Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.[CH2:18]=[C:19]([CH3:21])[CH3:20].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[CH2:18][C:19]([CH3:21])([CH3:20])[C:6]3[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=3)[NH:8]2)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=Cc1cccc(Br)c1
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(Br)c1)N2
Temperature: 85 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
To a stirred solution of 4-methyl-phenylamine (6.8 g, 64.0 mmol) and 3-bromobenzaldehyde (7.5 mL, 64.0 mmol) in acetonitrile (150 mL) were added isobutene (18.7 mL, 256.7 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.7 g, 7.7 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4,6-trimethyl-1,2,3,4-tetrahydro-quinoline (8.5 g, 40.0%) as a light yellow solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 330.0 & 332.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[F:12][C:13]([F:16])([F:15])I.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9][C:13]([F:16])([F:15])[F:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(S)cc1Br
Reactant: FC(F)(F)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(SC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-4-fluorobenzenethiol (2.071 g, 10 mmol) in dimethylformamide (10 mL) was treated with 60% sodium hydride (0.480 g, 12.00 mmol). The solution was stirred for 10 minutes at room temperature. Trifluoroiodomethane (2.74 g, 14.00 mmol) was released into a balloon with a three-way stopcock. The balloon was then put onto the flask and trifluoroiodomethane was released into the reaction. After 1 hour, all the content in the balloon was gone. And the balloon was filled with 2.74 g of trifluoroiodomethane again. The reaction mixture was stirred for 16 hours. The reaction mixture was poured into water, and extracted with ethyl acetate several times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting oil was used directly in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=O)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(Cl)CCl.C1C[O:33]CC1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([CH:11]3[N:20]([CH:25]=[O:33])[CH2:21][CH2:22][O:23][CH2:24]3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C(=O)O)cc2)n1
Reactant: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)c1cc(N)n(-c2ccc(C3COCCN3C=O)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 515 mg (1.98 mmol) 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-benzoic acid and 259 μL (2.98 mMol) morpholine in 8 mL THF, 495 mg (2.58 mmol) of EDC are added at rt. The reaction is stirred at rt for 2 h. After completion, the resulting reaction mixture is concentrated and the residue is taken up in CH2Cl2, washed with brine (2×), dried and concentrated. The residual crude product is purified by flash chromatography (SiO2, CH2Cl2/MeOH; gradient 0-5% MeOH) to give the title compound as an off white powder. MS: [M+1]+=329.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:17](=S)=[S:18]>C(O)C.O>[SH:18][C:17]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: S=C=S
Reactant: Nc1ccccc1Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Sc1nc2ccccc2n1-c1ccccc1
Yield: 74 %

Procedure:
To 18.6 g (0.10M) of N-phenyl-o-phenylenediamine in 100 ml ethanol, 4.8 g (0.12M) of sodium hydroxide in 20 ml water is added followed by 13 g (0.17M) of carbon disulfide. The mixture is heated to reflux for 5 hours. The reaction mixture is poured into 300 ml water and solid is collected. The crude material is recrystallized from ethanol and the recrystallized material weighs 25 g (74% yield) and melts at 195°-7° C.
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[C:12]([CH2:13][C:14]#N)=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[OH2:16]>C(O)C>[C:14]([CH2:13][C:12]1[C:4]([Cl:3])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])([OH:16])=[O:1]
Reactant: O
Reactant: N#CCc1cccc(C(=O)O)c1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1cccc(C(=O)O)c1Cl

Procedure:
Potassium hydroxide (2.976 g) in water (30 mL) was added to a suspension of 2-chloro-3-(cyanomethyl)benzoic acid (example 80, step a) (4.12 g) in ethanol (30 mL) and the resulting solution was heated at reflux for 2 hours, then allowed to cool overnight. The mixture was concentrated in vacuo to remove the ethanol and then diluted with water and washed twice with ethyl acetate. The organic phases were discarded, whilst the aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and extracted three times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the crude subtitled compound as a yellow solid. Yield 4.11 g. Used directly.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C[O-].[Na+].[CH3:17][S-:18].[Na+].O>CO>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[S:18][CH3:17])[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: C[S-]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 57.5 °C

