Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH:22]([CH3:24])[CH3:23])[C:3]([O:5]C(C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)=[O:4].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[K+].S(=O)(=O)(O)O>CN(P(N(C)C)(N(C)C)=O)C>[C:26]1([NH:25][C@H:2]([C:3]([OH:5])=[O:4])[CH:22]([CH3:24])[CH3:23])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: CC(C)C(Br)C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)[C@H](Nc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 90 h

Procedure:
To m-phenoxy-α-cyanobenzyl α-bromoisovalerate (2.0 g, 0.0052 mole) in 4 ml of HMPT, at 24°, is added aniline (1.5 g, 0.016 mole) and potassium iodide (21 mg). The reaction is stirred at 65° for 90 hours and then cooled and poured into ice-water (20 ml) plus 2 N sulfuric acid (10 ml). The reaction is worked up as in Example 4 and purified by preparative TLC to give the m-phenoxy-α-cyanobenzyl ester of N-phenylvaline.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:30](=[O:31])[C:27]3[CH:28]=[CH:29][C:24]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:26]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(OC(=O)c3ccc(-c4ccccc4)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-biphenylcarbonyl chloride (14 mg) and N,N-diisopropylethylamine (28 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.9 %

Procedure:
TFA (15 mL) was slowly added to a stirred solution of tert-butyl 4-isopropylpiperazine-1-carboxylate (13 g crude) in dry DCM (20 mL) under argon atmosphere at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 18 hr. The reaction mass was concentrated under vacuum and triturated the residue with n-hexane and diethyl ether. Dried under vacuum to afford the title compound (7 g, yield: 97%). MS (ESI): 129.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[I-].C[N+]1C=CN([C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C=1.C(N(CC)CC)C>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:18](=[O:27])[N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccc([N+](=O)[O-])cn1)c1ccccc1
Yield: 41.4 %

Procedure:
A solution of 2-hydroxy-5-nitropyridine (1.40 g, 10.0 mmol), 1-methyl-3-(methyl-phenyl -carbamoyl)-3H-imidazol-1-ium iodide (3.43 g, 10.0 mmol) and triethylamine (0.42 ml, 10.0 mmol) in acetonitrile (25 ml) was heated at 50° C. for 5 h. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate: heptane (25:75)) followed by crystallisation from ethyl acetate:heptane yielding the title compound (1.13 g, 41% yield) as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[O:11][CH3:12].C([Li])CCC.[C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]>O1CCCC1.O>[CH3:12][O:11][C:3]1[C:4]([CH3:10])=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([OH:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)c1ccccc1
Reactant: COc1c(C)c(C)cc(C)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)cc(C)c1C(O)(c1ccccc1)C(C)C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A solution of 2-bromo-3,5,6-trimethylanisole (3.0 g, 13.1 mmol) in tetrahydrofuran (20 ml) was cooled to -78° C. and n-butyllithium (1.6M solution in hexane, 8.2 ml, 13.1 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 15 minutes. Then a solution of isobutyrylbenzene (1.94 g, 13.1 mmol) in tetrahydrofuran (5 ml) was added dropwise and the resulting mixture was stirred at room temperature for additional 30 minutes. The reaction mixture was diluted with water and the product was extracted with isopropyl ether. The extract was washed with water, dried and then concentrated. The residue was crystallized from hexane to obtain the desired compound (3.13 g, yield: 80.2%), m.p. 80°-81° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=1>O>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=3)=[CH:8][C:7]1=2
Reactant: N#Cc1cc(Br)cs1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3csc(C#N)c3)cc21

Procedure:
Prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-thiophenecarbonitrile according to Procedure B. Yellowish solid: mp 230-231° C. (decomposed); 1H-NMR (CDCl3) δ 8.32 (s, 1H, D2O exchangeable), 7.83 (d, 1H, J=1.5 Hz), 7.61 (d, 1H, J=1.4 Hz), 7.43 (dd, 1H, J=8.2, 1.9 Hz), 7.29 (d, 1H, J=1.8 Hz), 6.85 (d, 1H, J=8.2 Hz), 1.78 (s, 6H); MS (EI) m/z 283(M−H, 100%). Anal. Calc. For C15H12N2O2S.0.2 H2O: C, 62.57; H, 4.34, N, 9.73. Found: C, 62.48; H, 4.31; N, 9.64.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:15]=[C:14]([F:16])[C:13]([S:17](Cl)(=[O:19])=[O:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>O1CCOCC1>[Cl:6][C:7]1[CH:15]=[C:14]([F:16])[C:13]([S:17]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:19])=[O:18])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F
Yield: 92 %

