Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[C:4]([O:7][C:8](=O)[CH3:9])(=[O:6])C.[C:11]([O:15][C:16](=[O:36])[NH:17][C@@H:18]([CH2:26][NH:27]OCC1C=CC=CC=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])(O)=O.[Na+]>ClCCl>[C:11]([O:15][C:16](=[O:36])[NH:17][C@@H:18]([CH2:26][NH:27][C:4]([O:7][CH2:8][C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:26]=1)=[O:6])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNOCc1ccccc1)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 176.5 %

Procedure:
To a cold mixture of formic acid (2.3 g, 73.0 mmol) and acetic anhydride (0.56 mL, 6.0 mmol) was added dropwise [(R)-1-(Benzyloxyaminomethyl)-2-phenyl-ethyl)-carbamic acid tert-butyl ester (0.20 g, 0.56 mmol) in dichloromethane (2.8 mL) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours, and then treated with saturated aq. NaHCO3 (5 mL). The aqueous layer was extracted with dichloromethane (10 mL×2). The organic extracts were washed with water and brine, and dried over MgSO4. After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (2:1) yielded 0.19 g (86%) of the title compound 1H NMR (400 MHz, CDCl3): δ 8.14 (br s, 1H), 7.32-7.07 (m, 10H), 4.90-4.67 (m, 2H), 4.15 (m, 1H), 3.74 (m, 1H), 3.36 (m, 1H), 2.78 (m, 1H), 2.68 (m, 2H), 1.32 (m, 9H). MH+385.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)#[N:7].[OH-].[Na+].CN([CH:22]=[O:23])C>>[CH:22]([C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:6]#[N:7])[CH:9]=2)[NH:13][CH:12]=1)=[O:23]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2[nH]cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add phosphorous oxychloride (11.76 g, 76.67 mmol) dropwise to DMF (24.3 ml) wile maintaining the temperature at less than 10° C. Warn to ambient temperature and stir for 15 minutes at ambient temperature. Add dropwise 5-cyanoindole (10.00 g, 70.34 mmol) as a solution in DMF (30 ml) while keeping the temperature below 35°. After 1 hour, pour the reaction mixture into ice/water (300 ml) and then add 5N NaOH (54 ml) with stirring. Add slowly an additional amount of 5N NaOH (19.7 ml) and then heated to 90° for 1 minute and then cooled to ambient temperature to give a precipitate. Filter the precipitate and washed with water and dry to give the title compound: mp 248–250° C. MS (ACPI): m/e 171.0 (M+1). Analysis for C10H6N2O: Calcd: C, 70.58; H, 3.55; N, 16.46; found: C, 70.41; H, 3.53; N, 16.33.
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.[F:15][C:16]1[C:36]([C:37]([F:40])([F:39])[F:38])=[N:35][CH:34]=[CH:33][C:17]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:29][C:28](=[CH:30][C:31]#[N:32])[CH2:27]2)[CH2:22][CH2:21]1)=[O:19].N12CCCNC1CCCC=C2>C(#N)C>[F:15][C:16]1[C:36]([C:37]([F:38])([F:39])[F:40])=[N:35][CH:34]=[CH:33][C:17]=1[C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[CH2:29][C:28]([CH2:30][C:31]#[N:32])([N:12]3[CH:13]=[C:9]([B:4]4[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]4)[CH:10]=[N:11]3)[CH2:27]2)[CH2:24][CH2:25]1)=[O:19]
Reactant: N#CC=C1CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)CC2)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: C1=CN2CCCNC2CCC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C3(CC#N)CN(C4CCN(C(=O)c5ccnc(C(F)(F)F)c5F)CC4)C3)c2)OC1(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a 25 mL flask equipped with a nitrogen inlet, a thermocouple, and a magnetic stirrer were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 210 mg, 1.08 mmol, 1.08 equiv), 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile (10, 370 mg, 1.0 mmol) and acetonitrile (3 mL) at ambient temperature. The solution was then treated with 1,8-diazabicyclo[5,4,0]undec-ene (DBU, 173 mg, 0.17 mL, 1.12 mmol, 1.12 equiv) at ambient temperature and the resulting reaction mixture was warmed to 50° C. and stirred at 50° C. for overnight. When the reaction was complete as monitored by HPLC, the reaction mixture was directly load on a solica gel (SiO2) column for chromatographic purification (0-2.5% MeOH in ethyl acetate