Procedure:
0.75 mol of 4-fluoro-3-nitrobenzoic acid was charged in 2 l of methanol, and 0.75 mol of sodium methoxide was added dropwise. 0.83 mol of sodium thiomethoxide was then added and the reaction mixture was heated to 55-60° C. for 5 hours. After cooling, 1 l of water was added, the precipitate was filtered off with suction and washed with 100 ml of methylene chloride. The residue was then taken up in 500 ml of 2 N hydrochloric acid and the precipitate formed was filtered off with suction and washed with water. The residue was then taken up in tetrahydrofuran and dried over sodium sulfate and the solvent was distilled off.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=O)C.NC1C=C(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=[O:27])C=2C=1>O>[OH:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:9])=[O:27]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reactant: Nc1cc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c2c1
Solvent: O
Product: Cc1c(O)cccc1C(=O)O

Procedure:
The process according to the invention for the preparation of 3-acetoxy-2-methylbenzoyl chloride avoids these disadvantages. It comprises reacting an alkali metal salt of 3-aminonaphthalene-1,5-di-sulfonic acid with alkali metal hydroxide and water in the weight ratio 1:(1 to 1.6):(l to 1.6) at 220 to 320° C. to give the dialkali metal salt of 3-hydroxy-2-methylbenzoic acid, separating off insoluble constituents from the reaction mixture, then adjusting the reaction mixture to a pH of 11.5 to 13.5 by addition of acid and reacting it with acetic anhydride at -5 to 25° C., precipitating the 3-acetoxy-2-methylbenzoic acid by addition of acid, separating off the 3-acetoxy-2-methylbenzoic acid and reacting it with an inorganic acid chloride to give 3-acetoxy-2-methylbenzoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)=[N:5][C:4]([CH2:26]O)=[N:3]1.S(Cl)([Cl:30])=O>>[Cl:30][CH2:26][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:14]=2)[N:2]([CH3:1])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1nc(CO)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Product: Cn1nc(CCl)nc1NCCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-methyl-5-[4-[3-(1-piperidinylmethyl)phenoxy]butyl]amino-1H-1,2,4-triazole-3-methanol (0.75 g) and thionyl chloride (4 ml) was stirred at room temperature for 2 h. The mixture was evaporated in vacuo and the residue was dissolved in chloroform and washed with sodium bicarbonate. The organic extract was dried and evaporated to give the title compound as an oil (0.75 g) T.l.c. System E Rf 0.65.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[N:19]=[C:18]([C:28]([N:30]3[CH2:34][C:33](=[O:35])[NH:32][CH2:31]3)=[O:29])[CH:17]=2)[CH:11]=1)(=O)=O.[NH:36]1[CH2:39][CH2:38][CH2:37]1.[CH:40]([OH:42])=[O:41].ClC1C=C(N2C(C3C=CC=C(OCCCN(C)C)C=3)=CC(C(N3CC(=O)NC3)=O)=N2)C=CC=1>O1CCCC1>[CH:40]([OH:42])=[O:41].[N:36]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[N:19]=[C:18]([C:28]([N:30]4[CH2:34][C:33](=[O:35])[NH:32][CH2:31]4)=[O:29])[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CS(=O)(=O)OCCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Reactant: C1CNC1
Agent: CN(C)CCCOc1cccc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccc(Cl)c2)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=C1CN(C(=O)c2cc(-c3cccc(OCCCN4CCC4)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 120A and azetidine without the addition of tetrahydrofuran in analogy to the synthesis of the compound of Example 29. 13 mg (11% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10]I)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][CH:23]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)[C:24](=[O:26])[CH3:25])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Cc1ccc(Cl)cc1
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(C(C)=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (215 g, 652 mmol) and 4-chlorophenylacetone (100 g, 593 mmol) in dry N,N-dimethylformamide (1.5 L) was added cesium carbonate (483 g, 1483 mmol) at room temperature. After 4 h, the mixture was then added to a stirring solution of pH 7 buffer and EtOAc. The aqeuous layer was extracted with EtOAc and the combined organics were washed with pH 7 buffer, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10% ethyl acetate/heptane→30% ethyl acetate/heptane) to provide the title compound as a mixture of diastereomers (150 g). MS 392.1 (M+Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:24][CH3:25])[CH:3]=1.[S:26]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][S:26]4(=[O:33])=[O:32])=[CH:3][C:4]=3[O:24][CH3:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Reactant: O=S1(=O)CCCCN1
Product: COc1cc(N2CCCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 74.2 %

