Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2ncccc2c1
Reaction time: 0.08 h
Yield: 20.8 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (164 mg, 0.728 mmol) in dichloromethane (4 mL) was added pyridine (140 μL, 1.74 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-aminoquinoline (100 mg, 0.694 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (10 mL) was added and the mixture was extracted into ethyl acetate (20 mL). The organic: phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a pale pink solid (48 mg, 21%), single spot at Rf 0.71 (ethyl acetate). mp 228.0-228.5° C., HPLC purity 99+% (tR 2.43 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.83 (1H, dd, J=4.2, 1.7 Hz), 7.98 (3H, m), 7.54 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=2.7 Hz), 7.39-7.32 (2H, m), 7.20 (1H, t, J=7.9 Hz), 7.05 (1H, s, N—H), 2.75 (3H, s). LCMS: 331.16 (M−). FAB-MS (MH+, C16H13CIN2O2S): calcd 333.0464, found 333.0461.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][C:16](=[O:18])[NH:15][CH2:14][CH:13]2[C:19](O)=[O:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:29][NH2:30])=[CH:24][CH:23]=1.Cl.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:28]([O:29][NH:30][C:19]([CH:13]1[CH2:14][NH:15][C:16](=[O:18])[CH2:17][N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:20])[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N2CC(=O)NCC2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CC(=O)NCC2C(=O)NOCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxylic acid (166 mg, 0.53 mmol) in methylene chloride (5 ml) is added 0-benzyl hydroxylamine hydrochloride (255 mg, 1.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153 mg, 0.8 mmol) and triethylamine (370 μL 2.65 mmol). The resulting mixture is stirred overnight, diluted with ethyl acetate and washed with 1N hydrocloric acid. The organic layer is dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with 5% methanol in methylene chloride) to provide N-(benzyloxy)-1-(4-methoxybenzenesulfonyl)-5-oxo-piperazine-2-carboxamide.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:12]2[N:11]([CH2:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH2:22][CH2:23][NH:24][C:25](=[O:26])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:28][C:29]1[N:30]=[CH:31][N:32](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:33]=1[CH3:34].C(=O)(O)[O-].[Na+]>COCCOC.C(O)(=O)C.O>[F:3][C:4]1[C:12]2[N:11]([CH2:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH2:22][CH2:23][N:24]([CH2:28][C:29]4[N:30]=[CH:31][NH:32][C:33]=4[CH3:34])[C:25](=[O:26])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NCCc2c1c1cccc(F)c1n2COCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2COCc2ccccc2)C1=O
Reaction time: 18 h
Yield: 306 %

Procedure:
Sodium hydride (60% dispersion in oil; 28 mg) was added to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-[(phenylmethoxy)methyl]-1H-pyrido[4,3-b]indol-1-one (190 mg) in dry DME (10 ml). The mixture was heated at 50° for 6 h then treated with 4-(chloromethyl)-5-methyl-1-(triphenylmethyl) -1H-imidazole (261 mg) and stirring was continued under nitrogen for 18 h. Water (2 ml) and acetic acid (2 ml) were added and the solution was heated at reflux for 2.5 h. The solution was poured into 8% sodium bicarbonate solution (50 ml) and extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 750 mg) which was purified by FCC eluting with System A (200:10:1) to give the title compound (188 mg), t.l.c (System A, 200:10:1) Rf 0.33.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13].CCOCC>C1(O)C=CC=CC=1>[ClH:1].[N+:8]([C:7]1[C:2]([NH:13][NH:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)NN
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)NNc1ncccc1[N+](=O)[O-]
Product: Cl

Procedure:
A 24 g (0.15 mole) portion of 2-chloro-3-nitropyridine in 153 ml of phenol at 45°-50° was treated portionwise with 20.5 g (0.20 mole) of ethyl carbazate, keeping the temperature below 60°, using rapid mechanical stirring. The reaction mixture was heated on a steam bath for 5 hr, cooled to 45 -55°, and poured into 750 ml of anhydrous ether, using rapid hand stirring. A light orange solid was collected, washing with 400 ml of anhydrous ether, m.p. 142°-152° dec. Yield: 34 g (85%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[N:6][CH:7]=1.C([Li])CCC.[O:27]1[CH2:30][C:29](=[O:31])[CH2:28]1.CO>C1COCC1>[CH3:15][C:14]1[O:13][N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[CH2:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:29]2([OH:31])[CH2:30][O:27][CH2:28]2)=[CH:3][CH:4]=1
