Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33]([C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][CH:36]=1)#[N:34]>ClCCl>[C:33]([C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:43])=[CH:39][CH:40]=1)#[N:34]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (33.6 mg, 0.33 mmol) (Aldrich), followed by the addition of 1-cyano-4-isocyanato-benzene (23.0 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-cyano-phenyl)-amide as a white solid (Yield 40 mg, 58%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[N:6]=1)=[O:4].O.[OH-].[Li+]>CO.C(OCC)(=O)C>[Cl:22][C:18]1[CH:17]=[C:16]([C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=2[CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A mixture of 6-(3-chlorophenyl)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (0.3 g, 1 mmol) and lithium hydroxide monohydrate (CAN 1310-66-3, 130 mg, 3 mmol) in THF/H2O 1/1 (20 mL) was stirred at room temperature for 1 h. After removal of the organic solvent under reduced pressure the aqueous phase was washed with ethyl acetate (10 mL) and acidified with 1 N HCl to pH=3. The resulting solution was extracted with ethyl acetate (2×20 mL). The organic layer was concentrated under reduced pressure to give the title compound (0.28 g, 98%) as black oil which was used in the next step without further purification; MS (EI): m/e=304.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]([OH:9])[C@H:6]1[OH:7])[CH:2]=[CH2:3].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:1]([O:4][C@H:5]1[O:13][C@H:12]([CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[C@@H:10]([OH:11])[C@H:8]([OH:9])[C@H:6]1[OH:7])[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C=CCO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
Into 200 mL of anhydrous pyridine, 6.3 g (28.6 mmol) of the compound (IV) was dissolved, and 195 mg of p-dimethylaminopyridine (DMAP) and 7.0 g of p-toluenesulfonyl chloride were added. The solution was reacted for 16 hours at room temperature while stirring. Thereafter, the reaction was quenched by adding 20 mL of cold distilled water, and the reaction mixture was extracted with ethyl acetate (3×200 mL). The organic layers were combined, neutralized to pH 4 with 1.0 M and 0.1 M hydrochloric acids, washed with brine (2×200 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel flash chromatography (dichloromethane:methanol=20:1) (yield: 8.6 mg (23.0 mmol), recovery: 83.8%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[OH:19][C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(Cl)Cl.C(Cl)Cl>[OH:19][C:20]1([C:23]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)=[O:24])[CH2:22][CH2:21]1
Reactant: O=C(O)C1(O)CC1
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccccc1-c1ccc(CNC(=O)C2(O)CC2)cc1
Reaction time: 0.08 h

Procedure:
Methyl 4′-(aminomethyl)biphenyl-2-carboxylate (0.325 g, 1.35 mmol), 1-hydroxycyclo-propanecarboxylic acid (0.151 g, 1.48 mmol) and 1-hydroxybenzotriazole hydrate (0.248 g, 1.62 mmol) were suspended in a mixture of THF/DCM (13 mL of THF/6.5 mL of DCM), followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.336 g, 1.75 mmol). Rapidly the solution turned homogenous, but returned to a heterogeneous mixture after 5 minutes. After 3 hours the solvent mixture was exchanged for pure DCM, prior to purification by silica gel chromatography eluted with 1-5% methanol in DCM to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([OH:12])(=O)[C:8]([CH3:10])=[CH2:9]>ClCCl>[CH3:1][C:2]1[S:3][C:4]2[C:7](=[O:12])[CH:8]([CH3:10])[CH2:9][C:5]=2[CH:6]=1
Reactant: Cc1cccs1
Reactant: C=C(C)C(=O)O
Solvent: ClCCl
Product: Cc1cc2c(s1)C(=O)C(C)C2
Temperature: 80 °C
Reaction time: 3 h
Yield: 44.8 %

Procedure:
A solution of 100 g of 2-methylthiophene (1.02 mol) and 104 ml of methacrylic acid (1.22 mol) in 200 ml of dichloromethane was added dropwise within 30 minutes at 80° C. to 1000 g of super-PPA. Afterwards, the reaction mixture was stirred at 80° C. for 3 hours. The dark red mixture was poured into 1000 g of crushed ice and stirred until the polyphosphoric acid had completely dissolved. The aqueous phase was extracted twice with 400 ml each time of a dichloromethane/hexane solvent mixture (30 parts by volume/70 parts by volume). The combined organic phases were washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over magnesium sulfate. After removal of the solvents on a rotary evaporator, 136 g of crude product were obtained. The distillation of the crude product (90° C., 0.1 torr) gave 76 g (46%) of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17]C)[CH:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15](=[O:17])[CH:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cn1)N(C(=O)OC(C)(C)C)CC2
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCc2cc(=O)n(Cc3ccccc3)cc21
Temperature: 60 °C
Reaction time: 40 h
Yield: 63.6 %

