Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([CH2:37]O)[CH:35]=2)[C@H:30]([N:41]([CH2:46][C:47]2[CH:52]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:50]=[C:49]([C:57]([F:60])([F:59])[F:58])[CH:48]=2)[C:42]([O:44][CH3:45])=[O:43])[CH2:29][C@@H:28]1[CH3:61])=[O:26])[CH3:23]>ClCCl.C(Cl)(Cl)Cl>[CH2:22]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([CH2:37][Br:20])[CH:35]=2)[C@H:30]([N:41]([CH2:46][C:47]2[CH:52]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:50]=[C:49]([C:57]([F:60])([F:59])[F:58])[CH:48]=2)[C:42]([O:44][CH3:45])=[O:43])[CH2:29][C@@H:28]1[CH3:61])=[O:26])[CH3:23]
Reactant: CCOC(=O)N1c2cc(CO)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1c2cc(CBr)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 71.5 %

Procedure:
To a solution of triphenylphosphine (0.457 g, 1.74 mmol) in anhydrous dichloromethane (15 mL) at 0° C. was slowly added bromine (84 μL, 1.6 mmol). After the reaction was stirred at 0° C. for 20 min, a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-hydroxymethyl-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 85) (0.630 g, 1.09 mmol) in dichloromethane (15 ml) was added. The reaction was stirred at 0° C. for 20 min, then at room temperature for 3 h. The reaction mixture was then diluted with chloroform and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent afforded the title product (0.500 g, 72%): MS m/z 642.1 (M+ +1); 1H NMR (CDCl3) δ 1.15 (d, 3H), 1.3 (t, 3H), 3.8 (s, 3H), 3.85 (s, 3H), 6.4 (s, 1H), 7.4 (s, 1H), 7.7 br, 2H), 7.8 (s, 1H).
Reaction SMILES: O.[CH3:2][C:3]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1>C(O)=O>[CH3:2][C:3]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][CH2:5][C:6](=[O:7])[CH2:11][CH2:12]1
Reactant: CCOC(=O)CC1(C)CCC2(CC1)OCCO2
Solvent: O=CO
Solvent: O
Product: CCOC(=O)CC1(C)CCC(=O)CC1

Procedure:
Water (0.5 mL) was added to a stirring solution of ethyl 2-(8-methyl-1,4-dioxaspiro[4.5]decan-8-yl)acetate (1.6 g, 6.60 mmol) and formic acid (10 mL) at room temperature. Analysis of the reaction mixture by LCMS indicated that the starting material was consumed and the desired product had formed. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc and brine, the layers were separated, the organic material washed with brine (2×), dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow liquid ethyl 2-(1-methyl-4-oxocyclohexyl)acetate (1.6 g, 8.07 mmol, 86% yield): 1H NMR (500 MHz, CDCl3) δ 1.22-1.31 (m, 6H), 1.77-1.91 (m, 4H), 2.39-2.43 (m, 6H), 4.12-4.23 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]CC2C=CC=CC=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=c1c(OCc2ccccc2)cccn1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=c1c(O)cccn1Cc1ccccc1

