Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34].C(C(CCCC)C([O-])=O)C.[Na+:46].CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:46]
Reactant: O=C(Nc1ccc2cc(Cl)ccc2n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Nc1ccc2cc(Cl)ccc2n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 0 °C
Yield: 82.7 %

Procedure:
6-Chloro-7-(4-(6-chloroquinolin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.050 g, 0.098 mmol) in THF (1.5 mL) was heated until a homogeneous solution resulted. The reaction was filtered and sodium 2-ethylhexanoate (0.020 g, 0.12 mmol) was added. The reaction was cooled to 0° C. Hexane was added in 0.5 mL portions and the solution was stored in the freezer overnight. The resulting solids were collected by filtration and dried to provide the desired product (0.043 g, 0.081 mmol, 82% yield). MS (ESI)=509.1 (M+1).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:57][C:58]1[CH:63]=[CH:62][C:61]([CH2:64][C:65](O)=[O:66])=[CH:60][CH:59]=1>CN(C=O)C.CO.C(Cl)Cl>[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:65](=[O:66])[CH2:64][C:61]1[CH:62]=[CH:63][C:58]([F:57])=[CH:59][CH:60]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(-c2ccc3c(c2F)CCN3C(=O)Cc2ccc(F)cc2)c2c(N)ncnc21
Reaction time: 1 h
Yield: 63 %

Procedure:
To a suspension of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride (200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA (314 uL, 1.80 mmol, 3.2 equiv) in one portion. To this mixture was added (4-fluorophenyl)acetic acid (97 mg, 0.56 mmol, 1 equiv) portionwise over a 1 hour period. After an additional 1 hour, the mixture was poured into ice cold water to give a suspension, which was filtered. The cake was washed with water and dried under house vacuum to afford crude product. This material was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an Analogix SF25-40 g silica gel cartridge using gradient elution of 1% A in CHCl3 to 65% A in CHCl3 (A was a mixture of 3200/800/80 CHCl3/MeOH/NH4OH, gradient: 0-5 min: 1% A, 5-35 min 5-60% A). The desired product eluted from 28-32% A. The combined fractions were concentrated in vacuo. The residue was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an Analogix SF25-60 g silica gel cartridge using gradient elution of 1% A in EtOAc 75% A (A was a mixture of 20% MeOH in EtOAc). The desired product eluted from 36-60% A (as a broad peak). The combined fractions were concentrated in vacuo. The residue was dissolved in 20 mL of 10% MeOH in DCM and concentrated in vacuo. The volume was reduced down to about 5 mL, and the mixture was diluted with 10 mL of MTBE. The resulting suspension was concentrated in vacuo to a wet paste, which was diluted with another 10 mL of MTBE. The suspension was filtered. The cake was washed with MTBE (3×4 mL) and dried under vacuum at 65° C. for 18 h to afford 5-{4-fluoro-1-[(4-fluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (148 mg) as white solids. LC-MS (ES) m/z=420 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 3.25 (t, J=8.3 Hz, 2H), 3.74 (s, 3H), 3.89 (s, 2H), 4.30 (t, J=8.3 Hz, 2H), 5.89-6.17 (br s, 1 h), 7.15-7.21 (m, 3H), 7.26 (s, 1H), 7.32-7.35 (m, 2H), 7.93 (d, J=8.3 Hz, 1H), 8.14 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.Cl.O1CCOCC1>C(O)(=O)C.O1CCCC1.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Nc1ccc(C=CC(=O)O)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 272.6 %