gradient elution) to afford 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (11, 263 mg, 562.4 mg theoretical, 46.7%) as a white solid. For 11: 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J=4.7 Hz, 1H), 8.22 (d, J=0.6 Hz, 1H), 7.88 (dd, J=4.7 Hz, 1H), 7.69 (s, 1H), 4.10-3.99 (m, 1H), 3.58 (d, J=7.8 Hz, 2H), 3.52-3.42 (m, 2H), 3.44 (s, 2H), 3.41-3.33 (m, 1H), 3.28-3.15 (m, 1H), 3.03 (ddd, J=12.9, 9.2, 3.2 Hz, 1H), 2.51-2.44 (m, 1H), 1.77-1.66 (m, 1H), 1.64-1.54 (m, 1H), 1.28-1.17 (m, 2H), 1.24 (s, 12H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.22, 152.13 (d, J=265.8 Hz), 146.23 (d, J=5.7 Hz), 145.12, 135.41, 134.66 (d, J=16.9 Hz), 134.43 (qd, J=35.0, 11.7 Hz), 127.58, 120.61 (qd, J=274.4, 4.6 Hz), 117.35, 106.59 (br), 83.10, 61.40, 60.53 (2C), 56.49, 44.17, 38.99, 28.55, 27.82, 27.02, 24.63 ppm; C26H31BF4N6O3 (MW 562.37), LCMS (EI) m/e 563 (M++H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH2:7]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I)[CH3:8]>N1C=CC=CC=1.[OH-].[NH4+]>[CH2:7]([NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:4][C:2]([CH3:5])([CH3:3])[CH3:1])[CH3:8]
Reactant: CCNC(=O)c1ccccc1I
Reactant: CC(C)(C)[O-]
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCNC(=O)c1ccccc1OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
Potassium t-butoxide (12.25 g, 0.109 mol) was dissolved in pyridine (50 mL) and cuprous chloride (10.81 g, 0.109 mol) was added. The black suspension was stirred at RT for 30 min and N-ethyl-2-iodobenzamide (10.00 g, 36.4 mmol) dissolved in pyridine (20 mL) was added dropwise. The mixture was stirred at room temperature for 1 h and was poured in aq ammonium hydroxide and extracted with ether. The organic extracts were washed with 1 N NaOH, brine, dried (MgSO4) and concentrated to afford a brown semi-solid. The crude product was purified by flash chromatography (ethyl acetate/hexanes) to afford the title compound as a light yellow solid (2.36 g, 29%). m.p. 34.5-36° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5](N)=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+].O>>[Br:1][C:2]1[C:3]([Cl:9])=[CH:4][C:5]([OH:11])=[N:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cc(Cl)c(Br)cn1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cc(Cl)c(Br)cn1
Reaction time: 3 h
Yield: 96 %

Procedure:
5-Bromo-4-chloropyridin-2-amine (2.01 g, 9.69 mmol) was dissolved in 75% (v/v) sulfuric acid (40.2 mL, 566 mmol) and then chilled in an ice bath. A solution of sodium nitrite (2.21 g, 32.0 mmol) in water (20.1 mL, 1116 mmol) was added drop-wise and the reaction mixture was then stirred for 3 hours. The mixture was concentrated under reduced pressure and aqueous ammonia (15 mL) was added drop-wise. The resulting white precipitate was collected via vacuum filtration and the filter cake washed with cold water (100 mL) then dried in a vacuum oven for 24 hours to give 1.94 g (95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13](=[N:20]Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=1.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:20]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:12][C:6]=2[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:22]
Reactant: COC(=O)c1ccc(OC)c(NC(=NCl)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c2[nH]c(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 63.5 %

Procedure:
4-methoxy-3-[(N-chloro-benzimidoyl)-amino]-benzoic acid methyl ester (8 g, 25.10 mmol) obtained in step 1 was dissolved in 50 ml of 50% methanol and NaHCO3 (5.32 g, 50.20 mmol) was added dropwise thereto at room temperature and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by recrystallization from ethyl acetate/hexane to obtain the title compound (6 g, 15.94 mmol) in a yield of 86%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][CH:5]1[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.O1CCOCC1.[ClH:24]>C(OCC)(=O)C>[ClH:24].