Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C@@H:19]([CH2:23][NH:24][C:25]([O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])[C:20](O)=[O:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:20]([C@@H:19]([CH:18]([CH3:34])[CH3:17])[CH2:23][NH:24][C:25](=[O:26])[O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:21])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC(C)[C@@H](CNC(=O)OCC[Si](C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](CNC(=O)OCC[Si](C)(C)C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a solution of (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (91 mg, 0.38 mmol), (S)-3-methyl-2-(((2-(trimethylsilyl)ethoxy)carbonylamino)methyl)butanoic acid (105 mg, 0.380 mmol), EDC (146 mg, 0.760 mmol) and HOBT (11.64 mg, 0.076 mmol) in CH2Cl2 (2 mL) was added Hunig's Base (0.199 mL, 1.140 mmol). Upon completion of addition, the reaction mixture was stirred at room temperature for 16 hrs. After this time, the reaction mixture was quenched with sat'd NaHCO3 and the crude product was extracted with EtOAc and the extract was washed with brine. The combined aqueous layers were back extracted with EtOAc. The EtOAc extracts were combined, dried over Na2SO4 and evaporated to give a solid residue. The solid residue was purified by Combiflash chromatography (40 g silica gel) eluting with 1:1 and 8:2 EtOAc-hexane to give 110.5 mg of the title compound as a white foamy solid. MS (ESI+)=497.15 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([OH:20])=O)=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.[CH3:31][NH:32][CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[OH:35].C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][NH:11][C:10]=1[C:18]([N:32]([CH2:33][C@H:34]([OH:35])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:31])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC[C@H](O)c1ccccc1
Reactant: COC(=O)c1[nH]nc(C(=O)O)c1OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1n[nH]c(C(=O)N(C)C[C@H](O)c2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4-benzyloxy-3-carboxy-1H-pyrazole-5-carboxylate (1.5 g, 5.43 mmol; prepared as in Example 31, Step 1) in DMF (20 mL) were added HOAT (1.11 g, 8.15 mmol), (1R)-2-(methylamino)-1-phenylethanol (1.23 g, 8.15 mmol; prepared as described in Gurjar, M. K., et al., Org. Process Res. Dev. 1998, 2, 422.), triethylamine (0.82 g, 8.15 mmol), and EDC (1.56 g, 8.15 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. The DMF was removed in vacuo and the residue was partitioned between saturated aqueous NH4Cl and EtOAc. The layers were separated and the aqueous was extracted twice more with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford the title product. ES MS (M+1)=410.
Reaction SMILES: C([S:9][CH2:10][C@@H:11]([CH3:28])[C:12]([N:14]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH:15]1[C:25]([OH:27])=[O:26])=[O:13])(=O)C1C=CC=CC=1.N>CO>[SH:9][CH2:10][C@@H:11]([CH3:28])[C:12]([N:14]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH:15]1[C:25]([OH:27])=[O:26])=[O:13]
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(C(=O)O)CCC1c1ccccc1
Agent: N
Solvent: CO
Product: C[C@H](CS)C(=O)N1C(C(=O)O)CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
20 g of 1-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-5-phenyl-2-pyrrolidinecarboxylic acid is dissolved in 50 ml of methanol. To this solution 100 ml of conc. ammonia is added, and the mixture is stirred at room temperature for 1.5 hours. Excess ammonia and methanol are removed in vacuo, and the residue is washed with ethyl acetate. The aqueous layer is acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give the titled compound, yield 8.5 g (58%), mp. 138.0°-142.5° C. (ethyl acetate), [α]D29 -29.4° (c=1.0, methanol).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Nc1noc2ccc(C=O)cc12
Reactant: O=C1CSC(=O)N1
Product: Nc1noc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 3-Amino-benzo[d]isoxazole-5-carbaldehyde (intermediate 68) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: C([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:9]=1)(=O)C.Cl.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:9]=1
Reactant: CC(=O)Nc1nc(CS(=O)(=O)c2ccc(N)cc2)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)(=O)Cc2csc(N)n2)cc1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
A solution of 2-acetylamino-4-(4-aminophenylsulfonylmethyl) thiazole (4.8 g) in a mixture of acetic acid (35 ml) and 6N-aqueous hydrochloric acid (10 ml) was refluxed for 2.5 hours with stirring. The reaction mixture was poured into ice-water and then the solution was adjusted to pH 8.0 using 10% aqueous sodium bicarbonate with stirring. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-4-(4-aminophenylsulfonylmethyl)thiazole (2.50 g, yield: 60.2%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.CCCCCC.CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]
Reactant: Cc1ccc(Cl)cc1Br
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(Cl)cc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a solution of 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol) in anhydrous THF (600 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (103 mL, 0.26 mol). After stirring for 1 hr at −78° C., a solution of the (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (67 g, 0.246 mol) in anhydrous THF (300 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylate (86 g), which was used immediately in the next step without purification.