Procedure:
Cyclobranyl ester of p-nitrocinnamic acid (165.0 g, 0.268 mole) prepared according to the procedure of Example 103 was suspended in a mixture of acetic acid (1.5 l) and tetrahydrofuran (2 l). To the suspension were added 6N-HCl-dioxane (125 ml) and zinc powder (165 g) and the mixture was stirred at 20° C. for 2 hours. Then the reaction mixture was filtered to remove zinc powder. The filtrate was concentrated under reduced pressure, and the residue was extracted with chloroform. The extracts were washed successively with water and saturated aqueous NaHCO3, then dried, and concentrated in vacuo. The residual crystals were recrystallized from chloroform-ethanol (1:3, v/v), giving cyclobranyl ester of p-aminocinnamic acid (119.2 g), in a 75.9% yield. m.p. 206°-207° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:20][CH:19]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Ethyl indole-2-carboxylate (0.5 g) was dissolved in DMF and sodium hydride (0.116 g) was added in a single portion. The reaction was stirred for 1 hour, then 4-chlorobenzyl chloride (0.468 g) was added dropwise. Stirring was continued for a further 2 hours and then the reaction was quenched by the addition of water. The reaction mixture was partitioned between water and ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-5% ethyl acetate as eluent to give the desired end product as a white solid (0.61 g, 74%), mp 107-108°; NMR δ(CD3SOCD3) 1.25 (t, 3H), 4.3 (q, 2H), 5.8 (s, 2H), 7.1 (t, 1H), 7.3 (m, 4H), 7.55 (d, 1H), 7.7 (d, 1H); M/z (+) 314 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[S:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>C1(C)C=CC=CC=1>[S:4]1[C:11]2([CH2:12][CH2:13][S:8][CH2:9][CH2:10]2)[NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: O=S1CCCCC1
Reactant: N[C@@H](CS)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)[C@@H]1CSC2(CCSCC2)N1
Yield: 74.4 %

Procedure:
5.22 g of L-cysteine and 5 g of tetrahydrothiopyranone are suspended in 50 ml of toluene and the suspension is boiled, using a water separator, until the theoretical amount of water has been separated off. When the suspension is cooled, the product separates out as a light yellow precipitate, which is recrystallized from methanol/water to give 6.9 g of light yellow crystals of melting point 196° C.
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[NH2:12][C:13]1[N:21]=[CH:20][C:19](Cl)=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].N[C@H](C(O)=O)CC>>[NH2:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: Nc1ncc(Cl)cc1C(=O)O
Agent: CC[C@H](N)C(=O)O
Agent: O=C1Nc2ccccc2C1=O
Product: Nc1ncccc1C(=O)O

Procedure:
Using the procedure in Example 56 and substituting 5-fluoroisatin for isatin and 2-amino-5-chloronicotinic acid (Abu El-Haj et al., U.S. Pat. No. 3,917,624, 1975) for 2-aminonicotinic acid gives the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([Br:9])=[C:7]([C:10](=[O:12])N)[S:6](=[O:13])[N:5]=1)[CH3:2].N([O-])=[O:15].[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[C:8]([Br:9])=[C:7]([C:10]([OH:15])=[O:12])[S:6](=[O:13])[N:5]=1)[CH3:2]
Reactant: CCOC1=NS(=O)C(C(N)=O)=C1Br
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC1=NS(=O)C(C(=O)O)=C1Br
Reaction time: 0.03 h
Yield: 64.9 %

Procedure:
3-Ethoxy-4-bromo-5-carbamoylisothiazole-1-oxide (267 mg, 1.0 mmol) was dissolved in 2 ml of trifluoroacetic acid and sodium nitrite (138 mg, 2.0 mmol) was added in small portions over a two minute period with stirring. Stirring was continued for two minutes at room temperature and then the solvent was removed in vacuo. The residual gum was stirred in 5 ml of ice water for five minutes. Filtration gave 174 mg (65% yield) of yellow solid; mp 158°-160° C., dec.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>CN(C=O)C.O>[CH3:26][N:25]([CH3:27])[C:23](=[O:24])[CH2:22][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CN(C)C(=O)CCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Yield: 113.6 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.8 g, 4.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), and 2-chloro-N,N-dimethylacetamide (0.47 mL, 4.5 mmol) in DMF (14 mL) was heated in a microwave at 90° C. for 1 hr. The crude reaction mixtures were then diluted with water (300 mL) and extracted with ethyl acetate (3×50 mL). Product was purified by silica gel column using DCM/EtOAc/MeOH (8/1.5/0.5) as eluent to provide N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (1.3 g) as a light yellow oil. ESI-MS:m/z 280.3 (M+H)+.
Reaction SMILES: [Zn:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[K+].[K+].[K+]>O>[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Zn+2:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Zn+2:1].[Zn+2:1]
Reactant: [Zn]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: [Zn+2]

