:17][C:15]1[N:16]=[C:8]([Cl:7])[CH:9]=[CH:10][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (2M solution, 20 mL) (Aldrich, Milwaukee, Wis.) was added to a mixture of 2,6-dichloronicotinic acid (6.2 g) and N,N-dimethylformamide (DMF) (0.5 mL) in DCM (100 mL) at room temperature. After stirring at room temperature for 2 hours, the reaction was concentrated to give 2,6-dichloro-nicotinoyl chloride (used directly in the next step).
Reaction SMILES: [CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([N:13]2[CH2:18][CH2:17][NH:16][C@H:15]([CH3:19])[CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH:2]=1.CS(O[CH2:25][CH2:26][C@H:27]1[C:32]2[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[O:38])=[CH:36][C:31]=2[CH2:30][CH2:29][O:28]1)(=O)=O>>[CH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][C@H:27]4[C:32]5[CH:33]=[CH:34][C:35]([C:37]([NH2:39])=[O:38])=[CH:36][C:31]=5[CH2:30][CH2:29][O:28]4)[C@H:15]([CH3:19])[CH2:14]2)=[CH:5][CH:4]=[C:3]3[CH:2]=1
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)C=C3)CCN1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)C=C3)CCN1CC[C@@H]1OCCc2cc(C(N)=O)ccc21

Procedure:
(3R)-1-(5-Acenaphthylenyl)-3-methylpiperazine was condensed with 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate, as described for Example 1b), to yield the title compound. M+H=454.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([Cl:18])[C:11]([F:17])=[CH:12][CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C>C(O)(=O)C.O.S(=O)(=O)(O)O>[CH:19]1([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([F:17])[C:10]=3[Cl:18])[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)ccc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)ccc2c1=O
Temperature: 25 °C

Procedure:
A quantity of 1.93 g of ethyl-1-cyclopropyl-1,4-dihydro-7-fluoro-8-chloro-4-oxo-quinoline-3-carboxylate is dissolved in 30 ml of a mixture of acetic acid, water and sulfuric acid (8/6/1). the mixture is refluxed for 3 hours and cooled to room temperature. The desired compound is collected by filtration and air dried.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][NH2:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:27])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>C(OCC)(=O)C>[O:28]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][NH:26][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:27])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCN)c2c1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCNc3ccccn3)c2c1
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]ethane-1,2-diamine (150 mg, 0.38 mol, prepared in analogy to Example 9-16), 2-bromo-pyridine (60 mg, 0.38 mol), tri(dibenzylideneacetone)dipalladium(0) (17.4 mg, 0.019 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthe (22 mg, 0.038 mmol), cesium carbonate (247.6 mg, 0.76 mmol) and N-methylpyrrolidinone (3 mL) was heated with stirring at 150° C. for 6 hours under nitrogen. The mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, concentrated in vacuo. The residue was purified by preparative HPLC to give 10 mg of produce as an off-white solid. MS obsd. (ESI+) [(M+H)+] 474, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.1 (d, J=6.4 Hz, 1 H), 7.96 (dd, J=1.2, 8.0 Hz, 1 H), 7.81 (d, J=6.8 Hz, 1 H), 7.54-7.39 (m, 5 H), 7.27 (dd, J=2.0, 8.8 Hz, 1 H), 6.63-6.56 (m, 2 H), 6.07 (s, 1 H), 5.10 (s, 2 H), 4.52 (brs, 2 H), 3.69 (t, J=6.4 Hz, 2 H), 3.55 (m, 4 H), 2.40 (s, 3 H).
Reaction SMILES: BrCC.[CH:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:11](Br)[CH:12]=[CH2:13].Cl>CCOCC.Cl[Cu]>[CH2:4]=[CH:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C=CCBr
Reactant: C#CCCCCC
Agent: Cl[Cu]
Agent: Cl
Solvent: CCBr
Solvent: CCOCC
Product: C=CCC#CCCCCC
Yield: 70 %

Procedure:
A solution of bromoethane (43.6 g, 400 mmol) in Et2O (280 ml) was added dropwise to a suspension of Mg (9.6 g, 400 mmol) in Et2O (140 ml). After 3 hours a solution of 1-heptyne (35.0 g, 360 mmol) in Et2O (140 ml) was added dropwise to the reaction medium. After 90 minutes at reflux, CuCl (1.8 g, 18.2 mmol) was added to the cold reaction mixture and after 15 minutes a solution of allyl bromide (48.4 g, 400 mmol) in Et2O (140 ml) was added dropwise. After 18 hours at reflux, the cold reaction mixture was poured onto 10% aqueous HCl (320 ml) at 0° C. The aqueous phase was extracted with Et2O, then the organic phase was washed with H2O, dried (MgSO4), concentrated and distilled through a Vigreux column (65°/15 mbar) to afford the pure desired compound (70%).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[OH-].[K+].CCO>[CH:27](=[C:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH2:14][CH2:13][C:11]3[N:10]=[CH:9][NH:8][CH:12]=3)[CH:17]=2)[C:22]1=[O:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 47.8 %

Procedure:
According to the method of Example 6, the product of Step 1 (0.271 g, 0.76 mmol) was reacted with benzaldehyde (0.121 g, 1.14 mmol) in 5 mL of 4% KOH in EtOH for 3 hours at room temperature to afford 0.125 g (46%) of the title compound as a foam which solidified on standing to give a yellow solid, mp 53-56° C.: CI-MS m/e 345 (M+ +1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:15]=[CH:14][C:9]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][C:6]1=[O:7].[N-:16]=[N+:17]=[N-:18].[Na+]>C(#N)C>[N:16]([CH2:2][CH2:3][CH2:4][N:5]1[CH:15]=[CH:14][C:9]([NH:10][C:11](=[O:13])[CH3:12])=[N:8][C:6]1=[O:7])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1ccn(CCCCl)c(=O)n1
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Nc1ccn(CCCN=[N+]=[N-])c(=O)n1
Temperature: 25 °C

Procedure:
A mixture of 1-(3-chloropropyl)-N4-acetylcytosine and sodium azide in acetonitrile was refluxed for 24 hours, cooled to room temperature, and filtered. The crude product was purified by silica gel column chromatography and gave 1-(3-azidopropyl)-N4-acetylcytosine as a white solid.