Procedure:
tert-Butyl amine (77 mL, 0.7 mol, 10 equiv) was added to 300 mL dioxane at 0° C. Ice chips were added to the flask for several minutes before the addition of 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid (20 g, 73.24 mmol, 1 equiv). Both the internal and external temperature of the reaction was maintained at or below 0° C. for 2 h. The reaction was then concentrated half-way and acidified to pH 2 with 1N HCl. The product was extracted into EtOAc. The organics were dried over Na2SO4, filtered and concentrated down to give 2-chloro-5-{[(1,1-dimethylethyl)amino]sulfonyl}-4-fluorobenzoic acid 883-4a as a brown solid (21 g; 92% yield).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[C:10]([O:15]C)[N:11]=[CH:12][CH:13]=3)[N:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[S:20][CH:21]=3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([C:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[N:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:24])=[O:23])[S:20][CH:21]=3)[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c(C3CCCC3)nn(-c3csc(C(N)=O)c3)c12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1cc(-n2nc(C3CCCC3)c3cc[nH]c(=O)c32)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of 4-(3-cyclopentyl-7-methoxy-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxamide (60 mg) in acetonitrile (5 mL) were added sodium iodide (52.5 mg) and chloro(trimethyl)silane (0.111 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% trifluoroacetic acid)), to the obtained fraction was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate and THF. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The suspension of the residue in ethanol was stirred at 100° C. for 2 hr, allowed to be cooled to room temperature, and the solid was washed with ethanol to give the title compound (35 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>>[N+:18]([CH:21]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[O:4][CH2:3][O:2][CH3:1])([O-:20])=[O:19]
Reactant: C[N+](=O)[O-]
Reactant: COCOc1ccccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COCOc1ccccc1C=C[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
2-Methoxymethoxybenzaldehyde (16.4 g) was suspended in nitromethane (54 mL), added with ammonium acetate (5.95 g), and stirred for 30 minutes at 80° C. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was suspended in water and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine in order and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residues were purified by diol silica gel column chromatography (5% ethyl acetate/hexane) to obtain the title compound (11.6 g) as a yellow oil.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:23])([F:22])[C:5]1[N:9]2[CH:10]=[C:11]([C:18]([O:20]C)=[O:19])[C:12]3[C:17]([C:8]2=[N:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C(O)C.Cl>O>[F:23][C:4]([F:3])([F:22])[C:5]1[N:9]2[CH:10]=[C:11]([C:18]([OH:20])=[O:19])[C:12]3[C:17]([C:8]2=[N:7][N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: COC(=O)c1cn2c(C(F)(F)F)nnc2c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c(C(F)(F)F)nnc2c2ccccc12

Procedure:
A solution of potassium hydroxide (2.8 g., 0.05 mol.) and 3-trifluoromethyl-6-methoxycarbonyl-s-triazolo-[3,4-a]-isoquinoline (14.8 g., 0.05 mol.) was allowed to reflux in 280 ml. of ethanol for 12 hours. Removal of the solvent provided a residue which was dissolved in water andfiltered. The aqueous filtrate was neutralized with 2N hydrochloric acid and the product, 9.7 g. (70%) was collected by filtration; m.p. 290°C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:21]#[C:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][N:6]2[N:8]=1)([CH3:13])[CH3:12]
Reactant: C#Cc1ccccc1
Reactant: CC(C)c1cc2ncc(Br)cn2n1
Product: CC(C)c1cc2ncc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, a brown solid, MS: m/e=245.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-isopropyl-pyrazolo[1,5-a]pyrimidine (example 38, step 1) and phenylacetylene.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4](C=O)[CH:3]=1.[CH2:9]([O:11][C:12](=[O:18])[CH2:13][C:14]([CH2:16][Cl:17])=[O:15])[CH3:10]>>[CH2:9]([O:11][C:12](=[O:18])[C:13](=[C:4]1[CH:3]=[C:2]([CH3:1])[O:6][NH:5]1)[C:14](=[O:15])[CH2:16][Cl:17])[CH3:10]
Reactant: Cc1cc(C=O)no1
Reactant: CCOC(=O)CC(=O)CCl
Product: CCOC(=O)C(C(=O)CCl)=C1C=C(C)ON1

