Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].Br[C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:6]2[C:5](=[O:27])[N:4]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:30][CH:29]=3)[C:3]([CH2:1][CH3:2])=[N:8][C:7]=2[CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1)#[N:26]
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C(=O)OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.5 g) in N,N-dimethylacetamide (20 mL) were added ethyl 2-bromo-2-methylpropionate (0.98 g) and cesium carbonate (1.6 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature, and the insoluble material was filtered off. The filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a colorless solid (1.6 g, 83%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.[S:35]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36]1>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:11]1[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:41](=[O:42])[CH2:40][C:37]3[CH:38]=[CH:39][S:35][CH:36]=3)=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12]1
Reactant: O=C(O)Cc1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)Cc3ccsc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 24(g), by condensing tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate and 3-thiopheneacetic acid using 1,1-carbonyldiimidazole as the condensation agent there was obtained tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(2-thiophen-3-ylacetoxy-ethyl)-phenyl]-piperidine-1-carboxylate as a colourless solid, MS: 603 (M+NH4)+.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1.C1C=CC=CC=1>[CH3:1][S:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1
Reactant: CSCCC=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: CSCCC1OCCO1
Reaction time: 2 h

Procedure:
1040 g (10 moles) of freshly distilled methional, 650 g (10.5 moles) of ethylene glycol, 400 cc of benzene, 800 cc of dioxan and 10 g of p-toluene sulphonic acid are heated under reflux until the azeotropic entrainment of the water formed during the reaction, which takes 2 hours, is over. The acid medium is then neutralized by the addition of 10 g of dry sodium carbonate, after which the solution is concentrated to dryness in a water pump vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36](O)=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1([N:45]=[C:46]=[N:47]C2CCCCC2)CCCCC1.ON1C(=O)CCC1=O.N#CN.[Na]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([NH:47][C:46]#[N:45])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: N#CN
Agent: O=C1CCC(=O)N1O
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)NC#N)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A mixture of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (0.030 g, 0.052 mmol; Example 141), N,N′-dicyclohexylcarbodiimide (10.64 mg, 0.052 mmol) and N-hydroxysuccinimide (5.94 mg, 0.052 mmol) in 3 mL of THF was stirred while cooling with an ice bath for 3 h. The reaction mixture was filtered and the filtrate was added dropwise to a solution of monosodium cyanamide (10.90 mg, 0.170 mmol) in 2 mL of water at an ice bath temperature. The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was purified by reverse phase HPLC (40 to 90% water/acetonitrile gradient with 0.1% TFA). Desired fractions were then collected and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[CH:5]2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=[N+]([O-])c1cc2cc(Cl)ccc2[n+]([O-])c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc2cc(Cl)ccc2nc1Cl

Procedure:
2,6-Dichloro-3-nitroquinoline was prepared by heating a mixture of 6-chloro-3-nitroquinoline-1-oxide and phosphorous oxychloride under reflux. The product was isolated as a nearly colourless crystalline solid, mp 190° C. Mass spectrum (m/e): 242 (parent ion; 90%); 196 (100%).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:13]=[N-:14]>>[ClH:1].[C:18]1([CH2:17][CH2:16][CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCCCc1ccccc1
Agent: Cl
Product: Nc1nc(CCc2cn(CCCc3ccccc3)nn2)c[nH]1
Yield: 36 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.0735 g, 0.428 mmol) was reacted with (3-azido-propyl)benzene, which was synthesized using previously reported methods (Suenaga et al., Tetrahedron Letters 2003, 44, 5799-5801), (0.083 g, 0.514 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(3-Phenyl-propyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.051 g, 36%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.87 (s, 1H), δ 7.32-7.22 (m, 5H), δ 6.54 (s, 1H), δ 4.31 (t, 2H), δ 3.05 (t, 2H), δ 2.93 (t, 2H), δ 2.67 (t, 2H), δ 2.23 (m, 2H) ppm; 13C (75 MHz CD3OD) δ 153.3, 146.6, 140.4, 134.3, 128.8, 128.7, 128.6, 126.6, 121.5, 67.5, 53.9, 32.8, 32.9, 29.5 ppm; HRMS (ESI) calcd for C16H20N6 (M+) 296.1822, found 296.1828.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([C:10]#[N:11])=[C:6]([C:8]#[N:9])[N:7]=1)=[CH2:2].[CH2:12](N(CC)CC)[CH3:13].S(OCC)(OCC)(=O)=O>C(OCC)(=O)C.C1COCC1.CCCCCC.C(OCC)(=O)C>[CH2:12]([N:7]1[C:6]([C:8]#[N:9])=[C:5]([C:10]#[N:11])[N:4]=[C:3]1[CH:1]=[CH2:2])[CH3:13]
Reactant: CCN(CC)CC
Reactant: C=Cc1nc(C#N)c(C#N)[nH]1
Agent: CCOS(=O)(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1nc(C#N)c(C#N)n1CC
Yield: 65 %

