Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]#[N:10])=[CH:5][CH:4]=1.[Cl-].Cl[C:13]1C=C([N+]#N)C=CC=1>>[Cl-:2].[C:8]1([CH3:13])[CH:3]=[CH:4][CH:5]=[C:6]([N+:9]#[N:10])[CH:7]=1
Reactant: N#[N+]c1ccc(Cl)cc1
Reactant: N#[N+]c1cccc(Cl)c1
Agent: [Cl-]
Product: Cc1cccc([N+]#N)c1

Procedure:
When these processes are repeated using variously substituted aryldiazonium salts, very variable yields of between 40 and 85% of theory are obtained. For example, p-chlorobenzenediazonium chloride gives 43%, m-chlorobenzenediazonium chloride gives 36%, m-toluenediazonium chloride gives 69%, o-chlorobenzenediazonium chloride gives 36%, p-dimethylaminobenzenediazonium chloride gives 54%, p-carbamoylbenzenediazonium chloride gives 58%, benzenediazonium chloride gives 72%, p-methoxybenzenediazonium chloride gives 80% and p-sulfobenzenediazonium chloride gives 10 to 20% of the corresponding diazosulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[C:10]([C:15]2[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[F:13])[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: Cc1ccc(B(O)O)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc(-c2ccc(C)cc2F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl 3-bromo-5-iodo-benzoate (13 g) and 2-fluoro-4-methylphenylboronic acid (6 g) were dissolved in DMF (120 mL) at room temperature. The solution was then cooled down to 0° C. with ice bath. To this solution was added aq. sodium carbonate (6 g in 50 mL of water), Pd(dppf)Cl2 (3 g) and DMF (10 mL). After the addition, the reaction was warmed up slowly to room temperature. The reaction mixture was then stirred at room temperature for 4 hrs. Solvent was evaporated under reduced pressure. The residue was re-dissolved in EtOAc (200 mL) washed with HCl (1M) 3×200 mL), sat. NaHCO3 (3×100 mL), brine (3×100 mL) and water (3×100 mL). The organic layer was separated and concentrated. The crude product was then purified with column chromatography (silica gel, eluted with EtOAc/Hexane, 0 to 1%) to give pure compound. Note a second column can be done to further remove unwanted bis cross coupled by-product.
Reaction SMILES: [S:1]([C:5]1[CH:19]=[CH:18][C:8]2[S:9][C:10]3([C:16](=[O:17])[C:7]=2[CH:6]=1)[CH2:14][CH2:13]OC3=O)(=[O:4])(=[O:3])[NH2:2]>C(O)C>[S:1]([C:5]1[CH:19]=[CH:18][C:8]2[S:9][C:10]3([C:16](=[O:17])[C:7]=2[CH:6]=1)[CH2:14][CH2:13]3)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1ccc2c(c1)C(=O)C1(CCOC1=O)S2
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(c1)C(=O)C1(CC1)S2

Procedure:
5-Sulfamoylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was prepared by a similar procedure to that of Example 8 except for the use of 5-sulfamoyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione obtained in Reference Example 16. Pale yellow needles (from C2H5OH), mp 256°-258° C. (decomp.) Anal. Calcd. for C10H9NO3S2 : C, 47.04; H, 3.55; N, 5.49. Found: C, 47.18; H, 3.57; N, 5.44.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[CH:6]=[CH:5]2.C[N:15](C=O)C.CC#N.C1(=O)NC(=O)C2=CC=CC=C12.[K].NN>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH2:15])[CH:6]=[CH:5]2
Reactant: ClCc1ccc2cc(Br)ccc2n1
Reactant: CN(C)C=O
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CC#N
Solvent: O
Product: NCc1ccc2cc(Br)ccc2n1
Temperature: 60 °C