[F:1][C:2]([F:17])([F:16])[CH2:3][O:4][CH:5]1[CH2:8][NH:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(OCC(F)(F)F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)COC1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 3-(2,2,2-trifluoroethoxy)azetidine-1-carboxylate (350 mg, 1.37 mmol) in ethyl acetate (1.0 mL) was mixed with 4 M hydrogen chloride-1,4-dioxane solution (3.0 mL) under cooling with ice and then stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a mixture containing the title compound as a colorless oil (224 mg). The mixture was used for next step without further purification.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:24]=[C:25]=[O:26]>>[F:23][C:3]([F:2])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][N:16]([C:25]([NH:24][CH:4]([CH2:5][CH3:6])[CH3:3])=[O:26])[CH2:15]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [N-]=C=O
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccccc1
Agent: Cl
Product: CCC(C)NC(=O)N1CC(OC(c2ccccc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)benzhydryloxy]azetidine hydrochloride (133) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([N:12]1[C:16](=[O:17])[C:15]([NH:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[C:14]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:13]1(=[O:39])=[O:38])([CH3:11])([CH3:10])[CH3:9].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8]([N:12]1[C:16](=[O:17])[C:15]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:14]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:13]1(=[O:39])=[O:38])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 97.2 %

Procedure:
TFA (1 ml) was added to a solution of tert-butyl 4-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]piperidine-1-carboxylate (Example 86) (2.138 g, 4.612 mmol) in DCM (20 ml) and the mixture was stirred at rt for 80 mins. TFA (1 mil) was added and the reaction mixture was stirred for 18 h. The reaction mixture was basified by addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, and evaporated to give the title compound (1.630 g, 97%) as a solid. 1H NMR (500 MHz, CDCl3): δ 7.54-7.50 (m, 2H), 7.50-7.40 (m, 3H), 5.20 (d, 1H), 3.08-2.92 (m, 3H), 2.19 (dt, 2H), 1.74 (s, 9H), 1.72-1.46 (m, 2H), 1.36-1.24 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.9, 134.0, 131.8, 130.1, 128.9, 125.3, 107.1, 61.8, 50.2, 44.7, 33.1, 27.9; Mass Spectrum: M+H+ 364.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:24](=O)[CH2:25][C:26]#[N:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:9][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[F:8])[N:1]=[C:24]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:25]([C:26]#[N:27])=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(F)c(Cl)cc1C(=O)c1ccccc1
Reactant: N#CCC(=O)C1CCCCC1
Product: N#Cc1c(C2CCCCC2)nc2cc(F)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-4-fluoro-phenyl)-phenyl-methanone (prepared as described in example 105 step D) and 3-cyclohexyl-3-oxo-propionitrile (prepared as described in example 110 step A). Off-white solid. MS (ESI): 365.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4](Cl)[CH3:5].[CH:12]1[CH:13]=[CH:14][N+:15]([O-:19])=[C:16]([S-:18])[CH:17]=1.[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]([S:18][C:16]1[CH:17]=[CH:12][CH:13]=[CH:14][N+:15]=1[O-:19])[CH3:5]
Reactant: CC(Cl)c1c(F)cccc1Cl
Reactant: [O-][n+]1ccccc1[S-]
Agent: [Na+]
Solvent: CCO
Product: CC(Sc1cccc[n+]1[O-])c1c(F)cccc1Cl
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2-chloro-6-fluoro-alpha-methylbenzyl chloride (46.2, 0.24 mol is dissolved in ethanol (120 Ml) and warmed to 75° C. A 40 percent solution of sodium omadine (98.1 g, 0.26 mol) is added dropwise over a period of 30 minutes maintaining a reaction temperature of 75° C. throughout. Once the addition is complete, the reaction mixture is kept at 75° C. for 2 hours and then stirred at room temperature for 16 hours. Thereafter the mixture is quenched in ice-water and crude product is filtered off. After recrystallization with ethyl acetate pure title product (27.7 g, 40.8%) is obtained; Melting Point 142°-144° C.