Procedure:
1-Benzyl-3-benzyloxy-1H-pyridin-2-one (Ghosh etal, J. Org. Chem. 1989, 54, 5073) is dissolved in anhydrous methanol (10 mL) and to the thoroughly degassed solution is added a catalytic amount of Pd-C (0.1%). The mixture is hydrogenated under a balloon of hydrogen, until all the starting material is consumed. At the completion, the solution is filtered through Celite™. The solvent is removed in vacuo, and the residue is washed with ether, to afford the desired product.
Reaction SMILES: Cl.Cl[CH:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1.Cl.[CH3:32][NH2:33].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:32][NH:33][CH:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1
Reactant: O=C1CCc2cc(C(=O)N3CCN(CCC(Cl)c4ccccc4)CC3)ccc2N1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CNC(CCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
One gram of 6-[4-(3-chloro-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril.hydrochloride, 0.17 g of methylamine.hydrochloride and 1.2 g of potassium carbonate were dispersed in 20 ml of acetonitrile and the dispersion was stirred at 60° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into water then extracted with methylene chloride. The extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation. Thus obtained residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =20:1), then the desired product was converted into a citrate, and recrystallized from ethanol-water to yield 0.5 g of 6-[4-(3-methylamino-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. dicitrate. White powdery substance. Melting point: 150° C.-156° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:20][CH3:21])[CH:7]=[O:8])[CH3:2]
Reactant: CCI
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C=O)cc1OCC
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
3-Ethoxy-4-hydroxy-benzaldehyde (Aldrich, 100 g, 0.602 mole) was dissolved in N,N-dimethylformamide (1 L). The reaction was placed under N2. Solid potassium carbonate (103 g, 0.662 moles) was added and the reaction was stirred 10 minutes. Iodoethane (175 g, 1.26 moles) was added and the reaction was stirred for 16 hours at room temperature. The reaction was monitored by thin-layer chromatography which indicated complete consumption of the phenol to give a new product. The reaction was filtered to remove the potassium carbonate and solvent removed in vacuo. The residue was dissolved in methylene chloride and filtered. Silica gel (200 g) was added and the dichloromethane removed in vacuo. The crude product absorbed on silica gel was submitted to flash chromatography (hexane, 100%, 2L, then ethyl acetate:hexane, 1:3, 2L, then ethyl acetate:hexane, 1:1) to yield 109.36 g of 3,4-diethoxy-benzaldehyde HNMR (CDCl3): 9.83 (s, 1H), 7.41 (m, 2H), 6.96 (d, 1H), 4.17 (m, 4H), 1.50 (t, 3H) 1.47 (t, 3H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[OH-].[Na+:15]>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Na+:15].[Na+:15].[Na+:15]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 78 °C

Procedure:
A 1 liter beaker was charged with 350 ml (462 g) citric acid process mother liquor containing 260.5 g citric acid and 201.5 g H2O. While stirring, 325.9 g of 50% (w/w) NaOH solution was added to bring the pH to 6.6. The solution was heated to 78° C. and filtered to remove impurities. The hot solution was placed in a 5 liter, 3 neck round bottom flask fitted with a reflux condenser, stirrer and heating mantle. The solution was heated to 80° C. and 1500 ml (1184 g) ethyl alcohol was added at a rate of 30 ml per minute which resulted in the formation of a slurry of tri-sodium citrate crystals. The flask was heated to the ethanol's reflux temperature which provided better crystal formation.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl-:9].[Cl-].[Cl-].[Al+3].ClCl>ClC(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[Cl:9]
Reactant: [Cl-]
Reactant: Clc1ccc(Cl)nn1
Agent: ClCl
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Product: Clc1cc(Cl)c(Cl)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a dry three-necked flask equipped with a refluxing condensor and a ventiduct (connected with a safety flask), 3,6-dichloropyridazine (purchased from Nanjingtianzunzezhong Chemical Agents Company) and anhydrous aluminum trichloride were added, heated by using external heat source to 120° C. to melt reactants, Cl2 gas was fed at this temperature for 3 hours, then the reaction was stopped, cooled to room temperature, trichloromethane was added to dissolve the product, the trichloromethane solution was washed with saturated sodium chloride aqueous solution for twice, the water phase was extracted with trichloromethane for twice, all trichloromethane solutions were combined together and dried over anhydrous sodium sulfate, after trichloromethane was removed by evaporation under vacuum, a reduced pressure distillation was employed to collect fraction of 110-114° C./8 mmHg or 128˜9° C./18 mmHg, a white solid was coagulated in a receiving flask. Yield: 55%, m.p. 57˜58° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.Br[CH2:30][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=O>C(#N)C>[S:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:31]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:6][N:7]2[CH:30]=1
Reactant: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reactant: O=C(CBr)c1cccs1
Solvent: CC#N
Product: O=C(Nc1ccc2nc(-c3cccs3)cn2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 100 %

Procedure:
Compound 6 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.11 g (0.53 mmol) of 2-bromo-1-(thien-2-yl)ethanone in 4 mL of acetonitrile. 0.126 g of the expected product is thus obtained in the form of a white solid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH:10]=[O:11]>S(=O)(=O)(O)O>[Br:6][C:7]1[C:14]([Cl:15])=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[C:9]([CH:8]=1)[CH:10]=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: O=Cc1ccc(Cl)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=Cc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 7 h
Yield: 47.8 %