Reaction SMILES: [NH3:1].Cl.[C:3]1([CH2:9][N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19](Cl)=[O:20])[CH:16]=3)[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1>[C:3]1([CH2:9][N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH2:1])=[O:20])[CH:16]=3)[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: O=C(Cl)c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 200 ml of conc. aqueous ammonia and 50 ml of tetrahydrofuran were added, in batches, 20.0 g (64.9 mMol) of 2,3-dihydro-2-(phenylmethyl)-1H-isoindole-5-carboxylic acid chloride-hydrochloride and the mixture was stirred overnight at ambient temperature. The precipitate formed was suction filtered, washed thoroughly with water and dried at 50° C. in a circulating air dryer. The desired compound was obtained in a quantitative yield in the form of colourless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=[O:14].[Ce+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Ce+3].Br([O-])(=O)=O.[Ba+2].Br([O-])(=O)=O>C(#N)C.O>[C:1]([C:5]1[CH:6]=[C:7]([C:11](=[O:14])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cccc(C(C)(C)C)c1
Reactant: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Agent: [Ce+3]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1cccc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a stirring solution of 1-tert-butyl-3-ethylbenzene (11.15) in acetonitrile (350 ml) and water (150 ml) at room temperature was added cerium (III) sulfate (6.05 g) and barium bromate (13.5 g). The resulting suspension was heated at reflux for 16 hrs. After cooling to room temperature, the reaction mixture was filtered. Saturated aqueous sodium thiosulphate solution was added to the filtrate, and the product was extracted into DCM (3×100 ml). Combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-(3-tert-butyl-phenyl)-ethanone as a yellow oil crude product (13.5 g). 1H NMR (CDCl3): δ 8.00 (s, 1H), 7.75 (d, 1H), 7.61 (d, 1H), 7.39 (t, 1H), 2.61 (s, 3H), 1.36 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
3.00 g (13.6 mmol) 4-iodophenol, 1.60 mL (15.0 mmol) 1-bromo-2-methylpropane and 7.50 g (54.5 mmol) K2CO3 are dissolved in 30 mL DMF and stirred at 80° C. for 4 h. Afterwards the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with diluted aq. NaOH (2×) and water (2×), dried over MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=2[CH3:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]1.[CH3:27][NH2:28]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:28][CH3:27])[C:18]=2[CH3:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]1
Reactant: CN
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(O)c(F)cc3F)c12
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(O)c(F)cc3F)c2c1C
Yield: 95.5 %

Procedure:
1-(2,4-Difluoro-5-hydroxyphenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg) was added to an aqueous solution (about 40%; 3.0 g) of methylamine to conduct a reaction at 75° C. for 4 days. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (4 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (2 ml) was added to the resultant residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (295 mg) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([OH:13])=[C:11]([C:14]([O:16]CC)=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[C:24]([CH:27]=1)[C:25]#[N:26]>N1C=CC=CC=1>[C:25]([C:24]1[CH:27]=[C:20]([NH:19][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[OH:13])=[O:16])[CH:21]=[CH:22][C:23]=1[O:28][CH2:29][CH:30]([CH3:31])[CH3:32])#[N:26]
Reactant: CC(C)COc1ccc(N)cc1C#N
Reactant: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1O
Solvent: c1ccncc1
Product: CC(C)COc1ccc(NC(=O)c2cnn(-c3ccc(F)cc3)c2O)cc1C#N
Temperature: 120 °C
Reaction time: 4 h
Yield: 12.7 %

Procedure:
