Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:4][CH:3]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(F)c1
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(C)CCc3cccc(F)c3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(3-fluoro-phenyl)-1-methyl-propyl]-amine and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:13][NH:14][C:15]([C:17]2[N:18]=[C:19]([C:35]#[N:36])[C:20]3[C:25]([C:26]=2[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:21]=3)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:35]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:21]=2)[C:26]([OH:27])=[C:17]([C:15]([NH:14][CH2:13][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:16])[N:18]=1)#[N:36]
Reactant: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCCC2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A mixture of 1-{[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-cyclopentanecarboxylic acid tert-butyl ester (164 mg), TFA (5 mL) and DCM (5 mL) was stirred at rt overnight; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (143 mg). LC MS ESI+: 432 (M+1)+.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]4[O:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:18][CH2:17]2)[CH:3]=1.[Cu][C:35]#[N:36]>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:35]#[N:36])=[CH:3][C:4]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]4[O:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:20][CH2:21]2)[N:9]=1
Reactant: Cc1ccc2c(OCCN3CCC(Cc4ccc5c(c4)NC(=O)CO5)CC3)cc(I)cc2n1
Reactant: N#C[Cu]
Product: Cc1ccc2c(OCCN3CCC(Cc4ccc5c(c4)NC(=O)CO5)CC3)cc(C#N)cc2n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
A mixture of 6-{1-[2-(7-Iodo-2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one (155 mg, 0.28 mmol) and copper (I) cyanide (50 mg, 0.56 mmol) in N-methylpyrrolidinione (2 mL) was stirred at 90° C. for 18 hrs. Upon cooling to room temperature the reaction mixture was partitioned between dichloromethane (5 mL) and ammonia (0.880, 5 mL). The organic layer was separated and applied directly to a 10 g pre-packed silica column eluting with 0-20% methanol in ethyl acetate to afford the title compound as a yellow oil (30 mg, 23%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+]=[N-].C1(C)C=CC=CC=1>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCOCCN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCOCCN
Reaction time: 18.5 h

Procedure:
A solution of tert-butyl 2-(2-azidoethoxy)ethylcarbamate (52 g, 226 mmol) in methanol (500 mL) was added to a Parr vessel containing 10% palladium on carbon (4 g) which had been wetted with toluene (30 mL). The mixture was placed under hydrogen pressure (30 psi; 2.0×105 Pa). After 18.5 hours analysis by thin layer chromatography indicated that the reaction was not complete. Catalyst (0.5 g) was added and the hydrogenation was continued for an additional 4 hours. The reaction mixture was filtered through a layer of Celite® filter aid and a glass wool filter pad. The filter cake was rinsed with a mixture of isopropanol and methanol. The filtrate was concentrated under reduced pressure to provide tert-butyl 2-(2-aminoethoxy)ethylcarbamate.
Reaction SMILES: [F:1][C:2]([F:30])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19](/[CH:22]=[CH:23]/[CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[NH2:31][OH:32]>C1COCC1.O>[OH:32][NH:31][CH:23]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH2:22][S:19]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:2]([F:1])([F:30])[CH:3]([F:4])[F:5])=[CH:12][CH:11]=2)[CH2:14][CH2:15]1)(=[O:20])=[O:21]
Reactant: NO
Reactant: O=S(=O)(/C=C/C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(CC(NO)C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-{[(E)-2-(tetrahydro-2H-pyran-4-yl)vinyl]sulfonyl}piperazine (3.13 g, 0.007 mol) was dissolved in THF (50 ml) and 50% hydroxylamine in H2O (12 ml) was added. Stirred at ambient temperature overnight, quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and evaporated to dryness to yield racemic 1-{[2-(hydroxyamino)-2-(tetrahydro-2H-pyran-4-yl)ethyl]sulfonyl}-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine This was separated into its enantiomers using an AD Chiralpak chiral prep HPLC column and eluting with 20% methanol/acetonitrile. The second compound off the column gave the required enantiomer, 1-{[(2S)-2-(hydroxyamino)-2-(tetrahydro-2H-pyran-4-yl)ethyl]sulfonyl}-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:4]=1[NH:5][C:6]1[C:7]([C:14](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:15])=[CH:8][N:9]([CH3:13])[C:10](=[O:12])[CH:11]=1>C1COCC1>[F:2][C:3]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:4]=1[NH:5][C:6]1[C:7]([C:14]([NH2:1])=[O:15])=[CH:8][N:9]([CH3:13])[C:10](=[O:12])[CH:11]=1
Reactant: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1
Reactant: N
Solvent: C1CCOC1
Product: Cc1ccc(Nc2cc(=O)n(C)cc2C(N)=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Conc. NH3 solution (0.5 ml) was added to 2,3,4,5,6-pentafluorophenyl 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (0.33 g, 0.6 mmol) in THF (10 ml) and the solution stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue dissolved in 5% EtOAc/MeOH. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated to give crude 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinearboxamide which was then recrystallised (EtOAc/Hexane) (0.11 g, 84%); m.p. (EtOAc/Hexane) 285-288° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.14 (s, 1H), 8.32 (s, 1H), 7.86 (br s, 1H), 7.43 (br s, 1H), 7.31 (t, J=8.4 Hz), 1H), 7.16 (dd, J=11.8, 1.1 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 5.38 (d, J=1.1 Hz, 1H), 3.34 (s, 3H), 2.32 (s, 3H). LCMS (ACPI−) 274 (100%). Anal. Calcd for C14H14FN3O2: C, 61.1; H, 5.1; N, 15.3. Found C, 61.0; H, 5.2; N, 15.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl-].[CH:28]1([S:31](C2CC2)(=[O:33])=[O:32])[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][NH:20][S:31]([CH:28]4[CH2:30][CH2:29]4)(=[O:33])=[O:32])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(C1CC1)C1CC1
Reactant: NC[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: [Cl-]
Product: O=S(=O)(NC[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C1CC1