Reactant: O=C1COC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C2(O)COC2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
A solution of 5-bromo-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine (100 mg, 0.29 mmol) THF (3 mL) was treated with n-butyl lithium (1.6 M in hexanes, 0.18 mL, 0.29 mmol) at −75° C. Then a solution of 3-oxetanone (22.0 mg, 0.29 mmol) in THF (1 mL) was added and the mixture was stirred for 10 min. Methanol was then added and the mixture was allowed to warm to room temperature. Purification by chromatography (SiO2, ethylacetate/heptane 2:8 to 1:1) afforded the title compound (65 mg, 66%) as a white solid. MS: m/e=339.1 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH:38]=[CH:39][CH2:40][NH2:41])[CH2:33][CH2:32]1>N1C=CC=CC=1>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:37][CH:38]=[CH:39][CH2:40][NH:41][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:22][CH:21]=2)[CH2:35][CH2:36]1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NCC=CCN1CCN(c2cccc(Cl)c2Cl)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: O=C(NCC=CCN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
1,1′-carbonyldiimidazole (0.18 g, 1.1 mmol) was added to a solution of the 4-hydroxy benzoic acid (0.15 g, 1.1 mmol) in absolute pyridine and the mixture was stirred at room temperature under Argon for 1 h. After that time a solution of 4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-but-2-enylamine (0.33 g, 1.1 mmol) in 3 ml amylene-stablized chloroform was added and the mixture was stirred overnight. All volatiles were removed in vacuo and the residue was purified by chromatography to give 0.23 g (51%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][CH2:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=[CH:9][CH:8]=[CH:7][N:6]2[C:21]=1[CH3:22].[C-:23]#[N:24].[K+].CS(C)=O.C(Cl)Cl>O>[C:23]([CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][CH2:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=[CH:9][CH:8]=[CH:7][N:6]2[C:21]=1[CH3:22])#[N:24]
Reactant: [C-]#N
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CCl)nc12
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(CC#N)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
2-chloromethyl-8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridine (2.4 mmol) and potassium cyanide (2.4 mmol) were added to dimethyl sulfoxide (25 ml) and stirred for 2 h. at room temperature. Methylene chloride and water were added to the reaction mixture and the organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by by column chromatography on silica gel using methylene chloride:methanol (10:1) as eluent. Crystallization from acetonitrile gave 0.25 g (34%) of the title compound.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:20](O)=[O:21])=[CH:14][C:15]=2[O:17][CH2:18][CH3:19])[N:10]([CH:23]2[CH2:25][CH2:24]2)[CH:9]=1)=[O:7])(C)(C)C.Cl.[NH:27]1[CH:31]=[C:30]([C:32]2[CH:33]=[C:34]3[C:44](=[CH:45][CH:46]=2)[O:43][C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][C:35]3=[O:47])[CH:29]=[N:28]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH:23]1([N:10]2[C:11]3[C:16](=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[C:13]([C:20]([N:40]4[CH2:41][CH2:42][C:37]5([CH2:36][C:35](=[O:47])[C:34]6[C:44](=[CH:45][CH:46]=[C:32]([C:30]7[CH:31]=[N:27][NH:28][CH:29]=7)[CH:33]=6)[O:43]5)[CH2:38][CH2:39]4)=[O:21])[CH:12]=3)[C:8]([C:6]([OH:7])=[O:5])=[CH:9]2)[CH2:24][CH2:25]1
Reactant: CCOc1cc(C(=O)O)cc2c1c(C(=O)OC(C)(C)C)cn2C1CC1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3cn[nH]c3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cn[nH]c4)ccc2O3)cc2c1c(C(=O)O)cn2C1CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.21 mL) was added to a solution of 3-(tert-butoxycarbonyl)-1-cyclopropyl-4-ethoxy-1H-indole-6-carboxylic acid (177 mg), 6-(1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (156 mg), WSC hydrochloride (106 mg) and HOBT (85 mg) in DMF (4 mL) and the mixture was stirred at 90° C. for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate, then washed with water, 1N hydrochloric acid solution, aqueous saturated sodium bicarbonate and saturated saline in this order, and dried over sodium sulfate. The solution was filtered, concentrated, and purified through silica gel column chromatography (chloroform/methanol) to give the methyl ester of the title compound as a colorless amorphous substance. TFA (3 ml) was added to the solution of this ester in chloroform (10 ml) at room temperature and stirred for 3 h. The solvent was evaporated and the residue was crystallized from a mixed solvent of methanol and ether to give title compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.03 (2H, s), 7.94 (1H, s), 7.87 (1H, d, J=2.4 Hz), 7.83 (1H, dd, J=8.5, 2.4 Hz), 7.33 (1H, d, J=1.0 Hz), 7.10 (1H, d, J=8.5 Hz), 6.79 (1H, d, J=1.0 Hz), 4.31-4.19 (1H, br m), 4.21 (2H, q, J=7.0 Hz), 3.85-3.21 (4H, br m), 2.89 (2H, s), 2.11-1.70 (4H, br m), 1.39 (3H, t, J=7.0 Hz), 1.10-1.00 (4H, m); MS [M+H]+=555.