Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:20]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:19][CH:18]=1.[I:34]I>C1COCC1.O>[F:16][C:17]1[C:18]([I:34])=[CH:19][C:20]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1
Reactant: II
Reactant: COCCOCOc1ccc(F)nc1C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1cc(I)c(F)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43.3 %

Procedure:
A dry 100 mL, 3-neck round bottom flask was fitted with an additional needle/septa, and inert atmosphere inlet, and a septa. The flask was charged with 2,2,6,6-tetramethylpiperidine (0.47 ml, 2.8 mmol), 5 mL dry THF and a stirbar. The flask was immersed in a ice-water bath and treated with a 1.6 M solution of butyllithium in hexanes (1.4 ml, 2.2 mmol) added over 15 minutes via syringe pump. The solution was stirred an additional 5 minutes and the ice-water bath was replaced with a dry ice acetone bath. To the stirring cold solution was added 6-fluoro-3-((2-methoxyethoxy)methoxy)-2-(trifluoromethyl)pyridine (0.5030 g, 1.9 mmol) dissolved in 5 mL dry THF over 2 minutes. The reaction was stirred for 1 h at −78° C. after which time a solution of iodine (0.12 ml, 2.2 mmol) dissolved in 5 mL dry THF was added via cannula over a 3 minute period. The reaction was stirred for 15 minutes, and then the cooling bath was removed. After stirring 5 minutes, the solution was poured onto sodium thiosulfate (1.8 ml, 19 mmol) dissolved in 50 mL water. The mixture was stirred for 10 minutes, and the layers were separated. The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with water (3×20 mL) and dried over MgSO4. The slurry was filtered and the filtrate was concentrated in vacuo. The sample was purified in one injection using a Waters Xterra Prep C18 MS Packed by Vydac/The Separations Group, 50 mm×300 mm (PN PA0000-050730), 10 μm particle size, spherical shape. 0→4 min@20 mL/min, 40% B; 4→5 min, 20→100 mL/min@ 40% B; 5→25 min@100 mL/min, linear gradient to 70% B; 25→35 min 100 mL/min, isocratic at 70% B; 35 min, step to 100% B @100 mL/min; 35→50 min@ 100 mL/min, 100% B; 50 min, step to 40% B @ 100 mL/min; 60 min end. A fraction that eluted from 24.4 to 26.1 minutes was isolated. The solvent was removed in vacuo to afford 2-fluoro-3-iodo-5-((2-methoxyethoxy)methoxy)-6-(trifluoromethyl)pyridine (0.3253 g, 44% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.39-3.42 (m, 3H) 3.60-3.65 (m, 2H) 4.00-4.06 (m, 2H) 5.26 (s, 2H) 7.65 (dd, J=4.11, 0.49 Hz, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −71.79 (d, J=3.90 Hz, 1 F)-65.02 (s, 3 F). 13C NMR (101 MHz, chloroform-d) 8 ppm 59.09 (s, 1 C) 70.25 (s, 1 C) 71.47 (s, 1 C) 100.53 (dq, J=1.73, 1.59 Hz, 1 C) 109.88 (d, J=8.67 Hz, 1 C) 119.98 (dq, J=275.70, 1.30 Hz, 1 C) 124.54 (dq, J=40.53, 1.08 Hz, 1 C) 137.97 (qd, J=35.04, 14.09 Hz, 1 C) 150.60 (d, J=5.20 Hz, 1 C) 157.42 (dq, J=245.79, 0.87 Hz, 1 C).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:18]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C>C(Cl)Cl>[C:18]1([CH2:24][CH2:25][CH2:26][NH:27][CH:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=3)[CH2:4][CH2:3]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCc1ccccc1
Reactant: NC(=O)c1ccc(OC2CCC(=O)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1ccc(OC2CCC(NCCCc3ccccc3)CC2)cc1
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Combine 4-(4-oxo-cyclohexyloxy)-benzamide (20 mg, 0.085 mmol), 3-phenyl-propylamine (11 mg, 0.085 mmol), triacetoxyborohydride (23 mg, 0.111 mmol) and acetic acid (5 μL, 0.085 mmol) in CH2Cl2 (1 mL). Let stir overnight. Purify by SCX column (ammonia in methanol 2.0M). Triturate the residue with EtOAc/hexanes 1/1 to provide a white powder (25 mg, 86%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O[C:10]([CH:12]1[C:17](=[O:18])[CH2:16][CH2:15][N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13]1)=O)C.[CH2:26](I)[CH2:27][CH2:28]C>CC(C)=O>[CH2:19]([N:14]1[CH2:15][CH2:16][C:17](=[O:18])[CH:12]([CH2:10][CH2:26][CH2:27][CH3:28])[CH2:13]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCCI
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC1CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a suspension of anhydrous potassium carbonate (22.8 g) and 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester (10 g) in acetone (125 ml) was added a solution of butyl iodide (13.4 g, 8.3 ml) in acetone (50 ml) under argon over a period of 30 minutes. The resulting suspension was stirred at RT for 30 min and then refluxed for 12 hours. The suspension was cooled, filtered and concentrated in vacuo. The residue was dissolved in DCM and the solution was washed with water and brine, dried over Na2SO4 and evaporated. To the residue was added aqueous HCl (20%, 100 ml) and the solution was refluxed for 24 hours. The solution was evaporated and the residue was dissolved in DCM, washed with 10% aq. Na2CO3 solution and brine, dried and evaporated. The crude product was purified by flash chromatography (ethyl acetate/hexanes 1:2) to give the product as a slightly yellow oil (6.4 g). MS (ESI): 246.4 (MH+).
