Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(F)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 423.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CCBr)cc1
Reactant: O=C(Nc1ccc(Cl)nc1)C(=O)c1ccccc1
Product: O=C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(Cl)nc1)c1ccccc1

Procedure:
In analogy to the procedure described for the synthesis example 43 (step 2), the title compound N-(6-chloro-pyridin-3-yl)-2-oxo-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-acetamide (MS m/e: 433.2 [M+H]+) was prepared from N-(6-chloro-pyridin-3-yl)-2-oxo-2-phenyl-acetamide and 1-(2-bromo-ethyl)-4-trifluoromethyl-benzene.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[CH:4][C:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[N:6][CH:7]=1.C([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[O:32][C:3]3[CH:4]=[C:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])[N:6]=[CH:7][C:2]=3[N:1]=2)=[N:29][CH:30]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cn1
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)cn3)nc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.3 %

Procedure:
To a solution of N-((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)acetamide (1.80 g) in ethanol (20 mL) were added iron powder (1.84 g) and iron(III) chloride (1.07 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give N-((2S)-1-((5-amino-4-chloropyridin-2-yl)oxy)propan-2-yl)acetamide (1.46 g). To a solution of N-((2S)-1-((5-amino-4-chloropyridin-2-yl)oxy)propan-2-yl)acetamide (830 mg) and 5-(benzyloxy)pyridine-2-carboxylic acid (781 mg), diisopropylethylamine (1.19 mL) in DMF (10 mL) was added HATU (1.49 g), and the mixture was stirred at room temperature for 30 min. The precipitated solid was washed with ethyl acetate-hexane. A suspension of the obtained solid, potassium carbonate (1.22 g) and copper(I) iodide (84.0 mg) in DMF (10 mL) was stirred at 160° C. for 1.5 hr. The reaction mixture was subjected to silica gel chromatography (NH, ethyl acetate), and washed with saturated brine, and the solvent was evaporated. The obtained solid was washed with ethyl acetate/hexane. A mixture of the obtained solid, 10% palladium/carbon (containing water (50%), 200 mg) and THF (10 mL) was stirred at room temperature for 30 min under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (37.4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[O:32][CH2:31][CH2:30][O:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:29]1[CH2:30][CH2:31][O:32][CH:28]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:18][C:16]1[CH:15]=[C:4]([CH:3]=[C:2]([Br:1])[CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(OCc1ccccc1)c1cc(O)cc(Br)c1
Reactant: BrCCCCCCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a stirred solution of benzyl 3-bromo-5-hydroxybenzoate (2.85 g, 9.22 mmol) in dimethyl formamide (50 mL), was added 2-(8-bromooctyl)-1,3-dioxolane (2.44 g, 9.21 mmol) and potassium carbonate (1.91 g, 13.8 mmol), and the mixture stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried (magnesium sulphate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-7% ethyl acetate in iso-hexane to afford the title compound (2.94 g, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([CH2:36]I)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(OC)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(OC)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-hydroxy-4-biphenyl carbonitrile and 3-Iodomethyl-1-(4-methoxy-benzoyl) pyrrolidine-3-carboxylic acid ethyl ester (Preparation 14) to afford the racemate as a white solid (124 mg, 71%)
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3([C:18]#N)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:8][CH2:7]2)[CH:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][NH:3]1.[C:26]1([Mg]Br)[CH:31]=[CH:30]C=[CH:28][CH:27]=1>C1COCC1>[C:20]1([CH:5]2[C:6]3([CH2:7][CH2:8][N:9]([C:12]4([C:18]5[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=5)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[CH2:10][CH2:11]3)[C:2](=[O:1])[NH:3][CH2:4]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Br[Mg]c1ccccc1
Reactant: N#CC1(N2CCC3(CC2)C(=O)NCC3c2ccccc2)CCCCC1
Solvent: C1CCOC1
Product: O=C1NCC(c2ccccc2)C12CCN(C1(c3ccccc3)CCCCC1)CC2