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH:5][C:6]1[O:7][CH2:8][C:9](=[O:15])[C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(OC)(=O)CC(OC)=O.ClCC(Cl)=O.FC1C=CC=CC=1CN.[NH:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][N:50]=2)[C:45]([CH:52]=O)=[CH:44]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:43]1[C:51]2=[N:50][CH:49]=[CH:48][CH:47]=[C:46]2[C:45]([CH:52]=[C:8]2[O:7][C:6]([NH:5][CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[F:1])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]2=[O:15])=[CH:44]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COC(=O)C1=C(NCc2ccccc2F)OCC1=O
Agent: NCc1ccccc1F
Agent: O=C(Cl)CCl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: COC(=O)CC(=O)OC
Solvent: CCO
Product: COC(=O)C1=C(NCc2ccccc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
To a solution of methyl 2-[(2-fluorobenzyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.35 g, 1.5 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and 2-fluorobenzylamine, and 7-azaindole-3-carboxaldehyde (0.22 g, 1.5 mmol) in ethanol (10 mL), L-proline (0.018 g, 0.15 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.13 g, y. 24%).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:27][CH3:28])[C:25]=1[OH:26])[C:20](O)=[O:21].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CO.ClCCl>[CH3:28][O:27][C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:25]=1[OH:26])[C:20]([N:9]1[CH2:10][CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:21]
Reactant: OCCC1(c2ccccc2)CCNC1
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1O
Reaction time: 18 h

Procedure:
Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.50 g, 2.7 mmol) (prepared by extraction from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and dichloromethane (25 mL). Add 3,5-dimethoxy-4-hydroxybenzoic acid (0.55 g, 2.78 mmol), 1-hydroxybenzotriazole hydrate (0.4 g, 2.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56 g, 2.9 mmol). After 18 hours, dilute the reaction mixture with dichloromethane and extract with saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with methanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1 to give the title compound; Rf=0.74 (silica gel, methanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1([CH3:21])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[S:16]([O:19][NH2:20])(=[O:18])=[O:17].CCOCC>ClCCl>[C:8]1([CH3:21])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[S:16]([O-:19])(=[O:18])=[O:17].[NH2:1][CH:2]1[N:7]([NH2:20])[CH:6]=[CH:5][CH:4]=[NH+:3]1
Reactant: Nc1ncccn1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: NC1[NH+]=CC=CN1N
Reaction time: 8 h
Yield: 80.7 %

Procedure:
2-Aminopyrimidine (0.8 g, 8.41 mmole) in dichloromethane (16 mL) at 4 C. was treated dropwise with O-mesitylenesulfonylhydroxylamine (2.65 g, 12.3 mmole) in dichloromethane (10 mL). After stirring overnight at 4 C., ether (25 mL) was added and the mixture stored at 4 C. for 3 hr. The product was filtered out and washed with 1:1 dichloromethane/ether, (50 mL) giving 2.26 g crude product. Recrystalization from methanol/dichloromethane/ether gave 2.12 g of the title compound, mp 190-191 C. Ref.: Tamura et al., J. Heterocycl. Chem. 1975;12:107.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]([SH:24])([Cl:23])[Cl:22]>CCOCC>[Cl:20][C:21]([Cl:23])([Cl:22])[S:24][N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:7](=[NH:12])[C:8]([Cl:9])([Cl:11])[Cl:10]
Reactant: CCOCCNC(=N)C(Cl)(Cl)Cl
Reactant: SC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOCCN(SC(Cl)(Cl)Cl)C(=N)C(Cl)(Cl)Cl
Reaction time: 4 h
Yield: 83.6 %

Procedure:
To 4.7 g (0.02 mole) N-(2-ethoxyethyl)trichloroacetamidine, 2.1 g (0.02 mole) triethylamine, and 50 ml ether, cooled in an ice bath, was added 3.8 g (0.02 mole) perchloromethylmercaptan over 15 minutes. The temperature rose from 1.5° C. to 8.5° C. The solution was stirred 11/4 hours longer, filtered and rotary evaporated to give 6.4 g solid. Recrystallization from petroleum ether (cooling in dry ice) gave 4.0 g (54% yield; mp 65°-66° C.). The structure was confirmed via IR and elemental analysis.