Procedure:
Prepared according to the procedure described for Example 1 from [(1S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-ethan-2-amine (41a, 31 mg, 0.09 mmol) cyclopropylsulphone chloride (28 μl, 0.27 mmol). Yield: 22 mg (54%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O.Cl>[OH-].[Na+].CS(C)=O>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Temperature: 80 °C

Procedure:
A solution of 6-hydroxy-2-naphthoic acid (1.04 g) in a mixture of 10% sodium hydroxide aqueous solution (4.44 ml) and dimethyl sulfoxide (18 ml) was stirred for half an hour at 80° C. Then heptyl bromide (0.872 ml) was added thereto and stirred for 5 hours at 60° C. The reaction mixture was added to water (50 ml) and the mixture was adjusted to pH 3 with conc. hydrochloric acid. The resultant precipitate was collected by filtration and dried to give 6-heptyloxy-2-naphthoic acid (1.39 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4].[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:29][C:28]1[CH:30]=[CH:31][C:25]([S:22]([NH:1][C@@H:2]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]([NH:5][C:6]2[C:7]([F:14])=[CH:8][C:9]([F:13])=[CH:10][C:11]=2[F:12])=[O:4])(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2c(F)cc(F)cc2F)cc1

Procedure:
Following the procedure of Example 52 only using the product of Example 50 and tosyl chloride, the title compound was obtained, mp 180°-181° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[N:13][C:14]([CH3:17])=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:17][C:14]1[N:13]=[C:12]([NH:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])[C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:16][N:15]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(F)cc2)c(C)c1
Reactant: C1COCCN1
Product: Cc1cc(C)c(Nc2nc(C)ncc2S(=O)(=O)c2ccc(N3CCOCC3)cc2)c(C)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of [5-(4-fluoro-benzenesulfonyl)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethylphenyl)-amine (100 mg, 0.26 mmol) and morpholine (5 mL) was heated at reflux under N2 for 2 h, and then cooled to room temperature. The mixture was concentrated in vacuo, and the residue was dissolved in EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc) to provide the target compound (108 mg, 92%) as a white solid: mp 221–223° C.; 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.24 (br s, 1H), 7.80 (d, J=9.0 Hz, 2H), 6.91 (s, 2H), 6.88 (d, J=9.0 Hz, 2H), 3.83 (t, J=5.0 Hz, 4H), 3.29 (t, J=5.0 Hz, 4H), 2.37 (s, 3H), 2.30 (s, 3H), 2.03 (s, 6H); APCI MS m/z 453 [(M+H)+, calcd for C24H29N4O3S, 453.2].
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5].[OH-].[Na+].Cl[CH:24]([F:26])[F:25]>C(COC)OC.O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][CH:24]([F:26])[F:25])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH3:15])=[O:5]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OC(F)F
Temperature: 60 °C