Procedure:
Ten ml of 17% zinc solution were added to a liter of water. Later 20 grams of potassium phosphate were added and dissolved. Zinc phosphate formed a precipitate. Phosphorous acid was then added to lower the pH and clear the solution. Once clear 30 ml of the solution prepared in example 35 was added. This acidic solution, which was acidic, then remained undisturbed for a day, after which the pH was adjusted to 10 with the addition of MEA. The zinc solution comprising chelated zinc remained clear, free of precipitates, and colorless.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[N:12][C:11]([Cl:17])=[CH:10][C:9]=2[C:8]1=O)=O)[CH3:2].[NH2:20][NH2:21].O>CCO>[CH2:1]([O:3][C:4]([C:5]1[NH:20][N:21]=[C:8]2[C:9]3[C:14](=[CH:13][N:12]=[C:11]([Cl:17])[CH:10]=3)[CH2:15][CH2:16][C:7]=12)=[O:19])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)C1CCc2cnc(Cl)cc2C1=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]nc2c1CCc1cnc(Cl)cc1-2

Procedure:
(3-Chloro-5-oxo-5,6,7,8-tetrahydro-isoquinolin-6-yl)-oxo-acetic acid ethyl ester (1.4 g; 4.8 mmol) in EtOH (15 ml) is combined with H2NNH2.H2O (242 mg; 4.8 mmol) and refluxed for 1 hour. The mixture is left over night at room temperature and delivers the title compound as yellowish crystals. 1H-NMR (400 MHz; DMSO-d6): 8.37 (s, 1H); 7.68 (s, 1H); 4.36 (q, 2H); 3.5 (bs, 1H); 2.99 (m, 2H); 2.97 (m, 2H); 1.35 (t, 3H). MS (m/z) ES+: 278 (MH+).
Reaction SMILES: [CH3:1][C@H:2]([C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:21]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH3:1][C@H:2]([C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:33]([C:32]2[CH:36]=[CH:37][C:29]([O:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:30][CH:31]=2)=[O:34])=[CH:16][CH:15]=1)=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCCC[C@H](C)C(=O)Oc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCC[C@H](C)C(=O)Oc1ccc(OC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
{circle around (3)}: A mixture comprising 1.66 g of (S)-4-(1′-methylnonylcarbonyloxy)phenol, 1.37 g of 4-benzyloxybenzoic acid, 1.24 g of DCC and 10 g of dichloromethane was stirred at room temperature for 30 minutes. Then, a catalytic amount of 4-N,N-dimethylaminopyridine was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After finishing the reaction, insoluble substances were filtered off, followed by distilling off dichloromethane from the filtrate under reduced pressure. The resultant residue was purified by means of silica gel column chromatography, whereby 2.0 g of (S)-4-[4′-(1″-methylnonylcarbonyloxy)phenyloxycarbonyl]-1-benzyloxybenzene was obtained in the form of a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[CH:11]([NH2:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].[C:19]([O:23][C:24]([NH:26][C@H:27]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:33][CH:32]=1)[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:19]([O:23][C:24](=[O:25])[NH:26][C@H:27]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:35][CH:36]=1)[C:28](=[O:29])[NH:17][C@H:11]([C:10](=[O:18])[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(C)(C)OCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CC(C)(C)CC(N)C(=O)Nc1ccc(I)cc1F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOC(C)(C)C)cc1)C(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To the solution of 2-amino-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide (364 mg, 1 mmol), (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid (1 M in DMF, 1.1 mL, 1.1 mmol), 1-Hydroxybenzotriazole (168 mg, 1.1 mmol) and diisopropylethyl amine (0.53 mL, 3.3 mmol) in N,N-dimethylformamide (5 mL) was added dropwise the solution of O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexaflurorophosphate (474 mg, 1.1 mmol). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate and the mixture washed with water and brine. The organic layers were successively washed with 1 M aqueous citric acid solution, brine, saturated aqueous sodium carbonate, brine, dried over sodium sulfate, filtered, and concentrated to give {(R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-[(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-3,3-dimethyl-butylcarbamoyl]-methyl}carbamic acid tert-butyl ester (652 mg, 91%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[CH3:17])[CH2:9]2)=[CH:4][CH:3]=1.[NH3:18]>>[CH3:17][CH:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C@H:10]1[CH2:11][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:2]3[CH:7]=[CH:6][C:5]([C:8]#[N:18])=[CH:4][CH:3]=3)=[CH:3][CH:4]=2)[CH2:9]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Reactant: N
Product: CC1CCCN1[C@H]1C[C@H](c2ccc(-c3ccc(C#N)cc3)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 2B except substituting the product from the Example 4A for the product from Example 2A. 1H NMR (300 MHz, CD3OD) δ 1.24 (d, J=6 Hz, 3 H), 1.60 (m, 1 H), 1.90 (m, 2 H), 2.12 (m, 1 H), 2.41 (m, 1 H), 2.53 (m, 1 H), 2.70 (m, 3 H), 2.92 (m, 1 H), 3.24 (m, 1 H), 3.62 (m, 2 H), 7.46 (d, J=9 Hz, 2 H), 7.67 (d, J=9 Hz, 2 H), 7.80 (s, 4H); (DCl/NH3) m/z 317 (M+H)+.
Reaction SMILES: Br[CH:2]([CH2:9][C:10]([Cl:13])([Cl:12])Cl)[C:3]([CH3:8])([CH3:7])[CH2:4][C:5]#[N:6].[Na]>C(O)C>[C:5]([CH:4]1[C:3]([CH3:7])([CH3:8])[CH:2]1[CH:9]=[C:10]([Cl:12])[Cl:13])#[N:6]
Reactant: CC(C)(CC#N)C(Br)CC(Cl)(Cl)Cl
Agent: [Na]
Solvent: CCO
Product: CC1(C)C(C#N)C1C=C(Cl)Cl