Procedure:
79.5 g of 5-methylisoxazole-3-aldehyde were reacted with 4-chloroacetoacetic acid ethyl ester as described in Example 24. A crude product, which was chromatographically pure, was obtained. This isomer ratio was 2:1.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[C:15]([F:16])=[C:14]([C:17](O)=[O:18])[C:13]([F:20])=[C:12]([F:21])[C:11]=1[CH3:22]>>[CH:1]1([NH:8][C:17](=[O:18])[C:14]2[C:13]([F:20])=[C:12]([F:21])[C:11]([CH3:22])=[C:10]([F:9])[C:15]=2[F:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCCC1
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Product: Cc1c(F)c(F)c(C(=O)NC2CCCCCC2)c(F)c1F

Procedure:
Prepared in a similar manner to Example 162 using cycloheptylamine and 2,3,5,6-tetrafluoro-p-toluic acid (94%). 1H NMR (CDCl3) δ 1.53 (m, 6H), 1.57 (m, 4H), 2.03 (m, 2H) 2.28 (m, 3H), 4.17 (m, 1H), 5.85 (bs, 1H). MS (304.1, M+H) m. p. 164-165° C.
Reaction SMILES: [NH2:1][CH:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.Cl>CC(C)=O.O>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][CH:2]([CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[C:13]([OH:15])=[O:14])=[O:28])=[CH:25][CH:24]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
10 Grams of DL-tryptophane was dissolved in a mixture of 100 ml of acetone with 20 ml of water, then to this solution was added 6 g of potassium carbonate. Under an ice-cooled condition, 9 g of 4-chlorobenzoyl chloride was added dropwise to the above-mentioned mixture, and the reaction mixture was stirred at the same temperature for 2 hours. Then, acetone was removed by evaporation, to the residue thus obtained was added water, and mixture was acidified by adding concentrated hydrochloric acid, the crystals formed were collected by filtration, and washed with water. Recrystallized from ethanol to obtain 14 g of 2-(4-chlorobenzoylamino)-3-(indol-3-yl)propionic acid. White powdery substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([CH2:16][CH2:17][F:18])[C:12]([O:14][CH3:15])=[O:13].CN1CCOCC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:11]([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)([CH2:16][CH2:17][F:18])[C:12]([O:14][CH3:15])=[O:13])=[CH:24][CH:23]=1
Reactant: COC(=O)C(CCF)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)C(CCF)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of compound from step B (68 mg, 0.189 mmol) and NMM (38 mg, 0.37 mmol) in DCM (7 mL) was added methylsulfonyl chloride (32 mg, 0.283 mmol) dropwise. Then the mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (50 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a white solid. LC/MS m/z=439.0[M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C1CCC(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)CCC(Cc2ccccc2)C1

Procedure:
A mixture of 5 g of 4-benzyl-cyclohexanone, 3.5 g of pyrrolidine, 500 mL of benzene and 10 mg of p-toluenesulfonic acid monohydrate was heated under a water separator apparatus for 48 h, removing the distillate periodically until there was about 50 mL remaining. The solution was cooled and concentrated to 8 g of an amber liquid. The NMR was consistent with complete conversion to the enamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:21]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[N:11]1[CH2:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([NH:1][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(NS(=O)(=O)c2ccccc2)c1

Procedure:
Sulfonation of 2-(3-(3-aminophenyl)propyl)isoindoline-1,3-dione by benzenesulfonyl chloride following the method used in Example 6 gave N-(3-(3-(1,3-dioxoisoindolin-2-yl)propyl)phenyl)benzenesulfonamide as a yellow semi-solid. Yield (0.80 g, 62%). 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 7.87-7.81 (m, 4H), 7.72 (d, J=7.6 Hz, 2H), 7.58-7.49 (m, 3H), 7.11 (t, J=8.0, 1H), 6.92 (s, 1H), 6.88-6.85 (m, 2H), 3.52 (t, J=7.2 Hz, 2H), 2.50-2.49 (m, 2H), 1.81-1.74 (m, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[CH:9]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:15]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[NH:16]
Reactant: N#CC1CCCCC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: N=C(NO)C1CCCCC1
Reaction time: 0.21 h