Ethyl 1-(4-fluorophenyl)-5-hydroxypyrazole-4-carboxylate (1 g) and 5-amino-2-isobutoxybenzonitrile (0.8 g) were added to pyridine (10 ml) and the mixture was stirred at 120° C. for 4 h. After evaporation of the solvent under reduced pressure, hydrochloric acid was added to the residue and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethanol-diisopropyl ether to give the title compound (0.2 g), melting point: 207–208° C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3].C[Si](C)(C)[C:32]([F:35])([F:34])[F:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]([OH:26])[C:32]([F:35])([F:34])[F:33])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)C(F)(F)F)C1=O
Reaction time: 1 h

Procedure:
A solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal (80 mg, 0.186 mmol) and trimethyl(trifluoromethyl)silane (82 μL, 0.558 mmol) in THF (929 μL) was treated at 0° C. with 1 M tetrabutylammonium fluoride in THF (93 μL, 0.093 mmol). After being stirred for 1 h, three additional equivalents of trimethyl(trifluoromethyl)silane (82 μL, 0.558 mmol) and 1 M tetrabutylammonium fluoride in THF (93 μL, 0.093 mmol) were added to the reaction at 0° C. and the reaction was stirred for 14 h. The reaction mixture was diluted (EtOAc), washed (1×H2O and 1×sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure. Purification by reverse phase preparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 60 to 90% acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) provided two compounds which are diastereomers at the secondary alcohol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@:12]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])([CH2:14][CH:15]=[CH2:16])[CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)=[C:4]([CH3:35])[CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@:12]([NH:17][C:18](=[O:19])[O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([CH2:14][CH:15]=[CH2:16])[CH2:11][CH2:10][NH:9]2)=[C:4]([CH3:35])[CH:3]=1
Reactant: C=CC[C@]1(NC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(F)cc2C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@]1(NC(=O)OCc2ccccc2)CCN[C@@H](c2ccc(F)cc2C)C1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,4S)-2-(4-fluoro-2-methylphenyl)-4-({[(phenylmethyl)oxy]carbonyl}amino)-4-(2-propen-1-yl)-1-piperidinecarboxylate (Intermediate 17 29 g, 60.1 mmol) in dry Dichloromethane (DCM) (500 ml), at 0° C., TFA (125 ml, 1622 mmol) was slowly added in 30 mins and the reaction mixture was stirred for 2 hours at the same temperature. The reaction was diluted with DCM (300 ml) and a saturated solution of NaHCO3 was added until pH=8. Two phases were separated and the aqueous layer was extracted with DCM (200 ml). Combined organic layers were dried (Na2SO4), filtered and evaporated affording the title compound (23.0 g, 60.1 mmol, quantitative yield) as a colourless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46-7.56 (m, 1H) 7.25-7.41 (m, 5H) 7.07 (br. s., 1H) 6.92-7.03 (m, 2H) 5.67-5.83 (m, 1H) 5.03-5.19 (m, 2H) 4.97 (s, 2H) 3.96 (d, 1H) 2.82-3.03 (m, 2H) 2.76 (d, 2H) 2.29 (s, 3H) 1.99 (d, 2H) 1.54-1.68 (m, 1H) 1.36 (t, 1H); UPLC: Rt=0.62 mins, m/z=383 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[N:24]([S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:25]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=4)[N:29]([CH3:40])[CH:28]=3)=[CH:26][C:19]=12>C(#N)C.O.C(OCC)(=O)C>[CH3:37][O:36][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][C:32]=1[O:38][CH3:39])[N:29]([CH3:40])[CH:28]=[C:27]2[C:25]1[N:24]([S:41]([C:44]2[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=2)(=[O:43])=[O:42])[C:20]2=[N:21][CH:22]=[CH:23][C:18]([CH2:17][N:1]3[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]3)=[C:19]2[CH:26]=1
Reactant: OC1CCNCC1
Reactant: COc1cc2c(-c3cc4c(CCl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2c(-c3cc4c(CN5CCC(O)CC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Temperature: 80 °C
Yield: 79.1 %

Procedure:
0.027 g of piperid-4-ol, 0.075 g of potassium carbonate and 0.016 g of sodium iodide are added to a solution of 0.055 g of 4-chloromethyl-2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 3 cm3 of acetonitrile, at a temperature in the region of 20° C. The reaction medium is heated at 80° C. for one hour. After cooling, the reaction medium is filtered through a sinter funnel and the filtrate is concentrated under reduced pressure. The residue obtained is taken up in 3 cm3 of water and 4 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. 0.049 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]piperid-4-ol is obtained, the characteristics of which are as follows:
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[C:21]1([N:18]2[CH2:17][CH2:16][N:15]([C@H:12]3[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]3)[CH2:20][CH2:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCN(c4ccccc4)CC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@H](N2CCN(c3ccccc3)CC2)CC1

Procedure:
270 mg (0.61 mmol) of trans-dibenzyl-[4-(4-phenyl-piperazin-1-yl)-cyclohexyl]-amine were dissolved in 5 mL MeOH and hydrogenated on 40 mg of Pd/C (10%) at 20-30° C. The solvent was eliminated in vacuo and the residue crystallised from ethanol and conc. HCl. Yield: 110 mg (69%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:8]=[C:7]([C:16]([O:18]C)=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH:13]([CH3:14])[CH3:15])[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: COC(=O)c1cc(OC(C)C)cc2c1CCNC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1cc(C(=O)O)c2c(c1)C(=O)NCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a solution of methyl 1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (Cpd E, 1.00 g, 3.80 mmol) in MeOH (20 mL) was added NaOH (3.00 mL, 12.0 mmol). The resulting reaction mixture was stirred at 50° C. for 3 hours. Volatiles were removed under vacuum and the resulting residue was dissolved in MeOH (30 mL), and neutralized with 1 M HCl to pH=2˜3. Precipitates were formed, collected by filtration, washed with water, and dried in an oven at 60° C. under vacuum to give 1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (77a, 918 mg, 97%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C([O-])(=O)C.[Na+].[OH-].[Na+]>COCCOC.O>[C:1]([C:3]1[CH:4]=[C:5]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)ccc1F
Temperature: 25 °C
Yield: 10.5 %

Procedure:
A solution of 3-cyano-4-fluoro-bromobenzene (0.63 g, 3.1 mmol), and tetrakis(triphenylphosphine)paladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (1.0 g, 4.7 mmol) and sodium acetate (1.0 g, 9.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.10 g, 10%) as white crystals. mp: 264-266° C.; 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.3 (dd, 1H, J=2.4, 3.7 Hz), 8.1-8.0 (m, 1H), 7.6-7.5 (m, 2H), 7.5 (dd, 1H, J=1.9, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=305.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[Na+]>CCCCCC.C1(C)C=CC=CC=1.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:11]2=[O:17])=[CH:3][CH:4]=1
Reactant: O=C1CCCCC1
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C=C2CCCCC2=O)cc1
Temperature: 65 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
In a 1,000-ml, four-necked flask equipped with a mechanical stirrer, a reflux condenser and a thermometer were placed 68 g (0.5 mole) of p-anisaldehyde, 147 g (1.5 moles) of cyclohexanone and then 200 ml of water slowly. Thereto was slowly added, in a water bath, an aqueous solution obtained by diluting 80 g (0.5 mole) of a 25% aqueous sodium hydroxide solution, with 300 ml of water. The system was stirred at 65° C. for 48 hours and cooled to room temperature. To the system were added 400 ml of toluene and 100 ml of water for phase separation. The aqueous layer was re-extracted with 100 ml of toluene. The toluene layers were combined and washed with water and a saturated aqueous sodium chloride solution in this order. The resulting toluene layer was dried over anhydrous sodium sulfate and subjected to vacuum distillation to remove toluene and the excessive (remaining) cyclohexanone. To the crude oil obtained were added 80 ml of toluene and 80 ml of n-hexane for recrystallization, to obtain 80.4 g of yellow crystals. Yield: 74% The purity of the intended product in the crystals was 88% as measured by high performance liquid chromatography.