Procedure:
A mixture of 5-methoxy-2,3-dihydro-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (0.065 g, 0.26 mmol), benzyl bromide (0.053 g, 0.31 mmol), sodium iodide (0.077 g, 0.52 mmol) and acetonitrile (2 mL) was stirred at 60° C. for 40 h. The mixture was poured into a mixture of water (10 mL) and saturated aqueous sodium thiosulfate (10 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography (SiO2; gradient elution with 0-100% EtOAc in petrol) gave the title compound (0.054 g, ˜64%) as a colourless oil. MS: [M+H]+=327.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([CH:17]=3)[NH2:16])[N:10]=2)[CH:7]=1.C(#N)C.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[C:15]([NH:16][C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[CH:17]=3)[N:10]=2)[CH:7]=1
Reactant: Nc1cc(-c2cn3cc(Cl)ccc3n2)ccc1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Cl)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
A 20 mL vial is charged with 5-(6-chloroimidazo[1,2-a]pyridin-2-yl)-2-(trifluoromethyl)aniline (0.156 g, 0.5 mmol), acetonitrile (4.12 mL) and pyridine (0.081 mL). The mixture is added trimethylacetyl chloride (0.123 mL, 0.001 mol) and stirred for 20 min at 80° C. The solution is concentrated, taken into EtOAc (10 mL) and washed once with HCl (10 mL, 1M) and NaOH (10 mL, 1M). Organics are dried, concentrated purified on silica (0-100% EtOAc in Hexanes) to give the title compound (106 mg, 54% yield). LCMS m/z=396.4 [M+H]+, tR=2.54 min. (compound same as Example 81)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[C:4]([CH2:25][CH3:26])[CH:3]=1.C([Li])CCC.C([O:34]B(OCC)OCC)C.Cl>O1CCCC1>[CH2:25]([C:4]1[CH:3]=[C:2]([OH:34])[CH:7]=[C:6]([CH3:8])[C:5]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH3:26]
Reactant: CCOB(OCC)OCC
Reactant: CCc1cc(Br)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(O)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
Then, 6.6 g of 4-bromo-2-ethyl-6-methyl-1-[3-(4-trifluoromethoxyphenoxy)propyloxy]benzene was dissolved in 200 ml of tetrahydrofuran, and the solution was stirred at -70° C., to which 9.6 ml of n-butyl lithium solution (in hexane, 1.58 mol/liter) was added dropwise, followed by further stirring at -70° C. for 2 hours. To this reaction mixture was added dropwise a solution of 2.2 g of triethoxy borane dissolved in 60 ml of tetrahydrofuran. Then, the reaction mixture was stirred for 1 hour, while warming to room temperature, and 13 ml of 10% aqueous hydrochloric acid solution was added in small portions, followed by stirring at room temperature for 20 minutes. The tetrahydrofuran layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated, to which 50 ml of toluene was added, and the mixture was heated at 70° C. under stirring, to which 6 ml of 30% aqueous hydrogen peroxide solution was added dropwise. The mixture was heated under reflux for 1 hour, and washed once with water, twice with 10% aqueous ammonium ferrous sulfate solution, and once with water. The toluene layer was dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 3.4 g of 3-ethyl-4-[3-(4-trifluoromethoxyphenoxy)propyloxy]-5-methylphenol (61% yield), nD25.4 1.4955.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:14][Si:15]([CH3:19])([CH3:18])[C:16]#[CH:17]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:11]([O:10][C:5]1[CH:4]=[CH:3][C:2]([C:17]#[C:16][Si:15]([CH3:19])([CH3:18])[CH3:14])=[CH:9][C:6]=1[C:7]#[N:8])([CH3:13])[CH3:12]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)Oc1ccc(Br)cc1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C#C[Si](C)(C)C)cc1C#N