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of rac-1-(1-oxo-4-phenyl-2,8-diaza-spiro[4.5]dec-8-yl)-cyclohexanecarbonitrile (400 mg, 1.2 mmol) in dry THF (12 mL) under argon at 0° C. was added phenylmagnesium bromide (1 M in THF, 3.5 mL, 3.6 mmol) and the resulting mixture allowed to warm up to room temperature overnight. The reaction was quenched by the addition of ammonium chloride solution (sat., 20 mL) and the product extracted with ethyl acetate (2×50 mL). The combined organic extracts were then washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with DCM:MeOH:NH4OH (95:4.5:0.5) to afford the title compound (430 mg, 94%) as a white solid. MS: m/e=389.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH2:10][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][C:4](=O)[CH:3]=1.C([O-])(=O)C.[NH4+:16].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[NH2:16][C:4]1[CH2:5][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:10][C:2](=[O:1])[CH:3]=1
Reactant: O=C1C=C(O)CC2(CCC2)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: NC1=CC(=O)CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
10 g 8-hydroxyspiro[3.5]non-7-en-6-one and 10.1 g ammonium acetate are dissolved in 100 ml toluene and 3.2 ml acetic acid. The mixture is refluxed for 2 hours using a Dean-Stark trap. After cooling to room temperature the mixture is cautiously added to 200 ml of a saturated solution of sodium bicarbonate and 100 g ice. Then the mixture is stirred for 15 minutes, the solid product is collected by filtration and dried at 50° C. in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[CH3:23][O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][O:21][C:19]1[CH:18]=[CH:17][C:9]2[C:10]([CH3:16])([CH3:15])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[C:7](=[O:22])[C:8]=2[CH:20]=1)=[CH:4][CH:3]=[C:2]([Br:1])[CH:14]=4
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)CCCOc1ccc2c(c1)C(=O)c1c([nH]c3cc(Br)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ2, 20 mg, 0.056 mmol), 4-bromo-butyric acid methyl ester (7.0 μl, 0.056 mmol) and cesium carbonate (36.6 mg, 0.112 mmol) were dissolved in DMA (0.09 ml), and then stirred at room temperature for 1 hr. Thereafter, 4-bromo-butyric acid methyl ester (7.0 μl, 0.056 mmol) was added thereto and the mixture was stirred at room temperature for 3 hr, followed by further stirring at 45° C. for 30 min. The reaction solution was added with water, extracted with diethyl ether and dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, the resulting residues were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain 4-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-butyric acid methyl ester. This compound was dissolved in MeOH (0.50 ml), added with aqueous solution of sodium hydroxide (6 mol/1), and then stirred at room temperature for 10 min. The reaction solution was added with hydrochloric acid (3 mol/1), extracted with diethyl ether, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain white solid. This white solid was washed with methylene chloride to obtain the title compound (6.1 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[C:16]([O:20]C)=[CH:17][CH:18]=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.B(Br)(Br)Br.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[C:16]([OH:20])=[CH:17][CH:18]=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1cccc2cc(-c3cnc4ccc(Cl)nn34)sc12
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1cccc2cc(-c3cnc4ccc(Cl)nn34)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
To a solution of 6-chloro-3-(7-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (103 mg, 0.326 mmol, 1.0 equiv) in dichloromethane at −78° C. was added boron tribromide (2.27 mL, 1.0 M solution in dichloromethane, 7.0 equiv). The reaction mixture was stirred at the reduced temperature for 10 min then warmed to room temperature and stirred for 15 h. Methanol (2 mL) was added to quench the reaction and extracted with dichloromethane. Purification by column chromatography using 5% methanol in dichloromethane elution gave 70 mg of the yellow solid, 70%.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(=CC)C.CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[C:8]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc(CC2CCN(C3CCCCC3)C2=O)c1
Agent: CC=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1C(Cc2cccc(O)c2)CCN1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.2 %