Procedure:
To a mixture of sulphuric acid (40 ml) and sodium nitrate (2.66 g, 31.3 mM) at 0°-5° C. was added 3-bromo-4-chlorobenzaldehyde (6.25 g, 28.5 mM). The resulting mixture was stirred at room temperature for 7 h and then diluted with ice water (300 ml). The precipitated solids were filtered, washed with water and dried to give a powder. Recrystallization of this material from the mixture of isopropanol and water (2:1) provided the title 2-nitrobenzaldehyde 1f (3.6 g, 51.5%) as a light yellow powder, m.p. 81°-82° C.
Reaction SMILES: [CH2:1]([Mg]Cl)C.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(=[O:7])[CH3:6].C(OCC)C.[Cl-].[NH4+]>C1COCC1>[OH:7][C:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)([CH3:1])[CH3:6]
Reactant: CC[Mg]Cl
Reactant: CC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
Ethyl magnesium chloride (3M) in anhydrous THF (10 ml) was treated at room temperature under argon with a solution of 1-(4-acetylphenyl)-4-(4-pyridyl)piperazine (281 mg) in anhydrous THF (15 ml). The resulting solid suspension was heated at 70° C. under reflux for 3 hours. The mixture was cooled in ice at 0-5° C. and treated with diethyl ether and a saturated solution of aqueous ammonium chloride. The reaction mixture was stirred for 10 minutes with ice cooling and at room temperature for 10 minutes. The aqueous phase was then extracted with dichloromethane and the ether phase was evaporated. The residue was dissolved in dichloromethane and combined with the other organic extracts. The combined extracts were then washed with saturated brine, dried over MgSO4, filtered and evaporated to give an impure orange solid. The solid was purified by chromatography on a prepacked silica column (“Varian bond elut-trademark), eluting with a mixture of methanol (1-2%) and ammonium hydroxide (1%) in dichloromethane to obtain a pale yellow solid which was triturated with diethyl ether to give 1-(4-(1-hydroxy-1-methylethyl)phenyl)4-(4-pyridyl)piperazine (21% yield) as a pale yellow solid, m.p. 234-235° C.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:51]([O:58][C:59](=[O:69])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C>[CH2:51]([O:58][C:59](=[O:69])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:61][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.3 %