Procedure:
A flask equipped with a magnetic stirbar was charged with 6.26 g of 2-vinyidicyanoimidazole. To this, 75 ml of distilled THF and 6.1 ml of triethylamine were added with stirring. After 5 minutes stirring, 5.7 ml of diethyl sulphate was added. This mixture was allowed to stir for 2 days. Analysis by TLC (50/50 hexane/ethyl acetate, UV visualization) showed the reaction was complete (starting material rf 0.3, product rf 0.6). The THF solution was rotovapped and the residue was dissolved in ethyl acetate. The ethyl acetate was washed with 10% aqueous sodium hydroxide. The combined aqueous layers were back extracted with methylene chloride. The combined organic layers were dried with magnesium sulphate and rotovapped to dryness. The crude residue was triturated with ether. The ether extracts were rotovapped and the residue recrystallized with ether/hexanes to yield 3.124 g of the product, mp 66-70° C. as yellow needles. A second crop yielded 1.72 g for a combined yield of 65%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([SH:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[O:26][C@H:21]2[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([S:8][C@@H:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[C@@H:21]([OH:26])[C:22]([O:24][CH3:25])=[O:23])[CH:7]=1
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1S
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](O)[C@@H](Sc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1

Procedure:
In a 25 ml flask equipped with thermometer and nitrogen admission, there are introduced 26 mg of zinc acetate dihydrate, 948 mg of 5-chloro-2-nitrothiophenol and 5 ml of toluene. To the suspension are added dropwise, within 5 mn, a solution of 1.093 g of methyl (-) (2R,3S) 3-(4-methoxyphenyl)-2,3-epoxy-propionate in 9 ml of toluene at 25° C. The temperature rises to 29° C., whilst stirring is maintained for 45 mn. The mixture is evaporated in vacuo, and a yellow oil is obtained, which is used as it is in the subsequent example.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1.[NH3:16].C1COCC1>S(Cl)(Cl)=O.CO.C(Cl)Cl>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([NH2:16])=[O:15])[CH2:9][CH2:8]1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2nccs2)CC1
Reactant: N
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@@H](Nc2nccs2)CC1
Temperature: 25 °C

Procedure:
A solution of cis-4-(thiazol-2-ylamino)cyclohexanecarboxylic acid (200 mg, 0.88 mmol) in thionyl chloride (1 ml) was stirred for 1 h at room temperature. The excess thionyl chloride was removed in vacuo to give the crude acid chloride. Liquid ammonia/THF (1:1, 15 ml) was added to the above prepared acid chloride solution at −60° C. and allowed to warm up to room temperature. The reaction mixture was diluted with 10% MeOH in DCM and filtered. The filtrate was concentrated under reduced pressure to afford 140 mg (70%) of cis-4-(thiazol-2-ylamino)cyclohexanecarboxamide as white solid.
Reaction SMILES: Cl.[C:2]1([O:12][CH2:13][CH2:14][CH2:15]Br)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:17]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:2]1([O:12][CH2:13][CH2:14][CH2:15][N:29]2[CH2:30][CH2:31][CH:26]([NH:25][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:27][CH2:28]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1cccc2ccccc12
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NC1CCN(CCCOc2cccc3ccccc23)CC1)c1ccccc1

Procedure:
The title compound as its hydrochloride, m.p. 228° C. (decomp.), was prepared by the method of Example 52 using 3-naphthyloxypropyl bromide (2.07 g.), 4-benzamidopiperidine (1.8 g.) and anhydrous potassium carbonate (1.24 g.). (Found: C, 70.4; H, 7.0; N, 6.6. C25H28N2O2HCl requires C, 70.65; H, 6.9; N, 6.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14](Cl)[CH:15]([Cl:20])[C:16]([Cl:19])([Cl:18])[Cl:17])[C:11](=[O:22])[N:10]([CH3:23])[C:9]1=[O:24].[F:25][C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28].C(N(CC)CC)C.Cl>C(#N)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[F:25])[CH:15]([Cl:20])[C:16]([Cl:19])([Cl:18])[Cl:17])[C:11](=[O:22])[N:10]([CH3:23])[C:9]1=[O:24]
Reactant: Nc1ccccc1F
Reactant: CN1C(=O)C(=NC(Cl)C(Cl)C(Cl)(Cl)Cl)N(c2ccccc2F)C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN1C(=O)C(=NC(Nc2ccccc2F)C(Cl)C(Cl)(Cl)Cl)N(c2ccccc2F)C1=O
Reaction time: 0.17 h