Procedure:
Using (4-bromo-2-methoxyphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (404 mg) described in Preparation Example 252 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (340 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5]1
Reactant: CCOC(=O)CCCBr
Reactant: CC1CNCC(C)O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN1CC(C)OC(C)C1

Procedure:
This intermediate (37.8 g.) was prepared using the procedure described in Example 4a except using 24.5 ml. (0.2 mole) of 2,6-dimethylmorpholine, 28.6 ml. (0.2 mole) of ethyl 4-bromobutyrate, 30.3 ml. (0.2 mole) of triethylamine, and 60 ml. of toluene and was isolated as a colorless liquid boiling 96.5°-97° C. at 4 mm of Hg.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)[CH3:3].[ClH:16].[Cl:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[ClH:17].[ClH:16].[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH:11]=2)[CH2:6]1)[CH3:1]
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC1CCc2cc(OCc3ccc4ccccc4n3)ccc2C1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of 2-(N,N-dimethylamino)methyl-6-hydroxytetralin (153 mg, a free form of Reference Example 16) and 2-chloromethylquinoline hydrochloride (189 mg) in DMF (5 ml) was added potassium carbonate (260 mg) and the reaction mixture was stirred at room temperature for 26 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate:hexane=1:2) and then converted into its dihydrochloride, which was further recrystallized from methanol-ethyl acetate to obtain the titled compound (191 mg).
Reaction SMILES: C(Cl)(=O)C.[C:5]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15](=[O:23])[CH2:14]1)(=[O:12])[C:6]1C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[C:5]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15](=[O:23])[CH2:14]1)(=[O:12])[CH3:6]
Reactant: O=C1CN(C(=O)c2ccccc2)c2ccccc2N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)N1CC(=O)Nc2ccccc21
Reaction time: 1 h

Procedure:
Acetyl chloride (0.36 ml) is added to 1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 1, 0.676 g) and triethylamine (0.76 ml) in THF (8 ml) at 0°. After stirring for 1 hr, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The layers are separated, the organic phase is filtered through sodium sulfate and concentrated. The concentrate is crystallized from methanol/methylene chloride/hexane to give the title compound, mp 164°-165°; NMR (CDCl3) 2.28, 4.54, 7.00, 7.11, 7.21 and 9.19 δ.
Reaction SMILES: [F:1][C:2]([P:8]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:11])[O:9]C)([F:7])[C:3]([F:6])([F:5])[F:4].[C:19]1([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:7][C:2]([P:8]([C:12]([F:17])([F:18])[C:13]([F:16])([F:15])[F:14])(=[O:9])[O-:11])([F:1])[C:3]([F:6])([F:5])[F:4].[CH3:2][S+:25]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: c1ccc(Sc2ccccc2)cc1
Product: C[S+](c1ccccc1)c1ccccc1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 45 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
Methyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OCH3, (1.77 g; 5.6 mmol) is slowly added dropwise to cooled (0° C.) diphenyl sulfide (1.01 g; 5.4 mmol) in a 25 ml glass flask. The two-phase reaction mixture is warmed and stirred at 45° C. for 17 h. The readily volatile constituents are removed in vacuo (10−3 mbar) at room temperature. Methyldiphenylsulfonium bis(pentafluoroethyl)phosphinate, [CH3S(C6H5)2][(C2F5)2P(O)O], (2.31 g, 4.6 mmol) is isolated as pale-yellow and highly viscous liquid in a yield of 85% and a purity of 90%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[OH-].[K+].O>CS(C)=O>[C:23]([O:22][C:20](=[O:21])[NH:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:32][CH:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 93.1 %