Procedure:
A solution of 5-bromo-2-isopropoxybenzonitrile (1.0 g, 4.16 mmol) in tetrahydrofuran was treated with copper (I) iodide (0.158 g, 0.83 mmol) and then purged with Argon for 5 minutes. Trimethyl silyl acetylene (2.85 g, 29.16 mmol) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (0.291 g, 0.41 mmol). The resultant mixture was heated at 80° C. overnight in a sealed tube. The mixture was evaporated and purified by column chromatography to give 2-isopropoxy-5-((trimethylsilyl)ethynyl)benzonitrile which was taken to the next step. 2-isopropoxy-5-((trimethylsilyl)ethynyl)benzonitrile (1.0 g, 3.8 mmol) in methanol (20 mL) was treated with potassium carbonate (1.07 g, 7.7 mmol) at room temperature overnight. The reaction was filtered and the filtrate was evaporated to give the crude product. The crude product was purified on a column (MPLC) using hexane:ethyl acetate and afforded Intermediate 1.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:24]1[CH2:25][CH2:26][CH2:27][C@H:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[C:11]([C:9]4[NH:10][C:6]5[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=5[CH:8]=4)[CH:12]=[CH:13][CH:14]=3)[N:19]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(O[C@H]5CCCNC5)nc34)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22.8 %

Procedure:
To a solution of (S)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate (117 mg, 0.25 mmol) in DCM (3.0 mL) at 0° C. was added TFA (0.5 mL, 6.73 mmol). The reaction was stirred at 0° C. for 20 min then at RT for 2 h. The solution was concentrated, the residue was dissolved in DCM and washed with a saturated aq. solution of NaHCO3. The organic layer was separated, and the aq. layer was extracted with DCM (2×). The combined organic layers were then concentrated, and the residue was dissolved in DMSO (3 mL). Purification by rpHPLC (Silicycle Silichrome XT C18 column; 30×150 mm, 5 m, 5-95% 0.1% TFA/ACN in 0.1% TFA/water by volume over 10 min.), then drying in a Genevac Series II Evaporator afforded (S)-2-(2-(piperidin-3-yloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (27.3 mg, 0.057 mmol, 22.7% yield) as an amorphous brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.62 (br. s., 1H), 8.69-8.85 (m, 2H), 8.33 (d, J=8.8 Hz, 1H), 7.95 (d, J=7.4 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 7.02 (br. s., 1H), 5.51 (br. s., 1H), 3.40-3.53 (m, 4H), 3.14 (br. s., 2H), 2.89 (t, J=6.8 Hz, 2H), 2.11-2.23 (m, 1H), 1.94-2.05 (m, 2H), 1.81-1.90 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −74.35 (s, 3F). m/z (ESI, +ve ion) 363.0 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:24][NH:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](=O)[CH3:26].C([BH3-])#N.[Na+]>CO>[CH2:25]([N:23]1[CH2:24][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[CH2:22]1)[CH3:26]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccc1)O2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN1CC(c2ccccc2)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Yield: 67.8 %

Procedure:
To a solution of tert-butyl 8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (735 mg, 2.21 mmol) in methanol (10 mL) was added acetaldehyde (107 mg, 136 μL, 2.43 mmol), then sodium cyanoborohydride (195 mg, 1.5 mL, 3.10 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with DCM (50 mL), washed with 1:1 aq. sat. NaHCO3/25% NaOH (10 mL), and the aqueous layer was extracted with DCM (2×25 mL). The combined organics were dried (MgSO4), concentrated in vacuo and purified by silica gel column chromatography using (0-75% EtOAc/DCM) as eluent to give tert-butyl 8-ethyl-10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (540 mg, 68%) as a viscous yellow oil. ESI-MS m/z calc. 360.5. found 361.7 (M+1)+; Retention time: 1.15 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]12[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]1([CH3:18])[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:3]2.C(=O)(O)[O-].[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C@@:10]2([CH3:18])[CH2:11][C:12]3[C:17]([C@@:2]12[CH3:1])=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC12Cc3ccccc3C1(C)Nc1ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1c2ccccc2[C@@]2(C)Cc3ccccc3[C@@]12C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4b,5,9b,10-tetrahydro-4b,9b-dimethylindeno[1,2-b]indole, (0.2 g, 0.85 mmol) was dissolved in acetic anhydride (1 cm3) and the solution stirred at room temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and stirred for a further 1/2 hour. The mixture was then extracted with ether (3×15 cm3) and the combined organic extracts collected washed with brine, dried (Na2SO4) and evaporated to yield the title compound as an oil. This was purified by flash chromatography on silica gel eluting with 5-7% ethyl acetate/60°-80° petrol, to yield a colourless solid. Yield: 0.15 g, 64% .M.p. 81° C. 1H NMR (CDCl3) δ: 7.82 (1H, s), 6.99-7.29 (7H, m), 3.26 (1H, d, J=15.9 Hz), 2.97 (1H, d, J =15.9 Hz), 2.42 (3H, s), 1.77 (3H, s), 1.25 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[N:27]1[CH:32]=[CH:31][C:30]([CH:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:35][CH:33]([C:30]1[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=1)[CH3:34]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(N)c1ccncc1
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccncc1