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cnc(F)c(C)c1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccc(F)cc2)c(C)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
A mixture of methyl 6-fluoro-5-methylnicotinate (2.40 g, 14.2 mmol, Step-1 of Amine-36), 4-fluorophenol (2.39 g, 21.3 mmol), and potassium carbonate (3.92 g, 28.4 mmol) in DMF (45 mL) is stirred at 90° C. for 3 hours. After cooling to rt, the mixture is filtered through a pad of Celite and rinsed with EtOAc (200 mL). The filtrate is washed with water (200 mL) and brine (200 mL), and the organic layer is dried over sodium sulfate. After filtration, and the filtrate is concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with n-hexane/EtOAc (20:1) to give 3.46 g (93% yield) of the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:29])([F:28])[C:14]1[N:19]=[CH:18][C:17]([C:20]2([CH2:26][NH2:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:20]1([C:17]2[CH:18]=[N:19][C:14]([C:13]([F:29])([F:28])[F:12])=[N:15][CH:16]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=434.1, tR (minutes, Method F)=2.34
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>[Pd].CCO>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 23 h
Yield: 98.9 %

Procedure:
A solution of 1-tert-butyl 1-piperazinecarboxylate (Sigma Aldrich, 3.37 g, 18.12 mmol), 5-fluoro-2-nitroanisole (Oakwood Products, West Columbia, S.C., 3.10 g, 18.12 mmol) and N-ethyl-N-isopropylpropan-2-amine (6.31 mL, 36.2 mmol) in DMSO (11 mL) in a 20 mL glass microwave tube was sealed and heated in a heating block at 95° C. overnight (20 h). Upon cooling, the reaction mixture crystallized to a yellow solid. It was diluted with 150 mL of EtOAc, washed sequentially with 20 mL of water, 20 mL of NaHCO3 and brine (20 mL). The organic solution was dried over MgSO4 and concentrated affording tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (6.14 g, 18.20 mmol, 99% yield) as a yellow crystalline solid. m/z (ESI, +ve ion) 359.9 (M+Na)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.96 (1H, d, J=9.2 Hz), 6.59 (1H, dd, J=9.4, 2.5 Hz), 6.55 (1H, d, J=2.3 Hz), 3.97 (3H, s), 3.56-3.65 (4H, 3.45-3.52 (4H, m), 1.51 (9H, s). Pd/C (10 wt. %, dry basis, wet activated, 284 mm, 0.267 mmol) and tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (600 mg, 1.78 mmol) were treated with EtOH (30 mL) and allowed to stir under an atmosphere of hydrogen (balloon) for 23 h. The reaction mixture was filtered through an acrodisc (0.20 um), the resulting purple solution was then concentrated on the rotovap and then under vacuum overnight affording tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (539 mg, 1.76 mmol, 99% yield) as a purple film. m/z (ESI, +ve ion) 307.0/309.0 (M+H)+. 1H NMR (400 MHz, MeOH) δ ppm 6.71 (1H, d, J=8.4 Hz), 6.62 (1H, d, J=2.3 Hz), 6.46 (1H, dd, J=8.3, 2.4 Hz), 3.85 (3H, s), 3.51-3.61 (4H, m), 2.92-3.02 (4H, m), 1.47-1.52 (9H, s).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[F:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:17](Cl)=[O:18].Cl>O.CC(C)=O>[F:15][C:16](=[CH:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:17]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:18]
Reactant: Cc1ccc(C=C(F)C(=O)Cl)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(C=C(F)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
L-phenylalanine (13.2 g, 0.080 mole) and 6N NaOH (43 ml, 0.086 mole) were dissolced in a solvent prepared by mixing water (77 ml) with acetone (240 ml). To the mixture, while cooling to less than 10° C. the acetone solution of α-fluoro-4-methyl cinnamic acid chloride prepared as above and 2N NaOH (38 ml, 0.076 mole) were alternately added over 20 minutes. Next, the mixture was stirred at normal temperature for 30 minutes, and the reaction solution was made acidic by the addition of 2N HCl. Then, water (200 ml) was gradually added thereto. The thus precipitated crystals were recovered by filtration and dried to give crude crystals (16.7 g). The crude crystals were recrystallized from a mixture of methanol and water to obtain N-(α-fluoro-4-methylcinnamoyl)-L-phenylalanine (yield 15.5 g) in the form of white needle-like crystals having a melting point of 163° to 163.5° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(Cl)(=O)C.CS(O[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](=[NH:24])[NH2:23])=[CH:16][CH:15]=1)(=O)=O>C(OCC)C>[C:1]([O:4][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](=[NH:23])[NH2:24])=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Reactant: CC(=O)O