Procedure:
To a solution of 1.9 g (27.4 mmol) of hydroxylamine hydrochloride in 22 mL of isopropyl alcohol, 3.3 g (40.3 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 2.0 g (18.3 mmol) of cyclohexanecarbonitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After the reaction period, the reaction mass was cooled to 25° C. to 30° C., filtered and washed with 10 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue was chased with 5 mL of toluene, to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:29]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:28])[NH:16][CH:17]3[CH:24]4[CH2:25][C:20]5(F)[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:30][C:31]([O:33]CC)=O.CC[N:38]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:38][C:31](=[O:33])[CH2:30][CH:7]1[C:6]2[C:29](=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:9]2([CH2:10][CH2:11][N:12]([C:15]([NH:16][CH:17]3[CH:18]4[CH2:26][CH:22]5[CH2:21][CH:20]([CH2:25][CH:24]3[CH2:23]5)[CH2:19]4)=[O:28])[CH2:13][CH2:14]2)[CH2:8]1
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC3CC(F)(C5)C4)CC2)c2c(Br)cccc21
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a solution of the compound 1 (200 mg, 0.47 mmol) in CH2Cl2 (5 mL), EDCI (187 mg, 0.95 mmol), HOBt (128 mg, 0.95 mmol), DIEA (303 mg, 2.35 mmol) were added under NH3 at 0° C., and then stirred overnight. The solvent was removed under reduced pressure to give crude product, which was purified by preparative TLC to afford (±)-3-(2-amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (110 mg, 56%). 1H NMR (CDCl3): δ=1.52-1.61 (m, 4H), 1.62-1.66 (m, 2H), 1.68-1.70 (m, 2H), 1.75-1.76 (m, 2H), 1.78-1.80 (m, 1H), 1.82-1.85 (m, 6H), 1.90-1.98 (m, 2H), 2.11-2.21 (m, 1H), 2.30-2.40 (m, 1H), 2.60-2.70 (m, 1H), 2.80-2.88 (m, 1H), 2.95-3.15 (m, 2H), 3.65-3.75 (m, 2H), 3.76-3.88 (m, 1H), 4.00 (s, 2H), 5.40-5.55 (d, 2H), 7.15-7.25 (m, 4H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1.[CH3:25][O-:26].[Na+].Cl>CN(C)C=O.CCOCC>[ClH:1].[CH:25]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1)=[O:26]
Reactant: CN1CCC2(CC1)CN(c1ccccc1N)c1ccccc12
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CCC2(CC1)CN(c1ccccc1NC=O)c1ccccc12
Temperature: 90 °C

Procedure:
To a mixture of 15.0 g of 1-(2-aminophenyl)-1'-methylspiro[indoline-3,4'-piperidine]dihydrochloride, Example 16, in 75 ml of dimethylformamide at 90° C. under nitrogen is added 8.6 g of sodium methoxide. Following this addition the reaction temperature is increased to 110°-115° C. and maintained at this temperature for 40 minutes. The resulting dark brown mixture is permitted to cool to 90° C. and then poured onto 800 ml of ice-water. The mixture is filtered and the filter cake is washed with water and then dissolved in chloroform. The chloroform solution is successively washed with brine, dried and concentrated leaving a red colored glass. The glass is dissolved in ether, where it is converted to its hydrochloric acid salt which is collected by filtration and then washed with ether and finally dried. The salt is recrystallized from a methyl alcohol-ether mixture to provide the product, mp 287.5° C., dec of 1-(2-formamidophenyl)-1'-methylspiro[indoline-3,4'-piperidine]hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C([Li])CCC.CCCCCC.[C:35]1([CH2:41][CH:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH:42]([OH:43])[CH2:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:3]=3)[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=2)=[CH:18][CH:19]=1
Reactant: O=CCc1ccccc1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(Cc1ccccc1)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.1 %

Procedure:
To a solution of 5-bromo-3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazole (0.50 g, 1.0 mmol) in dried tetrahydrofuran (15 mL) under nitrogen at −78° C. was added dropwise a 1.6 M solution of butyl lithium in hexane (1.1 mL, 1.7 mmol). After stirring for 20 minutes, to the reaction mixture was added phenylacetaldehyde (0.228 g, 1.9 mmol). The reaction mixture was stirred additional 1 hour at −78° C. and the temperature was gradually raised to room temperature. It was quenched with water and extracted with dichloromethane. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide the title compound (0.246 g, 44% yield): 1H NMR (CDCl3) δ 7.86 (m, 2H), 7.80 (d, 1H), 7.09–7.47 (m, 9H), 6.98 (dd, 1H), 5.70 (dd, 1H), 5.07 (t, 1H), 4.08 (m, 1H), 3.65 (m, 1H), 3.06 (d, 1H), 2.67 (m, 2H), 2.11 (m, 2H), 1.75 (m, 3H); ES-MS (m/z) 417 [M+1]+.