Procedure:
Use a method similar to the General Procedure 5-3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (400 mg, 0.94 mmol) and (±)-1-pyridin-4-yl-ethylamine (prepared as described in Bull. Kor. Chem. Soc. 1998, 19 (8), 891-893) (172 mg, 1.41 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 4:1 and 1:1) to give (±)-7-chloro-6-[(1-pyridin-4-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:6]=1[C:7]([OH:9])=[O:8])=[O:4].[CH2:17]=[C:18]1[O:22][C:20](=O)[CH2:19]1.C(OC(=O)C)(=O)C>CO.O1CCCC1.[C].[Pd]>[O:8]=[C:7]1[C:6]2=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=[CH:12][CH:11]=[C:10]2[N:14]=[C:20]([CH2:19][C:18](=[O:22])[CH3:17])[O:9]1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: C=C1CC(=O)O1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: COC(=O)c1cccc2nc(CC(C)=O)oc(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of 2-methoxycarbonyl-6-nitrobenzoic acid (22.5 g, 0.1 mol) in methanol (100 mL) was added 10% palladium-carbon (2.0 g, 50% hydrate), and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was dissolved in acetone (100 mL). To the solution was added dropwise diketene (23 mL, 0.30 mol) at room temperature. After the mixture was stirred at room temperature for 16 hours, the solution was concentrated under reduced pressure. The resulting crude crystals were collected by filtration, washed with acetone and diethylether, and air dried (15.4 g). The crude crystals were suspended in a mixture of acetic anhydride (10.4 mL, 0.11 mol) and tetrahydrofuran (60 mL), and the suspension was heated under reflux for 12 hours. The suspension was allowed to cool to room temperature, and the solvents were evaporated under reduced pressure to give crude crystals. The crystals were collected by filtration, washed with diethylether, and air dried to give the title compound (8.03 g, 31% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([OH:14])([CH3:13])[CH3:12])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([OH:14])([CH3:12])[CH3:13])[C:5]([O:7][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:6]
Reactant: CC(C)(O)c1ccc(C(=O)O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(C(=O)OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.3 %

Procedure:
To a solution of 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (9.1 g, 45.7 mmol) in DMF (40 mL) was added cesium carbonate (22.3 g, 68.5 mmol) followed by benzyl bromide (11.7 g, 8.1 mL, 68.5 mmol) and reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed sequentially with H2O (3×10 mL), brine solution. The organics were separated and dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography eluting with 10-20% EtOAc-hexanes to provide benzyl 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoate (2.8 g, 21%) ESI-MS m/z calc. 288.2. found 289.3 (M+1)+; Retention time: 1.79 min (3 min run). To a solution of benzyl 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoate (2.8 g, 9.71 mmol) in MeOH (50 mL) was added palladium on carbon (100 mg, 0.09 mmol) and the reaction mixture was subjected to an atmosphere of hydrogen for 16 hours. The catalyst was removed via filtration over Celite® and the solvent removed in vacuo to provide 3-fluoro-4-(1-hydroxy-1-methyl-ethyl)benzoic acid (1.8 g, 96%) as a white solid. ESI-MS m/z calc. 198.2. found 199.9 (M+1)+; Retention time: 0.91 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][C:14]([C@H:17]1[CH2:21][CH2:20][NH:19][C@H:18]1[CH3:22])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Li+].[Li+].O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8]([N:19]2[CH2:20][CH2:21][C@H:17]([C:14]([OH:13])([CH3:16])[CH3:15])[C@@H:18]2[CH3:22])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)c(CO)c1Cl
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1CO
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 34.1 %

Procedure:
To a solution (2 mL) of 2-chloro-4-fluoro-3-(hydroxymethyl)benzonitrile (150 mg) in dimethyl sulfoxide were added (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (167 mg) and lithium carbonate (66 mg), and the mixture was stirred at 140° C. for 10 min in a microwave reaction apparatus. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) and recrystallized from ethyl acetate-isopropyl ether to give the compound as a pale-yellow solid (yield: 85 mg).