Reaction SMILES: Br[CH2:2][Br:3].[C:4]1([Li])[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1>CCCCC>[CH:8]1([CH2:7][C:4]2[C:16]3[CH2:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8]=3[CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:14][CH:15]=[CH:16]1.[Br:3][CH2:2][C:4]1[C:16]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Reactant: BrCBr
Solvent: CCCCC
Product: BrCc1cccc2c1Cc1ccccc1-2
Product: C1=CC(Cc2cccc3c2Cc2ccccc2-3)C=C1
Reaction time: 2 h

Procedure:
The ligand (cyclopentadienyl)(fluorenyl)methane was prepared as follows. To 0.4 mole dibromomethane dissolved in 200 mL pentane was added 0.2 mole fluorenyllithium powder. After the addition was complete, the reaction mixture was stirred for two hours. The reaction mixture was filtered and the filtrate washed with 100 mL of distilled water. The organic phase was dried with Na2SO4 and the solvent was stripped under vacuum. The residue was washed with 150 mL pentane to remove unreacted fluorene and dried under vacuum to yield pale yellow colored (bromo)(fluorenyl)methane. The yield was 80%. The (bromo)(fluorenyl)methane was dissolved in 20 mL ether and 19 mL (2M in THF) cyclopentadienylsodium was added at a rate of 0.15 mL/min. The reaction mixture was stirred for two hours and washed with 50 mL distilled water. The organic phase was dried over Na2SO4 and the solvent removed under vacuum to yield pale yellow (cyclopentadienyl)(fluorenyl)methane. The yield was 70%.
Reaction SMILES: O[C@H:2](C)[C@H:3](NC(C1C=CC(C(C2C=CC=CC=2)=O)=CC=1)=O)C(OC)=O.NCCNCC(N[C:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([CH2:51][CH3:52])=CC=2)=[CH:41][CH:40]=1)=[O:38])C(=O)NO.C1C[O:56]CC1>O.CCCCCC.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:49]1([C:50]#[C:45][C:42]2[CH:41]=[CH:40][C:39]([C:37]([OH:38])=[O:56])=[CH:44][CH:43]=2)[CH:48]=[CH:51][CH:52]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(C(=O)c2ccccc2)cc1)[C@@H](C)O
Reactant: C1CCOC1
Reactant: CCc1ccc(-c2ccc(C(=O)NC(CNCCN)C(=O)NO)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: O
Product: O=C(O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 10 °C
Reaction time: 2.5 h

Procedure:
The 4-iodo-benzoic acid methyl ester 1 (20.0 g, 76.34 mmol), ethynyl-benzene 2 (8.56 g, 83.96 mmol), PdCl2(PPh3)2 (0.65 g, 0.92 mmol), and CuI (0.35 g, 1.83 mmol) were mixed with THF (110 ml) in a round bottom under argon. The dry THF was sparged with dry, oxygen-free argon for at least 5 min. immediately before use. The reaction was cooled to 10° C. and TEA (16 ml) was added. The cooling bath was removed and the reaction was stirred at RT under argon. After 2.5 h, the reaction was diluted with EtOAc (400 ml) and the solids were filtered off through a pad of celite. The organic filtrate was washed with 1M HCl (60 ml), sat. aq. NaHCO3 (60 ml), water (60 ml), brine (60 ml), dried with Na2SO4, filtered and concentrated under reduced pressure. The crude solid methyl ester was dissolved in MeOH (400 ml), 6M NaOH (30 ml) and water (50 ml). The reaction was stirred at 70° C. until a clear solution was formed (about 1 h). The reaction could be followed by LCMS. The reaction was cooled and diluted with water (500 ml) and hexane (100 ml). The pH was adjusted to pH 6-7. The white solid that formed was collected and washed with water (3×60 ml) and hexane (3×60 ml). The solid 3 was dried in vacuo yielding 17.3 g (approximately quantitative yield in 99% purity).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li][CH2:9][CH2:10][CH2:11]C.BrCCC.O>O1CCCC1>[CH2:9]([CH:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:1]1=[O:7])[CH2:10][CH3:11]
Reactant: O=C1CCCCN1
Reactant: [Li]CCCC
Solvent: CCCBr