Procedure:
A mixture of 3-bromo-1-cyano-2,2-dimethyl-5,5,5-trichloropentane (0.5 g.) and a solution of sodium (0.2 g.) in ethanol (10 ml.) is refluxed for 2 hours after which the ethanol is removed by evaporation under reduced pressure. The residue is partitioned between chloroform (20 ml.) and water (20 ml.) and the chloroform layer separated, washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure yields 1-cyano 2-(2,2,-dichlorovinyl)-3,3-dimethylcyclopropane, identified by infra-red and nuclear magnetic resonance spectroscopy.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[C:11]1([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:38])[CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[CH2:18]2)[CH2:13][CH2:12]1.O.CCOC(C)=O>C(Cl)Cl>[F:7][C:11]1([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:38])[CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(O)(c3nccs3)CC2)C1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(F)(c3nccs3)CC2)C1
Temperature: 0 °C
Yield: 33.4 %

Procedure:
DAST (0.2 mL, 1.5 mmol) was added to N-[2-({(3R)-1-[4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (0.06 g, 0.12 mmol) in CH2Cl2 (5 mL) at −78° C. with stirring under N2. The solution was allowed to warm to 0° C. slowly and stirred for 1 h. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl, dried (MgSO4), concentrated and purified by flash chromatography and reverse-phase HPLC to give 0.020 g of the title compound in 31% yield. MS (EI) calcd: (M+H)+=499.2; found: 499.1.
Reaction SMILES: OS(O)(=O)=O.Cl.[CH3:7][C:8]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1.[N+:18]([O-])([OH:20])=[O:19].[NH4+].[OH-]>O>[CH3:7][C:8]1([CH3:17])[C:16]2[C:11](=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=2)[NH:10][CH2:9]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CNc2ccccc21
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Temperature: -2.5 °C
Reaction time: 1 h