Reaction SMILES: B([O-])=O.[Na+].[N:5]1([CH:10]=[C:11]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=[CH:8][N:7]=[CH:6]1>CO>[N:5]1([CH:10]=[C:11]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:12]([OH:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CC(C)(C)C(=O)C(=Cn1ccnc1)Oc1ccc(Cl)cc1
Agent: O=B[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O)C(=Cn1ccnc1)Oc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 92.6 %

Procedure:
12.4 g (0.33 mols) of sodium boranate were introduced in portions into a solution of 98.8 g (0.33 mols) of 1-(imidazol-1-yl)-2-(4-chlorophenoxy)-4,4-dimethyl-1-penten-3-one in 1,000 ml of methanol at 20° to 30° C. in the course of 30 minutes, with slight external cooling. After 3 hours, the solution was filtered and the filtrate was acidified with 10% strength acetic acid and evaporated under reduced pressure. The solid residue which remained was stirred into 1.3 liters of water. The water-insoluble reduction product was filtered off and dried at 50° C. in vacuo. 93.7 g (92.55% of theory) of 1-(imidazol-1-yl)-2-(4-chlorophenoxy)-4,4-dimethyl-1-penten-3-ol of melting point 141°-143° C. were obtained in the form of colorless crystals.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1.CO.[H][H]>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[CH3:19][O:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][C:9]=1[OH:8]
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2[nH]ccc2cc1O

Procedure:
5-(benzyloxy)-6-methoxy-1H-indole (3.00 g) was added to methanol (100 mL) and ethyl acetate (100 mL) in a pressure bottle. Palladium hydroxide on carbon (0.832 g,) was added and the solution was shaken under 30 psi of hydrogen at room temperature for 40 minutes. The mixture was filtered through a nylon membrane, the solvent removed under vacuum, the residue taken up in ethyl acetate, the solution was filtered over a pad of silica gel, and the solvent was removed from the filtrate under vacuum.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.C(O)(=O)C>S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([C:18]([F:20])([F:21])[F:19])[C:9]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:10]([N+:1]([O-:4])=[O:2])[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Nc1ccc(Br)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
To acetic anhydride (10 ml) was added dropwise conc. nitric acid (d=1.42, 1.300 ml) during 10 minutes in an ice bath and added one drop of conc. sulfuric acid (96%). To this solution was added a solution of ethyl 4-bromo-2-(trifluoromethyl)phenylcarbamate in acetic anhydride (7 ml)/acetic acid (1 ml) during 30 minutes in an ice bath. After stirring for 2.5 hours, the reaction mixture was poured into ice-water, and the precipitated solid product was filtered. The resultant solid product was purified by silica gel column (120 g, hexane:ethyl acetate=15:1) to give the title compound (2.3265 g, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:18][C:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:16][CH:15]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[CH:29]([Si:32](Cl)([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30].C(N(CC)CC)C.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:12][O:11][CH2:10][C@H:9]([CH3:13])[O:8][C:6]1[CH:5]=[C:4]([C:14]2[NH:18][C:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[CH:16][CH:15]=2)[CH:3]=[C:2]([O:1][Si:32]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:29]([CH3:31])[CH3:30])[CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C(=O)OCc3ccccc3)[nH]2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)OCc3ccccc3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
Benzyl 5-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylate (27.35 g, 71.7 mmol) synthesized in Example (106a) was dissolved in methylene chloride (350 mL), and triisopropylsilyl chloride (18.4 mL, 86.0 mmol), triethylamine (30.0 mL, 215 mmol) and 4-dimethylaminopyridine (10.53 g, 86.2 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. Water (400 mL) was added to separate the solution, and the organic layer was washed with saturated brine, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=3%-20%) to afford the desired product (34.41 g, yield 89%) as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1>[Pd].CO.O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c(-c3ccccc3)[nH]c3ccccc23)CCNC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: c1ccc(-c2[nH]c3ccccc3c2C2CCNCC2)cc1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