Procedure:
To 4a (440 mg, 1.7 mmol) in 1:1 DMF/MeCN (3 mL) at room temperature was added potassium phthalimide (350 mg, 1.9 mmol), and the reaction was heated to 60° C. overnight. The mixture was poured into water and filtered, and the solid was suspended in EtOH (10 mL). Hydrazine (82 mg, 2.5 mmol) was added, and the mixture was heated to 70° C. for 30 minutes. The reaction was then concentrated, and the crude material, 4b, was used directly in the next step.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:13]=[C:14]([C:18]2[N:23]=[C:22]([CH3:24])[C:21]([C:25](Cl)=[O:26])=[CH:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([NH2:41])[CH:36]=[CH:35]2)(=[O:31])=[O:30]>C1COCC1.N1C=CC=CC=1>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([NH:41][C:25]([C:21]1[C:22]([CH3:24])=[N:23][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=3)=[N:19][CH:20]=1)=[O:26])[CH:36]=[CH:35]2)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)c1ccc2c(ccn2N)c1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(S(C)(=O)=O)ccc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
2.0 M of NaHMDS (sodium bis(trimethylsilyl)amide) in THF is added to a stirred solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid chloride (0.72 mmol) and 5-methanesulfonyl-indol-1-ylamine (0.72 mmol) and in anhydrous pyridine (10 mL) at rt. The reaction mixture is stirred at 90° C. overnight and then concentrated in vacuo. The residue is purified ny silica gel chromatography eluting with 1.5% MeOH in DCM to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-methanesulfonyl-indol-1-yl)-amide (50 mg, 8%) as a solid. MS: 425 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.86 (s, 3H), 3.02 (s, 3H), 6.55 (s, H) 6.92 (d, H), 7.17-7.38 (m, 3H), 7.53 (m, H), 7.78 (s, H), 8.27 (d, H), 8.38 (d, H), 9.16 (s, H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]#[CH:27]>CC(C)=O>[C:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)#[C:26][CH3:27]
Reactant: C#CCBr
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2c(=O)c(-c3ccccc3)coc2c1

Procedure:
A mixture of 7-hydroxyisoflavone (2.38 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.1 g of a product with the following characteristics: m.p. 130-131° C.; 1H NMR (CDCl3) δ: 2.6 (m, 1H), 4.8 (s, 2H), 6.99-8.28 (m, 7H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:25][CH:26]=[CH2:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:25]([O:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28])[CH:26]=[CH2:27]
Reactant: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
The mixture of 2-(2-allyloxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (4) (168 mg, 0.44 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (5) as white solid (150 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12][N:13]([CH2:17][CH2:18][OH:19])[C:14]=2[CH2:15][CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CN=C1.[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[Si:34]([O:19][CH2:18][CH2:17][N:13]1[C:14]([CH2:15][CH3:16])=[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36]
Reactant: CCOC(=O)c1nn(CCO)c(CC)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(CCO[Si](C)(C)C(C)(C)C)c(CC)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82.4 %

Procedure:
To a solution of Example 46 (1.03 g, 2.65 mmol) in dimethylformamide (5 ml) was added imidazole (361 mg, 5.30 mmol), followed by tert-butyldimethylchlorosilane (600 mg, 3.97 mmol). The solution was stirred at room temperature for 4 days. The reaction mixture was partitioned between ethyl acetate and water and the aqueous phase was further extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography on silica gel eluting with cyclohexane:ethyl acetate (20:1, by volume), followed by cyclohexane:ethyl actetate (5:1, by volume) to afford the title compound (1.1 g) as a white powder, m.p. 83-84° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:18]=[O:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.[Cl-].[NH4+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:18][OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(C=O)cccc2C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(CO)cccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
To solution of 5-formyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 20a (0.44 g, 1.71 mmol) in 40 mL of methanol:tetrahydrofuran (1:1) at room temperature was added sodium borohydride (0.072 g, 1.88 mmol), and the mixture was stirred to room temperature for 3 h. Water (30 mL) was added followed by ammonium chloride saturated solution (20 mL) and the product was extracted with dichloromethane. The combined organics were dried over magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes, to yield 0.31 g of 5-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 21a.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19](=[CH2:24])[C:20]([O:22][CH3:23])=[O:21]>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:24][C:19](=[CH2:18])[C:20]([O:22][CH3:23])=[O:21])[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: C=C(CBr)C(=O)OC
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: C=C(Cn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21)C(=O)OC