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCCNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
A solution of 4.2 g (42.3 mmol) of δ-valerolactam (5) in 35 mL of tetrahydrofuran was cooled to -78° C. under argon atmosphere. To this cooled solution, 32 mL of n-BuLi (2.5 M solution in hexane, 80 mmol) was added dropwise over a period of 40 minutes. The reaction mixture was warmed to room temperature and was magnetically stirred for 2 hours. The reaction mixture was cooled to 0° C. and a solution of 3.87 mL (42.5 mmol) of 1-bromopropane in 20 mL of tetrahydrofuran was added dropwise. The reaction mixture was warmed up to room temperature and stirred magnetically for 16 hours. The reaction mixture was treated with 75 mL of water and concentrated to remove tetrahydrofuran. The residue was extracted with 3×200 mL of diethyl ether. The organic layers were combined, washed with brine, dried over MgSO4 and concentrated to yield a white solid which was recrystallized from petroleum ether to yield 3.2 g (22.6 mmol, 54%) of tetrahydro-3-propylpyridin-2(1H)-one (6). NMR, IR and MS data confirmed the compound identity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1Cl>ClC1C=CC=CC=1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[O:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cc(F)c(O)cc1F
Reactant: Clc1ccncc1Br
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1cc(F)c(Oc2ccncc2Br)cc1F
Temperature: 145 °C
Yield: 37.8 %

Procedure:
2,5-Difluoro-4-nitro-phenol (1.739 g, 9.93 mmol) and 3-bromo-4-chloro-pyridine (0.637 g, 3.31 mmol) were dissolved in chlorobenzene (6 mL) and heated at 145° C. overnight. The solvent was removed under reduced pressure and the residue partitioned between EtOAc and 10% aqueous K2CO3. The mixture was extracted with EtOAc (2×), and the combined organic extracts were washed with 10% aqueous K2CO3 and brine, dried, evaporated and purified by silica gel chromatography (hexanes/EtOAc) to yield 3-bromo-4-(2,5-difluoro-4-nitrophenoxy)pyridine (414 mg, 38% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.84 (s, 1H), 8.51-8.45 (m, 2H), 7.82-7.78 (m, 1H), 7.22 (d, 1H); MS (ESI) m/z: 331.0 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.O.[Br:12]Br>C(O)(=O)C>[Br:12][C:5]1[S:1][C:2]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:3]=2[CH:4]=1
Reactant: O=C1CCCc2sccc21
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2sc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
In a 500 mL round bottomed flask was placed 6,7-dihydro-4-benzo[b]thiophenone (8.3 g, 54 mmol) and then dissolved in acetic acid (30 mL). To the mixture was added water (30 mL) and the solution was stirred for 30 min at rt. To the mixture was dropwise added freshly prepared solution of bromine (9.4 g, 59 mmol) in acetic acid (50 mL) over 10 min. After addition of the Br2, the mixture was stirred for 1.5 h at the same temperature. The mixture was concentrated under reduced pressure and the residue was diluted with ether (150 mL), which was washed with 1N NaOH aq (100 mL). The aqueous phase was extracted with ether (100 mL) and the combined organic phase was washed with brine (100 mL), dried over anhydrous MgSO4 and then decolorized with activated carbon. Insoluble materials were removed by filtration through Celite pad and the filtrate was concentrated under reduced pressure. The residue was suspended in 50 mL of MeOH and then stirred for 15 min for washing. The precipitate was collected by filtration to obtain the title compound (5.65 g; 45%) as a yellowish crystalline solid. From the mother liquid, 2nd crop of the title compound (6.66 g; 53%) has been obtained. LCMS: (FA) ES+ 231, 233. 1H NMR (300 MHz, d1-chloroform) δ: 7.35 (s, 1H), 2.95 (t, 2H), 2.52-2.56 (m, 2H), 2.17-2.25 (m, 2H).