3-(1,2,3,6-Tetrahydropyridin-4-yl)-2-phenyl-1H-indole (25 g, 91 mmol), palladium on carbon (10% w/w, 2.5 g) and NH4HCO2 (57 g, 0.72 mol) were refluxed in MeOH (300 ml) for 8 h. Palladium on carbon (10% w/w, 1.25 g) and NH4HCO2 (29 g, 0.36 mol) were added, and refluxing continued for 8 h. The mixture was cooled, filtered, and evaporated to give a white solid. This was suspended in H2O (1 l) and 1M NaOH (100 ml), and the mixture extracted with CH2Cl2 (5×150 ml). The combined organic layers were washed with water and brine, dried, and evaporated in vacuo to give a white solid, which was recrystallised from MeOH (300 ml) and H2O (100 ml) to give the title compound (19 g, 75%) as white crystals, mp 187-188° C. Oxalate salt, white crystals, mp 209-211° C. (from EtOH). Found C, 69.09; H, 6.65; N, 7.52. C19H20N2. C2H2O4 requires C, 68.84; H, 6.05; N, 7.65%; δH (360 MHz, d6-DMSO) 1.80 (2H, d, J 13, NCH2CHAHB), 2.30-2.50 (2H, m, NCH2CHAHB), 2.91 (2H, t, J 12, NCHAHB), 3.10-3.20 (1H, m, CH2CH), 3.32 (2H, d, J 12, NCHAHB), 6.98 (1H, t, J 7, indole-H), 7.08 (1H, t, J 7, indole-H), 7.20-7.50 (6H, m, ArH), 7.88 (1H, d, J 7, ArH), 11.3 (1H, br s, indole NH); m/z (ES+) 277 (M++H).
Reaction SMILES: COC1C=C(C=CC=1)C=O.[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:23][CH3:24])=[C:19](C)[CH:20]=2)[CH:15]=[CH:14][N:13]=1.[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:36]C)=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1>>[Cl:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:23][CH3:24])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([OH:36])=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1
Reactant: COc1cc2ccnc(Cl)c2cc1C
Agent: COc1ccc2c(Cl)nccc2c1
Agent: COc1cccc(C=O)c1
Product: Oc1ccc2c(Cl)nccc2c1

Procedure:
The 1-chloro-6-methoxyisoquinoline was prepared as described in WO 00/24718 (Akzo Nobel N.V.). Alternatively it can be prepared from 3-methoxybenzaldehyde using the same procedure as in Example 15A (for the synthesis of 1-chloro-6-methoxy-7-methyl-isoquinoline). The 1-chloro-6-methoxyisoquinoline is demethylated according to the procedure described in WO 00/24718 to afford 1-chloro-6-hydroxyisoquinoline. A suspension of 1-chloro-6-hydroxyisoquinoline (0.18 g, 1 mmol), 3-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (336 mg, 1.2 mmol) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (500 mg, ˜2.2mmol/g loading) in acetonitrile (4 ml) were heated at 120° C. over a period of 900 seconds using the microwave. The excess supported reagent was removed by filtration, washing with methanol, and the filtrate evaporated to dryness under reduced pressure. Since the reaction had not gone to completion, the above procedure was repeated. Purification of the crude material was achieved by chromatography on silica (eluent: 0-25% ethyl acetate in heptane) to afford 3-(1-chloroisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (106 mg), El-MS: m/z=363.7 [M+H]+.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[Si:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CNC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
Add 20% palladium hydroxide on activated carbon (0.946 g) and ethanol (20 mL) to a Parr pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the mixture at RT for 15 min. Vent the hydrogen from the reaction vessel and purge the reaction vessel with nitrogen. Add 1-benzhydryl-3-(tert-butyl-dimethylsilanyloxy)-azetidine (3.89 g, 0.0110 mol) and ethanol (80 mL) to the pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the reaction at RT for 6 h. Turn off the agitation, vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Sample the reaction mixture for analysis. Once the reaction is shown to be complete, filter the reaction mixture to remove the catalyst, concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 2 M ammonia in methanol:DCM) to give the title compound (889 mg, 43%).