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and methyl 2-(bromomethyl)-2-propenoate: 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 6.23 (s, 1H), 4.99, (s, 2H), 4.81 (s, 1H), 3.84 (s, 3H), 2.43 (s, 3H); MS (ES) m/z 323 (M+1).
Reaction SMILES: N1(C(Cl)=O)CCCC1.[N:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1)[NH2:23].C1(C)C=CC=CC=1>C(O)C>[N:9]1([C:14]([N:16]=[C:17]=[S:18])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:17]([NH:16][C:14]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:15])=[S:18])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:40][CH3:41])=[C:35]([O:38][CH3:39])[CH:36]=2)[N:31]=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)N1CCCC1
Agent: O=C(N=C=S)N1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)N4CCCC4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
1-Pyrrolidinecarbonyl isothiocyanate was prepared using commercially available 1-pyrrolidinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Pyrrolidinecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (52 mg, yield 70%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[NH4+].[Cl-].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]1[NH:13][N:12]=[N:11][N:7]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nnn[nH]1
Temperature: 100 °C

Procedure:
To a solution of ethylcyanoacetate (20.0 g, 0.177 mol) in dimethylformamide (DMF) (180 mL) was added NH4Cl (10.4 g, 0.19 mol) and sodium azide (12.6 g, 0.19 mol) sequentially. The mixture was heated for 5 hours at 100° C., allowed to cool, and the DMF removed in vacuo. The residue was taken up in water (150 mL), acidified to pH 2 with concentrated HCl, and filtered. The filtrate was cooled to 5° C. and allowed to crystallize. The solid was filtered, dried in vacuo over self-indicating silica gel to give 10.61 g, 42%, mp 124°-129° C.
Reaction SMILES: [Na+:1].[Na+].[CH2:3]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([O-:23])=[O:22])[C:15](=[CH:19][CH:20]=1)[C:16]([O-:18])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na+].[Na+].[CH2:26](NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCC.[Na+].[Na+].CC(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCCCC.[Na+].[Na+].CC(C)CCCCCCCCCCCCCNC1C=C(C([O-])=O)C(=CC=1)C([O-])=O.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C(=CC=1)C([O-])=O)CCCCCCCCCCCCCCCCCC>>[Na+:1].[Na+:1].[CH2:3]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([O-:23])=[O:22])[C:15](=[CH:19][CH:20]=1)[C:16]([O-:18])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCNc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Reactant: CCCCCCCCNc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Agent: CC(C)CCCCCCCCCCCCCNc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Agent: CCCCCCCCCCC(C)Nc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Agent: CCCCCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])c(C(=O)[O-])c1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])c(C(=O)[O-])c1