Procedure:
Dissolve 1-cyclohexyl-3-(3-methoxy-benzyl)-pyrrolidin-2-one (example 67) (440 mg, 1.5 mmol) in methylene chloride (50 ml) and add 2-methyl 2-butene (0.97 ml, 9.2 mmol) followed by borontribromide (0.43 ml, 4.6 mmol) and stir at room temperature for 20 minutes. Pour reaction mixture into an ice, methanol, sodium bicarbonate mixture and stir for 5 minutes. Separate layers wash organic with brine dry over sodium sulfate, filter and concentrate. Purify by silica gel (10-20% ethyl acetate in hexanes) to yield 165 mg (39%) of the title compound: Mass spectrum (apci) m/z=274 (M+H).
Reaction SMILES: C(O)=O.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=O.[CH3:16][C:17]1([CH3:25])[O:24][C:22](=[O:23])[CH2:21][C:19](=[O:20])[O:18]1.Cl>C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:9][CH:21]1[C:22](=[O:23])[O:24][C:17]([CH3:25])([CH3:16])[O:18][C:19]1=[O:20]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: COc1ccc(CC2C(=O)OC(C)(C)OC2=O)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
Under ice-cooling, to formic acid (20 mL) was added dropwise triethylamine (29.6 mL). Then, 3,4-dimethoxybenzaldehyde (9.22 g) and Meldrum's acid (8.00 g) were added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was poured into a mixture of ice (80 g) and 1 mol/L hydrochloric acid (50 mL), and the precipitate was collected by filtration to give the title compound (14.4 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Yield: 48.8 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methyl-phenyl)-acrylonitrile (2.3 g, 7.5 mmol) prepared in Example 57a, AgF (1.3 g, 10 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 49%).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:18]3[CH2:21][CH:20](O)[CH2:19]3)[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1.C(N(S(F)(F)[F:30])CC)C>ClCCl>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:18]([F:30])[CH2:19][CH:20]=[CH2:21])[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1
Reactant: OC1CC(c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C=CCC(F)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Yield: 32.3 %

Procedure:
3-[3-(4-Difluoromethoxy-phenylethynyl)-phenyl]-cyclobutanol (0.820 gm, 2.61 mmol) was dissolved in dichloromethane (10 ml) and treated with (diethylamino)sulfur trifluoride (DAST, 0.500 gm, 3.20 mmol). Upon completion of reaction as determined by thin layer chromatography (TLC) the crude material was absorbed onto silica and purified by column chromatography (gradient elution; 0%-10% EtOAc in hexanes) to yield an oil 267 mg (32%); 1H NMR (500 MHz, DMSO-d6) δ ppm 2.55-2.75 (m, 2H) 4.97-5.20 (m, 2H) 5.52-5.83 (m, 2H) 7.04-7.32 (m, 3H) 7.40-7.48 (m, 2H) 7.50-7.55 (m, 2H) 7.62 (d, J=8.8 Hz, 2H); MS (EI) m/z 316 [M+·].
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[C:13]([I:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].[C:26]([OH:31])(=[O:30])[C:27]([OH:29])=[O:28]>CO>[C:26]([OH:31])(=[O:30])[C:27]([OH:29])=[O:28].[C:21]([NH:25][CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[C:13]([I:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)([CH3:24])([CH3:23])[CH3:22]
Reactant: ICCCC1c2ccccc2C=Cc2ccc(I)cc21
Reactant: CC(C)(C)N
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CC(C)(C)NCCCC1c2ccccc2C=Cc2ccc(I)cc21

Procedure:
5-(3-Iodopropyl)-3-iodo-5H-dibenzo[a,d]cycloheptene (2.1 g., 0.0043 mole) is dissolved in 1.82 g. (0.025 mole) of t-butylamine and the solution stirred 18 hours at room temperature. The suspension is evaporated in vacuo, treated with 0.5 N NaOH, and extracted three times with methylene chloride. The methylene chloride fractions are combined, washed three times with water, dried over sodium sulfate, and evaporated in vacuo. The residue is chromatographed on 45 g. of silica gel GF (eluted with chloroform and 2%, 5%, and 8% methanol in chloroform). The product fraction is evaporated in vacuo. The resulting oil is dissolved in methanol, treated with one equivalent (one half mole) of oxalic acid in methanol, and evaporated in vacuo. The residue, triturated with ether, provides 1.25 g. of pale yellow powder. This solid, recrystallized from methanol/acetonitrile, melts at 217.5°-218.5°.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13](C1C=CC=CC=1)[C:14](=[O:16])[O-])(=[O:12])=[O:11].[NH2:24][C:25]1[N:30]=[C:29]([CH2:31][CH3:32])[N:28]=[C:27]([O:33][CH3:34])[N:26]=1>O1CCOCC1.C(OCC)(=O)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:24][C:25]1[N:30]=[C:29]([CH2:31][CH3:32])[N:28]=[C:27]([O:33][CH3:34])[N:26]=1)=[O:16])(=[O:11])=[O:12]
Reactant: O=C([O-])N(c1ccccc1)S(=O)(=O)c1ccccc1OC(F)F
Reactant: CCc1nc(N)nc(OC)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(OC)n1
Temperature: 0 °C
Yield: 80.5 %