Procedure:
H2SO4 (1.42 kg) and 3,3-dimethylindoline HCl salt (Example 3, 200 g) were charged to a dry 5 L RB-flask under nitrogen at 20-25° C. The reaction mixture was cooled to −15 to 10° C. A solution of HNO3 (75.6 g) in water (18.89 g) was added drop-wise. The resulting reaction mixture was stirred for 1 h. The mixture was transferred into a mixture of 2.084 L of 30% NH4OH and 600 mL of water at 0-5° C. The pH was adjusted to 8-9 with NH4OH, and after the addition of 800 mL of IPAC, phases were separated. The aqueous phase was extracted with IPAC (400 mL). The combined organic phase was washed with saturated brine (400 mL) to give a solution of 3,3-dimethyl-6-nitroindoline. (190.5 g, 91%, 94 A %).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[OH-].[Na+].O.[C:16]([O:20][C:21](N=[N+]=[N-])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([NH:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: NCC1=C(CC(=O)O)CC=CC1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC1=C(CC(=O)O)CC=CC1

Procedure:
To a stirred solution of 8.0 g. (0.048 mole) of α-(2-aminomethyl-1,4-cyclohexadienyl)acetic acid and 3.8 g. (0.096 mole) of NaOH in 150 ml. of water was added a solution of 10.3 g. (0.072 mole) of t-butoxycarbonylazide in 80 ml. of THF and the mixture was stirred for 18 hours at room temperature. The THF was removed under reduced pressure and the residual solution was washed with ether (2×100 ml.), acidified with 6 N HCl and extracted with ether (3×100 ml.). The combined extracts were washed with water (2×100 ml.) and a saturated NaCl solution (100 ml.), dried with Na2SO4 and evaporated to dryness. The oily residue was triturated with n-hexane to give 10.5 g. (82%) of colorless powder melting at 113° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27](O)=[O:28])=[CH:23][NH:24]2)=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:27]([C:22]4[C:21]5[C:25](=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=5)[NH:24][CH:23]=4)=[O:28])[CH2:14][CH2:15]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Reactant: O=C1Nc2ccc(Br)cc2C12CCNCC2
Product: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)C(=O)Nc1ccc(Br)cc12

Procedure:
Following the general procedure I as described above, the acylation of 5-bromospiro[indole-3,4′-piperidin]-2(1H)-one with 6-chloro-1H-indole-3-carboxylic acid (preparation described in example 5 above), gave the title compound. ES-MS m/e (%): 458.3 (M+H+).
Reaction SMILES: [C:1]1(=[N:13]O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(Cl)=NC(Cl)=NC=1Cl.[OH2:24].[OH-].[Na+]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[C:1]1(=[O:24])[NH:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: ON=C1CCCCCCCCCCC1
Reactant: O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCCCCCCCCCCN1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
In 500 mL three-necked flask equipped with a reflux condenser were placed 20 g of cyclododecanone oxime (Tokyo Chemical Industry Co., Ltd.), 0.13 g of zinc chloride and 80 g of toluene, and the mixture was heated to a temperature of 90° C. To the three-necked flask was added dropwise a solution of 0.28 g of cyanuric chloride dissolved in 30 g of toluene via a dropping funnel. Two hours after the end of dropping, the reaction solution was transferred to a 1 L separable flask equipped with a jacket. To the mixture was added 50 g of ultrapure water, and the mixture was stirred at a temperature of 80° C. for 15 min. After allowing the mixture to stand for 15 min, the aqueous layer was drained. Then, to the mixture was added 50 g of a 1% by weight aqueous solution of NaOH, and the mixture was stirred for 15 min. After allowing the mixture to stand for 15 min, the aqueous layer was drained. This operation was further conducted twice followed by addition of 50 g of ultrapure water, and then the mixture was stirred for 15 min. Then, the mixture was allowed to stand for 15 min, and an aqueous layer was drained. The reaction solution thus obtained was concentrated and a light transmittance difference (LT. diff) of laurolactam was determined to be 69.5%.