Procedure:
To N-(toluene-4-sulfonyl)-L-alanine (2.0 mmoles) in DMF (10 mL) was added BOP (2.1 mmoles) and N-methylmorpholine (4.0 mmoles) and the reaction stirred at room temperature for 45 minutes. L-Phenylalanine benzyl ester (2.0 mmoles) was added and the reaction stirred for 16 hours at room temperature. The reaction mixture was extracted with water (100 mL) and diethyl ether (3×50 mL) The combined organic layers were successively washed with 0.2 N HCl (2×50 mL), sat. NaHCO3 (50 mL), and sat. NaCl (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to yield a colorless oil (387 mg, 40%). The crude product was purified by silica gel chromatography (50% EtOAc /Hexane, Rf=0.61). The title compound was crystalized from CHCl3/Hexane to yield a white solid, mp=109-110° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.C[O:14][C:15]([C:17]1[C:26]2[C:25]3[N:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH2:23][NH:22][CH2:21][C:20]=2[NH:19][CH:18]=1)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([C:17]2[C:26]3[C:25]4[N:27]=[CH:28][CH:29]=[CH:30][C:24]=4[CH2:23][NH:22][CH2:21][C:20]=3[NH:19][CH:18]=2)=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: COC(=O)c1c[nH]c2c1-c1ncccc1CNC2
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)c1c[nH]c2c1-c1ncccc1CNC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.38 mL (4 mmol) of 3-fluoroaniline in 2 mL of methylene chloride under a nitrogen atmosphere is added dropwise 1.5 mL (3 mmol) of trimethyl aluminum (2M solution of toluene). This mixture is stirred at room temperature for 30 minutes. To this mixture is added a solution of 0.12 g (0.5 mmol) of 3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylic acid methyl ester dissolved in 8 mL of methylene chloride. The reaction mixture is heated to 40° C. for 24 hours; cooled to room temperature and quenched with 0.5 mL of saturated NaCl. After stirring for 30 minutes an additional 5 mL of methylene chloride and 2 grams of anhydrous sodium sulfate is added. The reaction mixture is filtered. The filtrate is evaporated and chromatographed on 10 grams of silica gel using 10/1/0.5 chloroform/methanol/ammonium hydroxide as the eluant. Appropriate fractions are combined and evaporated to 23 mg of 3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylic acid (3-fluoro-phenyl)-amide. 1H NMR (CD3OD) δ8.70 (m, 1H), 7.90 (m, 1H), 7.80 (m, 1H), 7.60 (s, 1H), 7.30 (m, 3H), 6.90 (m, 1H), 3.87 (s, 2H), 3.70 (s, 2H). Mass spectrum: m/e=323.2 (p+1). TLC (10/1/0.1 chloroform/methanol/ammonium hydroxide) Rf=0.3.
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:18][CH2:10][C:9]1[C:2]([F:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1cccc(C#N)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: N#Cc1cccc(CBr)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-fluoro-3-methylbenzonitrile (200 mg, 1.5 mmol) in 1,2-dichloroethane (30 ml) was added NBS (266 mg, 1.49 mmol) and AIBN (29 mg, 0.15 mmol) at RT. The reaction mixture was then heated to 80° C., and the reaction mixture was stirred for 2 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT. The volatiles were removed under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 2-3% EtOAc/hexane afforded compound I-6 (250 mg, 1.15 mmol, 78%) as colorless liquid. 1H NMR (500 MHz, CDCl3): δ 7.69-7.65 (m, 1H), 7.62-7.58 (m, 1H), 7.28-7.25 (m, 1H), 4.50 (s, 2H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH:14]1[C:19]2[C:20](=O)[CH2:21][CH2:22][C:18]=2[CH:17]=[CH:16][N:15]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH:14]1[C:19]2[CH:20]([CH2:3][C:1]#[N:2])[CH2:21][CH2:22][C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: O=C1CCc2ccncc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC1CCc2ccncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (346 mg, 1.95 mmol) in tetrahydrofuran (10 mL) was added 60% sodium hydride (54.0 mg, 1.35 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The mixture was added to a solution of 5,6-dihydro-7H-cyclopenta[c]pyridin-7-one (130 mg, 0.976 mmol) in tetrahydrofuran (5 mL) under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=50/50→80/20). To a solution of the purified product in methanol (10 mL) was added palladium-carbon powder (30 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hr. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→70/30) to give the title compound (95.0 mg, yield 62%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH:23]=[C:24]2[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][CH:22]=1>>[CH:26]1[C:25]2[C:24](=[CH:23][C:20]3[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]4[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]5[CH:15]=[CH:14][N:13]=[CH:12]5)=[CH:4][CH:3]=4)[N:19]=3)[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1coc(C=C2c3ccccc3-c3ccccc32)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: C(=C1c2ccccc2-c2ccccc21)c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 84 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(9-fluorenylidene)methyloxazole to give 2-(9-fluorenylidenemethyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 84%. Recrystallization from ethyl acetate gave yellow prisms, mp 116-117° C.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a solution of [4-(6-nitropyridin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.089 g, 0.23 mmol) in 1:1 THF:MeOH (5 mL) was added 10% Pd/C (0.051 g). The resulting mixture was stirred under hydrogen atmosphere at 25° C. for 4 h. After filtering through a celite cake, the solution was concentrated in vacuo and yielded the title compound as a light yellow solid (0.039 g, 49% yield). MS (ES+) m/z 351.3.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:46]([O:48][C:49]([C:51]1([CH2:57][CH2:58][O:59][CH3:60])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)=[O:50])[CH3:47]>>[CH2:46]([O:48][C:49]([C:51]1([CH2:57][CH2:58][O:59][CH3:60])[CH2:52][CH2:53][N:54]([C:5](=[O:7])[CH2:4][CH2:3][C:2]([CH3:1])([CH3:9])[CH3:8])[CH2:55][CH2:56]1)=[O:50])[CH3:47]
Reactant: CC(C)(C)CCC(=O)O
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(CCOC)CCN(C(=O)CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 52.8 %

Procedure:
To a solution of 4,4-dimethyl-pentanoic acid (0.351 g) in acetronitril (15 ml) were added under an argon atmosphere N-ethyldiisopropylamin (0.7 g, 0.96 ml) and BOP (1.195 g) and the mixture was stirred for 50 minutes at RT. Then 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.581 g) was added and the mixture was stirred for further 12 h at RT. The reaction mixture was then partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (methylene chloride/AcOEt, gradient from 0 to 30%) to give 1-(4,4-dimethyl-pentanoyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.466 g) as a yellow semi-solid that was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH2:27]([NH:29][CH2:30][CH3:31])C>>[CH2:30]([N:29]([CH3:27])[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[C:31]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CCNCC
Product: CN(Cc1ccccc1)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and diethylamine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 498.5 (MH+).