Procedure:
A solution of 5.4 g of N-(2-difluoromethoxyphenylsulfonyl)phenylcarbamate and 2.42 g of 2-amino-4-ethyl-6-methoxy-1,3,5-triazine in 60 ml of dioxane is refluxed for 5 hours and then poured into 600 ml of ice-water. The precipitate is taken up in ethyl acetate. The ethyl acetate phase is washed with water, dried and concentrated. The residual oil is dissolved in ethyl acetate and washed 5 times with saturated sodium bicarbonate solution. The combined aqueous phases are acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is dried and evaporated to dryness. Recrystallisation from methanol yields 5.1 g of N-(2-difluoromethoxyphenylsulfonyl)-N'-(4-ethyl-6-methoxy-1,3,5-triazin-2-yl)urea with a melting point of 114°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1OC
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(C=CC(=O)O)cc1OC
Reaction time: 7 h
Yield: 88.5 %

Procedure:
To a solution of 1000 g (6.024 mol) of 3,4-dimethoxybenzaldehyde in 3 L pyridine, 1378.3 g (13.25 mol) of malonic acid and 100 mL of piperidine were added. The resulting mixture was stirred at 105° C. to 110° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and slowly quenched the reaction mixture into 10 L of 5% sodium hydroxide solution at 25° C. to 30° C. (pH: 9-10). The reaction mixture was washed with ethyl acetate (2×5 L) and the organic layer separated was washed with 2 L of 5% sodium hydroxide solution. The aqueous layers were combined and cooled to 15° C. to 20° C. The aqueous layer was acidified slowly with 2.5 L of 50% sulphuric acid below 20° C. (pH: 1-2). After an additional 30-45 min stirring at 15° C. to 20° C., the solid obtained was collected by filtration, washed with 10 L of water followed by 4 L of n-hexane. The partially dried compound was unloaded into trays and dried at 55° C. to 60° C. for 8-10 h to give 1110 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]([CH2:14][CH:15]=[CH2:16])[CH3:13].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:12]([CH2:14]/[CH:15]=[CH:16]/[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[C:7]([CH3:8])[CH:6]=1)[CH3:13]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: Cc1cc(Br)cnc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cnc1N
Temperature: 131 °C
Yield: 123.5 %

Procedure:
A mixture of 2-amino-5-bromo-3-methylpyridine (1.41 g, 7.53 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.50 g, 7.53 mmol), palladium(II) acetate (33.8 mg, 0.15 mmol), tri-o-tolylphosphine (183.2 mg, 0.60 mmol), triethylamine (4.50 mL, 32.3 mmol), and anhydrous acetonitrile (8 mL) was stirred and heated at 130-132° C. in a sealed glass tube for 18 h. The mixture was further heated at 140° C. for 84 h. The resulting dark-brown solution was cooled to ambient temperature and concentrated by rotary evaporation. The residue was diluted with water (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried producing a dark-brown oil (2.84 g). The crude product was purified by column chromatography on silica gel (135 g), eluting with ethyl acetate-hexane (3:1, v/v) to remove impurities, followed by elution with CH3OH—Et3N (98:2, v/v) to collect the product. Fractions containing the product (Rf 0.70) were combined and dissolved in CHCl3. The CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation, and vacuum dried to give 1.11 g (48.4%) of an amber-brown oil.