Procedure:
To a solution of 2,6-dichloro-5'-hydroxy-4'-methoxy-2'-methyl-benzophenone (1.0 g; 3.2 mmol) in dimethoxyethane (7 ml) a solution of sodium hydroxide (0.6 g; 15 mmol) in water (1 ml) is added. The mixture is heated to 60° C. with stirring, then a stream of chlorodifluoromethane is introduced for 20 minutes. After further stirring for 1.5 hours the solvent is evaporated. The residue is extracted with a mixture of trichloromethane and water. The organic phase is separated, dried and the solvent is evaporated. For purification, a flash column with silicagel (30 g) is used (elution with mixtures of petrolether/ethylacetate 9:1, then 8:2, then 7:3 (v/v)). The resulting compound forms white crystalls (0.6 g; 51.8% y); mp. 126-128° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2([NH:14][C:15]([C:17]3[C:18]4[CH:19]=[N:20][N:21]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:22]=4[CH:23]=[C:24](Br)[CH:25]=3)=[O:16])[CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].CS([C:38]1C=C(C2(NC(C3C4C=NN(C5C=CC(F)=CC=5)C=4C=C(I)C=3)=O)CC2)C=C[N:39]=1)(=O)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2([NH:14][C:15]([C:17]3[C:18]4[CH:19]=[N:20][N:21]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:22]=4[CH:23]=[C:24]([C:38]#[N:39])[CH:25]=3)=[O:16])[CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(C2(NC(=O)c3cc(I)cc4c3cnn4-c3ccc(F)cc3)CC2)ccn1
Reactant: CS(=O)(=O)c1cc(C2(NC(=O)c3cc(Br)cc4c3cnn4-c3ccc(F)cc3)CC2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C2(NC(=O)c3cc(C#N)cc4c3cnn4-c3ccc(F)cc3)CC2)ccn1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid [1-(2-methanesulfonyl-pyridin-4-yl)-cyclopropyl]-amide, and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-carboxylic acid [1-(2-methanesulfonyl-pyridin-4-yl)-cyclopropyl]-amide (150 mg) in DMF (1.0 mL, degassed and anhydrous) is added tetrakis(triphenylphosphine)palladium (33 mg, 0.028 mmol) and zinc cyanide (40 mg, 0.34 mmol). The solution is evacuated and purged with Argon (3 times) and warmed to 120° C. After 3 hours, the reaction is cooled to room temperature, diluted with saturated aqueous ammonium chloride (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers are washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified on SiO2 using a gradient of 50-100% ethyl acetate in heptane to give a solid, which is triturated with ethyl ether to afford the title product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=O)[NH:13][N:14]=2)=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:18])=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([Cl:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
A 3.42 g. portion of 6-(p-cyanophenyl)-3(2H)-pyridazinone in 25 ml. of phosphorus oxychloride is stirred and heated at reflux temperature for 3 hours. Most of the excess phosphorus oxychloride is removed under reduced pressure. Cracked ice-water is added to the concentrate which is stirred until the excess phosphorus oxychloride hydrolyzes. The solid is collected by filtration, dried and recrystallized from dimethylformamide-water, yielding 6-(p-cyanophenyl)-3-chloropyridazine, m.p. 236°-238° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]#[CH:12])[N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[N:3]=[C:4]([S:9][CH2:10][C:11]#[CH:12])[N:5]=1
Reactant: C#CCSc1nc(Cl)cc(Cl)n1
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCSc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1