Procedure:
A mixture of N-(4-fluoro-3-nitrophenyl)benzamide (1.00 g, 3.8 mmol), N-Boc-4-hydroxyaniline (0.83 g, 3.8 mmol) and 85% KOH (0.51 g, 7.7 mmol) in DMSO (20 mL) was heated at 80° C. for 1 hour, and then poured into H2O (100 ml) under stirring. The resulting oily crystal was extracted with EtOAc. The extract was washed with H2O (3 times) and brine, dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound, which was purified by washing with i-Pr2O to give the desired compound as yellow crystals (1.59 g, 92%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH3:18])[C:6]=1[Cl:19].[NH4+:21].[OH-]>>[Cl:19][C:6]1[C:7]([CH3:18])=[CH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:10][C:5]=1[CH2:4][C:3]([NH2:21])=[O:2]
Reactant: COC(=O)Cc1cc(N2CCN(C)CC2)cc(C)c1Cl
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1cc(N2CCN(C)CC2)cc(CC(N)=O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(5-Bromo-2-chloro-3-methyl-phenyl)-acetic acid methyl ester (2.0 g, 7.2 mmol), N-methylpiperazine (960 μL, 8.6 mmol) and Cs2CO3 (3.3 g, 10.1 mmol) are suspended in toluene (80 mL). Pd(OAc)2 (81 mg, 0.36 mmol) and BINAP (224 mg, 0.36 mmol) are added and the reaction is stirred at 100° C. overnight. The mixture is filtered through Celite and the solvent is evaporated. The residue is purified by FCC (AcOEt/AcOH/H2O 60:15:15) to afford 2-[2-chloro-3-methyl-5-(4-methyl-piperazin-1-yl)-phenyl]-acetic acid methyl ester. The ester is suspended in NH4OH 25% (60 mL). The mixture is stirred overnight at RT and the precipitate is filtered off to yield the amide. 1H NMR (DMSO, 400 MHz) δ 2.20 (s, 3H), 2.27 (s, 3H), 2.40-2.45 (m, 4H), 3.07-3.13 (m, 4H), 3.48 (s, 2H), 6.78 (s, 1H), 6.82 (s, 1H), 6.91 (br s, 1H), 7.34 (br s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([O-:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20].[K+].CC(C)([O-])C.[K+]>C1COCC1>[F:11][C:12]1[CH:18]=[CH:17][C:15]([O:16][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: [O-]c1ccc(F)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1 M solution of a potassium 4-fluoro-3-trifluoromethyl-phenoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1 M solution of potassium t-butoxide in THF) was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the reaction mixture was treated with cold H2O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product could be used directly for further transformation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]#[N:24])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:32][OH:33]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([C:23]([NH:32][OH:33])=[NH:24])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)N2C(C#N)CCC2c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2C(C(=N)NO)CCC2c2ccc(F)cc2)cc1
Yield: 38.2 %

Procedure:
To a stirred suspension of (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonitrile (0.74 g, 2.15 mmol) in EtOH (25 ml) was added potassium carbonate (0.89 g, 6.45 mmol) and hydroxylamine hydrochloride (0.30 g, 4.30 mmol). The reaction mixture was heated under reflux conditions for 18 h, the formed precipitate collected, washed with dichloromethane/methanol. The organic solvents were evaporated and the crude product purified by column chromatography on silica gel (ethyl acetate/hexane 3:2). Crystallization from diethyl ether/methanol yielded the title compound (0.31 g, yield 38%) as a white solid, m.p. 217° C. and MS: m/e=378.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3].[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][CH2:24][CH:25]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][C:2]([NH:10][CH2:25][CH2:24][CH2:23][CH2:22][N:13]1[C:14](=[O:21])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]1=[O:11])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:3]
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(N)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(C)(NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1

Procedure:
Using General Procedure B, reaction of 1-methyl-1-pyridin-2-yl-ethylamine (Chakravarty, PK et al. Bioorg. Med. Chem. Lett. 2003, 13, 147-150) with 4-(1,3-Dioxo-1,3-dihydroisoindole-2-yl)-butyraldehyde and NaBH(OAc)3 gave 2-[4-(1-methyl-1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dione as a colorless oil. 1H NMR (CDCl3) δ 1.46 (s, 6H), 1.50-1.56 (m, 2H), 1.60-1.74 (m, 2H), 2.31 (t, 2H, J=7.0 Hz), 3.65 (t, 2H, J=7.1 Hz), 7.07-7.14 (m, 1H), 7.39 (d, 1H, J=8.3 Hz), 7.63 (td, 1H, J=7.7, 1.8 Hz), 7.66-7.74 (m, 2H), 7.77-7.87 (m, 2H), 8.56 (d, 1H, J=3.9 Hz).