Procedure:
In this example 0.02 mol of 1-(2-fluorophenyl)-3-methyl-5-(1,2,3,3,3-pentachloropropyl)imino-1,3-diazolidine-2,4-dione is dissolved in 20 ml of acetonitrile and then 0.02 of mol of 2-fluoroaniline is added. After about 10 minutes, triethylamine is added to neutralize the byproduct HCl produced by the reaction. The mixture is stirred for five hours and 20 ml of ethyl ether is then added. The mixture is filtered and the filtrate evaporated under high vacuum affording 1-(2-fluorophenyl)-3-methyl-5-(1-2'-fluorophenylamino-2,3,3,3-tetrachloropropyl)imino-1,3-diazolidine-2,4-dione.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH2:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@H:8]32)[O:3]1.[OH-].[Na+:24]>O>[CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH-:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:14])([CH3:15])[O:11][C@H:8]32)[O:3]1.[Na+:24]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@H]23)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS([NH-])(=O)=O)OC(C)(C)O[C@@H]23)O1
Temperature: 60 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
10.09 g (29.73 mmoles) of topiramate (Cheminor Drugs Ltd., Hyderabad, India, Batch TP001 J00) was placed in a 250 mL beaker and 100.0 mL of HPLC grade water (J T Baker, Phillipsburg, N.J. USA, Lot V32E17) was added. 1.36 g (34.0 mmoles) of sodium hydroxide (Sigma, St. Louis, Mo. USA, Lot 99H0120) was added and the mixture was stirred with a TEFLON® coated magnetic stir bar using a hot plate/stir plate. The mixture was heated to 60° C. to dissolve. The solution was filtered and evaporated at 60° C. while blowing air over the surface using a TYGON tube attached to an air source to reduce the volume to 15 mL, and the flask was placed in a cold room (4° C.) overnight. Crystals grew overnight. The mixture was filtered and dried to yield 305 mg topiramate sodium as large, block-like crystals. Elemental analysis: calc. C 34.70, H 6.31, N 3.37%; found C 34.90, H 6.04, N 3.36%. mp 80-85° C., recrystallization from melted material 110-120° C., second mp 170-175° C. PXRD Cu—Kα radiation (1.5406 Å) first 8 peaks (peak number/2Θ value), #1/4.51°, #2/12.09°, #3/12.709°, #4/13.67°, #5/15.01°, #6/16.17°, #7/17.19°, #8/17.55°. The pH of a 400 mg/mL solution of the compound in distilled water was about 11.2, which was determined using a Thermo Orion pH meter, Model 525A+(Orion Research, Inc., Beverly, Mass. USA).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[S:5][CH:6]=[CH:7][C:8]=1[CH2:9]Br.Cl.[CH3:12][O:13][C:14](=[O:24])[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[NH2:16].C(N(C(C)C)CC)(C)C.CCCCCC>C(#N)C.C(OCC)(=O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C@H:15]([N:16]1[CH2:2][CH2:3][C:4]2[S:5][CH:6]=[CH:7][C:8]=2[CH2:9]1)[C:14]([O:13][CH3:12])=[O:24]
Reactant: COC(=O)[C@@H](N)c1ccccc1Cl
Reactant: BrCCc1sccc1CBr
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Yield: 88.3 %

Procedure:
5.0 g of 2-(2-bromoethyl)-3-bromomethylthiophene obtained in Example 7 was dissolved in 50 mL of acetonitrile, and added thereto was a solution obtained by dissolving 4.6 g of (S)-(+)-2-(2-chlorophenyl)glycine methyl ester hydrochloride and 6.8 g of diisopropylethylamine in 20 mL of acetonitrile over 30 minutes. The resulting mixture was refluxed for 8 hours, and concentrated by evaporation under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate, and washed twice with 70 mL portions of water. The organic layer was washed with 50 mL of saturated sodium chloride aqueous solution and condensed under reduced pressure. The dark yellow colored oily residue thus obtained was subjected to a silica gel column chromatography (eluent, n-hexane:ethyl acetate=5:1) to obtain 5.0 g (yield of 88%) of the title compound as a yellowish oil.
Reaction SMILES: COP([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=O)OC.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1/[CH:26]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COP(=O)(Cc1ccc(S(=O)(=O)c2ccccc2)cc1)OC
Reactant: O=Cc1ccccc1F
Product: O=S(=O)(c1ccccc1)c1ccc(/C=C/c2ccccc2F)cc1