Procedure:
A stirred mixture of 6.57 g. of 4,6-dichloro-2-(2-propynylthio)pyrimidine, 4.2 g. of p-chlorobenzylamine and 3.18 g. of sodium carbonate in 50 ml. of ethanol was heated under reflux for 5 hours. The reaction mixture was filtered and the filtrate was diluted with 100 ml. of water. The precipitate thus formed was collected and recrystallized from benzene (petroleum ether was added to initiate precipitation) to afford 3.3 g. of product, m.p. 85°-88°C.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[CH2:13]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[CH:14]=[CH:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:13]([N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[C:3](=[O:4])[CH:2]([Br:1])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH:14]=[CH:15][CH3:16]
Reactant: CC=CCNc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C(Br)c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CC=CCN(C(=O)C(Br)c1ccc(F)cc1)c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
In 40 ml of toluene, 2.6 g of 2-bromo-2-(4-fluorophenyl)acetyl chloride were gradually added dropwise at 20°-30° C. under stirring to 2.2 g of N-(2-butenyl)-N-(3-trifluoromethylphenyl)amine. After the reaction mixture was stirred for further 20 minutes, the precipitated insoluble matter was filtered off and 50 ml of toluene were added. The resulting toluene solution was washed twice with a saturated aqueous solution of sodium bicarbonate and twice with saturated saline. The toluene solution was dried over anhydrous sodium sulfate and then concentrated in an evaporator, whereby the intended compound was stoichiometrically obtained in an oily form.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6]2.CN1CCOCC1>CO>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH2:12])[CH2:6]2
Reactant: NC1Cc2ccc(Br)cc2C1
Agent: Br
Solvent: CO
Solvent: CN1CCOCC1
Product: N[C@@H]1Cc2ccc(Br)cc2C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
25 g of 5-bromo-indan-2-ylamine hydrobromide (85.32 mmol) and 9.85 ml of 4-methylmorpholin (89.59 mmol) were dissolved in 53 ml of methanol. The mixture was heated to 60° C. and a solution of 25.77 g of (1S)-(+)-campher-10-sulfonic acid (110.92 mmol) in 42 ml of methanol added within 25 minutes. The reaction mixture was stirred for 10 minutes at 60° C. and then allowed to cool down to room temperature over a 2 h time period, with stirring continuing for another 2 h. The precipitate was filtered, washed twice with 20 ml of ethyl acetate/methanol (2:1) and 20 ml of water, and finally dried at 50° C. under vacuo for 15 h to give 13.3 g of the salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH:13](=[C:6]1/[CH2:7][O:8][C:9]2[C:4]([C:5]/1=[O:12])=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCOc2ccc(F)cc21
Solvent: CCO
Product: O=C1/C(=C/c2ccccc2)COc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Fluoro-4-chromanone (5.0 g, 30.1 mmol) and 3.35 g (31.6 mmol) benzaldehyde were dissolved in 100 mL of EtOH, and HCl gas was bubbled through the solution until it was nearly boiling. The flask was then capped, allowed to cool to room temperature and stirred overnight. The solids were filtered off and rinsed with a minimum amount of Et2O to provide 1-1 as a light-pinkish solid. Data for 1-1: 1HNMR (500 MHz, CDCl3) δ 7.9 (s, 1H), 7.65 (m, 1H), 7.5-7.4 (m, 3H), 7.3 (m, 2H), 7.2 (m, 1H), 6.95 (m, 1H), 5.35 (s, 2H) ppm. LC-MS: rt=2.8 min, m/z=255 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([O:34]CC5C=CC=CC=5)=[O:33])=[CH:28][CH:27]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:11]([F:44])[C:10]=2[F:45])=[CH:6][C:5]=1[O:48]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:47]=[CH:46][C:7]([O:8][C:9]2[C:10]([F:45])=[C:11]([F:44])[C:12]([C:17]3[C:22]([F:23])=[C:21]([F:24])[C:20]([O:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:34])=[O:33])=[CH:30][CH:31]=4)=[C:19]([F:42])[C:18]=3[F:43])=[C:13]([F:16])[C:14]=2[F:15])=[CH:6][C:5]=1[OH:48]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc([N+](=O)[O-])c(OCc5ccccc5)c4)c(F)c3F)c(F)c2F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc(C(=O)O)cc4)c(F)c3F)c(F)c2F)cc1O
Reaction time: 8 h
Yield: 91 %

Procedure:
49.9 g of the 4-(4-nitro-3-benzyloxyphenoxy)-4′-(4-benzyloxycarbonylphenoxy)octafluorobiphenyl prepared as described in Example 2 (0.065 mol) are dissolved in 400 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are then added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The yellow-beige solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 91%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[OH:10][S:11](O)(=[O:13])=[O:12].O=S(=O)=O>>[C:3]1([F:7])([C:2]([F:9])([F:8])[F:1])[S:11](=[O:12])(=[O:10])[O:13][C:4]1([F:6])[F:5]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=S1(=O)OC(F)(F)C1(F)C(F)(F)F
Temperature: 50 °C
Yield: 65 %

Procedure:
Using essentially the procedure of Example 1, the reactor was charged with 44.7 g hexafluoropropene, 45.9 g of 67 wt. % oleum and 41.5 g Fluorinert FC-77™. The reaction mixture was heated at 50° C. for 6 hours. The reactor was vented of excess HFP and the sultone layer (95.0 g) was separated and distilled to provide the HFP sultone (45 g, b.p. 48°-52° C., purity 93% by gc). The yield was 65% based on consumed HFP.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]2=[C:8]([CH:18]=1)[C:9](=[O:17])O[C:11]3=[O:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]>>[N+:1]([C:4]1[CH:5]=[C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]2=[C:8]([CH:18]=1)[C:9](=[O:17])[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:11]3=[O:16])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])cc3cccc1c23
Reactant: NCCCCCC(=O)O
Product: O=C(O)CCCCCN1C(=O)c2cccc3cc([N+](=O)[O-])cc(c23)C1=O

Procedure:
2.45 g (0.01 mmol) of 5-nitro-1H,3H-benzo[de]isochromene-1,3-dione and 1.23 g (0.01 mmol) of 6-aminohexanoic acid was alloyed with at 210-220° C. for 35 min. The obtained crude 6-(5-nitro-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-2-yl)hexanoic acid was recrystallized from ethanol. Yield 1.7 g (48%). The product was dissolved in 50 mL of ethanol and was added dropwise to the hot solution of 8 g of tin chloride in 9 mL of hydrochloric acid at boiling. The reaction mixture was boiled for 4 h, then poured with water and neutralized with 5% solution of sodium hydrate. Yellow sediment was filtered and purified by a column chromatography (Silica gel, chloroform). Yield 1.1 g of ethyl 6-(5-amino-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-2-yl)hexanoate (31.5% counting on 5-nitro-1H,3H-benzo[de]isochromene-1,3-dione). M.P. 108-110° C.