Procedure:
Similarly, the 4-alkylaminophthalic acids described in Example 12 give, respectively, 4-octylaminophthalic acid disodium salt, 4-nonylaminophthalic acid disodium salt, 4-decylaminophthalic acid disodium salt, 4-undecylaminophthalic acid disodium salt, 4-(1-methylundecyl)aminophthalic acid disodium salt, 4-dodecylaminophthalic acid disodium salt, 4-tridecylaminophthalic acid disodium salt, 4-tetradecylaminophthalic acid disodium salt, 4-pentadecylaminophthalic acid disodium salt, 4-(14-methylpentadecyl)aminophthalic acid disodium salt, 4-heptadecylaminophthalic acid disodium salt, 4-octadecylaminophthalic acid disodium salt, and 4-nonadecylaminophthalic acid disodium salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1>C(O)C.Cl.[Fe]>[CH3:1][C:2]1([CH3:25])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1
Reactant: CC1(C)Cc2cc(C(F)(F)F)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC1(C)Cc2cc(C(F)(F)F)ccc2NC1c1cccc(N)c1
Temperature: 95 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
To a mixture of 3,3-dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.4 g, 6.8 mmol) in ethanol 95% (100 mL) and 10% hydrochloric acid (5 mL) was added iron (1.2 g, 20 mmol). The reaction mixture was stirred at 95° C. for 3 h. Then the insoluble solid was filtered off and the filtrate was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with 30% sodium hydroxide in water (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-(3,3-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (1.8 g, 86%) as a brown solid: LC/MS m/e calcd for C18H19F3N2 (M+H)+: 321.36, observed: 321.1.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16]4)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.CO.[Pd]>[C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16]4)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Cc2cc(C3=CCN(c4ccccc4)CC3)ccc2N1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1Cc2cc(C3CCN(c4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a solution of 5-(1-phenyl-1,2,3,6-tetrahydropyridin-4-yl)indolin-2-one (75.8 mg, 0.261 mmol) in THF (3 ml) and MeOH (3 ml) was added 10% Pd/C (210 mg) and stirred at room temperature under H2 (1 atom) atmosphere for 2 h. The reaction mixture was filtered through a Celite pad and concentrated. The residue was purified by column chromatography (CHCl3/MeOH) to afford 5-(1-phenylpiperidin-4-yl)indolin-2-one (51.2 mg) as mixture of triphenylphosphine oxide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:13][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:14])[C:10](=[O:12])[NH:30][CH2:29][C:28]([F:32])([F:31])[F:27]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
To a stirred solution of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (4.58 g, 22.6 mmol) in methylene chloride (50 mL) was added EDC HCl (4.75 g, 24.8 mmol) followed by 2,2,2-trifluoroethylamine (2.67 g, 27.0 mmol) and DMAP (3.03 g, 24.8 mmol). The reaction mixture was stirred at ambient temperature for 18 h, then washed with aqueous 5% NaHSO4 (2×), aqueous 10% HCl (1×) and aqueous saturated NaHCO3 (2×). The organic phase was dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (2.97 g, 46%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[F:23][C:24]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([F:34])([F:35])[F:36])[C:24]=3[F:23])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1F
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(C(F)(F)F)c4F)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) and 2-fluoro-3-trifluoromethyl-benzoyl chloride (0.6 g, 2.8 mmol) in dry methylene chloride (60 mL), was added diisopropylethylamine (0.7 g, 5.4 mmol). The mixture was stirred at room temperature overnight then quenched with methanol (1 mL). The resulting suspension was filtered and the solid was washed with methylene chloride to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-fluoro-3-trifluoromethyl-benzamide (0.8 g, 72%) as a white solid: mp 155-157° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.23 min. (99%); 1H NMR (DMSO-d6) δ 2.04-2.11 (s, 1H), 2.53-2.64 (m, 2H), 2.85-2.97 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5.3 and 12.6 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.79-8.01 (m, 5H), 9.26 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.96, 30.91, 38.46, 48.87, 117.03 (117.29, 117.45), 120.65 (124.26), 122.03, 125.09 (125.15), 125.45 (125.64), 127.22, 129.24 (129.29), 131.58, 132.97, 134.89, 138.41, 154.37 (157.77), 162.90, 166.91, 167.45, 169.80, 172.73; Anal. Calcd. for C22H15N3O5F4: C, 55.35; H, 3.17; N, 8.80; F, 15.92. Found: C, 55.13; H, 2.95; N, 8.73; F, 15.69.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].Cl[CH2:31][C:32]([NH2:34])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCCCCC.O>[CH3:1][N:2]([S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:5])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][N:27]([CH2:31][C:32]([NH2:34])=[O:33])[CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C3=NCC4(CCN(CC(N)=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A mixture of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg), chloroacetamide (30 mg), potassium carbonate (40 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate:hexane=1:1 from a fraction to give the title compound (62 mg, yield 56%) as white crystals. melting point 226° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([O:5][CH3:6])=[O:4].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][CH:2]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[C:3]([O:5][CH3:6])=[O:4])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=O)C(N)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(NC(=O)c1ccc(F)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of methyl α-amino-2-thiophene acetate (1.48 g), 4-fluorobenzoyl chloride (1.64 g) and sodium hydrogen carbonate (2.89 g) in methylene chloride (20 ml) and water (20 ml) was stirred at room temperature overnight. The organic layer was collected, washed with water and brine, and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate-hexane to obtain methyl α-(4-fluorobenzoylamino)-2-thiophene acetate (2.40 g) as colorless powder.