Procedure:
The title compound was prepared from dimethyl[4-(phenylsulfonyl)benzyl]phosphonate (Step 2) and 2-fluorobenzaldehyde according to the method of Example 46 Step 5. δH (500 MHz, CDCl3): 7.97-7.92 (4H, m), 7.63-7.55 (4H, m), 7.52-7.49 (2H, m), 7.35 (1H, d, J=16.5 Hz), 7.30-7.25 (1H, m), 7.18-7.14 (2H, m), 7.10-7.06 (1H, m).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH3:13].Cl.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21]([CH:26]=[CH:27][C:28](O)=[O:29])=[CH:20][C:19]=2[CH2:18][CH2:17]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH3:13])[C:28](=[O:29])/[CH:27]=[CH:26]/[C:21]1[CH:22]=[N:23][C:24]2[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: O=C(O)C=Cc1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1cccc2c1ccn2C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cccc2c1ccn2C)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 40 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of N-methyl(1-methyl-1H-indol-4-yl)methanamine (418 mg, 2.40 mmol), 3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid hydrochloride (617 mg, 2.42 mmol), HOBt (327 mg, 2.42 mmol) and DIPEA (1.71 mL, 9.82 mmol) in anhydrous DMF (40 mL) was added EDC hydrochloride (460 mg, 2.40 mmol). The mixture was stirred overnight at 40° C. Water (60 mL) was added and the solution was stirred for 1 h. The reaction mixture was extracted with CH2Cl2 (3×100 mL). Combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated to give a red solid which was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford (E)-N-methyl-N-((1-methyl-1H-indol-4-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (320 mg, 36%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.64-10.61 (m, 1H), 8.36-8.32 (m, 1H), 8.07-7.98 (m, 1H), 7.56-7.51 (m, 1H), 7.37-7.23 (m, 3H), 7.19-7.09 (m, 1H), 6.92-6.79 (m, 1H), 6.49-6.48 (m, 1H), 5.05-4.87 (m, 2H); 3.78-3.77 (m, 3H), 3.01-2.82 (m, 5H), 2.54-2.52 (m, 2H); ESI MS m/z 375 [C22H22N4O2+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([F:13])[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.C1COCC1.O.[Fe]>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([F:13])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(C2CC2)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(C2CC2)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
4-Cyclopropyl-2-fluoro-1-nitrobenzene (prepared as described in General Procedure 1.2C) (2.2 g, 12.14 mmol) was dissolved in 7 mL of an ethanol:THF:water 3:3:1 (v/v) mixture. To this was added ammonium chloride (1.02 g, 19.07 mmol) followed by iron powder (3.50 g, 62.7 mmol). The resulting mixture was heated in a 90° C. oil bath under a nitrogen atmosphere with rapid stirring for one hour. The reaction mixture was vacuum filtered through a sand and diatomaceous earth plug. The filtrate was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to provide an orange oil (1.90 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.N#N.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:11]1([C:17]#[C:18][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 99.2 %

Procedure:
1-Bromo-4-iodobenzene (20.0 g, 70.7 mmol), bis(triphenylphospine)palladium(II) dichloride (PdCl2(PPh3)2) (250 mg), and CuI (68 mg) were suspended in 50 mL triethylamine (NEt3) and 100 mL tetrahydrofuran (THF). The suspension was treated with 3 cycles of evacuation and refilling with N2. Phenylacetylene (7.21 g, 7.75 mL, 1.0 eq) was added in 0.5 mL portions every 5 minutes to the stirred suspension. The solution was then stirred at room temperature for 22 hours. The solvents were then evaporated. Methylene chloride (100 mL) and 1 M HCl (aqueous) (50 mL) were added, the organic layer was retained, and then was washed again with 1 M HCl (aqueous) (50 mL) and 2×50 mL water, dried (MgSO4), filtered, and the solvent evaporated in vacuum to give 18 g of the title compound as a yellow solid, which was used without further purification.