Solvent: CC(=O)Cl
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C=CC(=N)N)cc1

Procedure:
To a mixture of 8 ml of glacial acetic acid and 8 ml of acetyl chloride, was added 2.0 g of 4-(β-amidinoethenyl)phenol methanesulfonate. The mixture was heated with stirring under reflux for one hour. After cooling, the reaction mixture was mixed with ethyl ether to precipitate a white solid substance which was recrystallized from ethanol to yield 1.8 g of colorless needle crystals of 4-(β-amidinoethenyl)phenyl acetate methanesulfonate.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.C([O-])([O-])=O.[K+].[K+].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].CCO>CC#N>[CH2:19]([O:18][C:14](=[O:17])[CH2:15][CH2:16][N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH3:2])[CH3:20]
Reactant: C[C@@H]1CCCN1
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)CCN1CCC[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
In a round-bottom flask, 2-(R)-methylpyrrolidine HCl (5.5 g, 45 mmol) was dissolved in CH3CN (20 mL). To the stirred solution was added milled K2CO3 (8.3 g, 60 mmol). The suspension was stirred at room temperature for approximately 1 h. Ethyl acrylate (3.25 mL, 30 mmol) and EtOH (40 mL) were then added. The reaction mixture was stirred until analysis by GC showed completion (the Area % of ethyl acrylate was less than 1% (approximately 2 h)). The reaction mixture was filtered and the wet cake (excess K2CO3) was washed with CH3CN (5-10 mL). The filtered solution was then concentrated under reduced pressure to minimum volume (white slurry). Methyl t-butyl ether (MTBE) and H2O were added, at which time all solids dissolved. The organic layer was washed a second time with water and then concentrated to yield 5.6 g of the title compound. The oil product was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.Cl.O1CCOCC1>ClCCl>[CH2:13]1[N:5]2[C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[NH:8][C:2](=[O:1])[CH2:3][CH:4]2[CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1CC2CNCCN2c2ccccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 1C (1.78 g, 5.61 mmol) in dichloromethane (100 mL) was added 4 M HCl/dioxane (14.02 mL, 56.1 mmol). The solution was stirred for 2-4 hours at room temperature, and title compound was collected by filtration as the hydrochloric acid salt. 1H NMR (500 MHz, pyridine-d5) δ ppm 7.34-7.42 (m, 1H), 7.24-7.31 (m, 1H), 7.16-7.23 (m, 1H), 7.11 (d, J=7.02 Hz, 1H), 3.92-4.00 (m, 1H), 3.88 (d, J=11.90 Hz, 1H), 3.80 (d, J=12.82 Hz, 1H), 3.64-3.74 (m, 1H), 3.57 (t, J=11.90 Hz, 1H), 3.11-3.24 (m, 2H), 2.64 (dd, J=13.43, 7.02 Hz, 1H), 2.37 (d, J=12.82 Hz, 1H); MS (ESI) m/z 217.9 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C>CCO>[NH2:19][C:18]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[N:10]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: NNc1ccc(F)cc1
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCO
Product: N#Cc1cnn(-c2ccc(F)cc2)c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A flask was charged with (4-fluorophenyl)hydrazine hydrochloride (50.9 g, 313 mmol), EtOH (320 mL) and 2-(ethoxymethylene)malononitrile (40.1 g, 329 mmol). The stirred suspension was treated with TEA (45.8 mL, 329 mmol). After about 10 min the mixture was warmed in an oil bath heated to about 80° C. for about 1.5 h. The mixture was allowed to cool and stir overnight at rt. The solvent was removed under reduced pressure then the material was stirred with water (300 mL). After about 30 min the solids were collected by filtration, washed with water (3×100 mL) and dried under vacuum at about 65° C. to yield 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (110, R1=4-Fluorophenyl) (56.2 g, 89%); LC/MS, method 3, Rt=1.64 min, MS m/z 201 (M−H)—. 1H NMR (400 MHz, DMSO) δ 7.77 (s, 1H), 7.59-7.45 (m, 2H), 7.43-7.27 (m, 2H), 6.68 (s, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2[S:14][C:15]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[Cl:26])=[N:16][C:12]=2[CH:11]=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[C:13]2[S:14][C:15]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[Cl:26])=[N:16][C:12]=2[CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc2nc(-c3c(Cl)cc(C#N)cc3Cl)sc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(-c2nc3ccnc(N)c3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
A mixture of [2-(2,6-dichloro-4-cyano-phenyl)-thiazolo[5,4-c]pyridin-4-yl]-carbamic acid tert-butyl ester (0.48 g, 1.14 mmol) and TFA (2 mL) in DCM (8 mL) was stirred at room temperature for 2 hours then concentrated to dryness under reduced pressure. The resultant residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M ammonia in isopropanol. The relevant fractions were combined and concentrated under reduced pressure to afford the title compound as a pale yellow solid (0.309 g, 82% yield). 1H NMR (300 MHz, CDCl3): δ 8.21 (d, J=5.8 Hz, 1H), 7.77 (s, 2H), 7.50 (d, J=5.8 Hz, 1H), 4.94 (s, 2H). LCMS (Method D): RT=2.04 min, m/z: 321 [M+H+].
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([N:5]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][C:9]([O:23]C)=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[F:26][C:2]([F:1])([F:25])[C:3]([N:5]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][C:9]([OH:23])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COc1ccc(C2CN(C(=O)C(F)(F)F)Cc3cc(OC)ccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(N1Cc2cc(O)ccc2C(c2ccc(O)cc2)C1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 2,2,2-trifluoro-1-[7-methoxy-4-(4-methoxy-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone (1.74 g, 4.76 mmol, see Example 82) in CH2Cl2 (100 ml) cooled to 0° C. was added BBr3 as a 1.0 M solution in CH2Cl2 (14.28 ml, 14.28 mmol) in a dropwise manner. The reaction mixture was stirred at 0° C. for 60 minutes, the ice bath removed, and stirring continued at RT for 90 minutes. MeOH (10 ml) was added to the reaction and stirring was continued at RT for 10 minutes. The reaction mixture was concentrated in vacuo and purified by flash chromatography (Biotage, SiO2, 25-40% EtOAc/hexanes) to give the title product (1.36 g, 4.03 mmol, 85% yield).
Reaction SMILES: [Cl-].[C:2]1([N:8](C2C=CC=CC=2)C([N+]2C=CC=CC=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH2:45][C:46](O)=[O:47])[CH:43]=2)[NH:38][CH:37]=1.C(N(CC)CC)C>O>[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([CH2:45][C:46]([NH:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:47])[CH:43]=2)[NH:38][CH:37]=1
Reactant: O=C(N(c1ccccc1)c1ccccc1)[n+]1ccccc1
Reactant: O=C(O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
An ice-cold solution of diphenylamino carbonyl pyridinium chloride (3.5 g) in water (35 ml) was added dropwise to a mixture of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetic acid (3.5 g), triethylamine (2.8 ml) and ice-water (70 ml) with rapid stirring over 15 min. After stirring the mixture for a further 10 min. it was extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with water (1×50 ml), dried (Na2SO4), and evaporated in vacuo to give an orange solid (3.6 g).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].Br[CH2:32][C:33]([OH:35])=[O:34].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:30]=[C:5]1[N:6]([CH2:27][CH2:28][CH3:29])[C:7]2[N:8]=[C:9]([C:22]3[CH:26]=[N:25][N:24]([CH2:32][C:33]([OH:35])=[O:34])[CH:23]=3)[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]=2[C:12](=[O:13])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: O=C(O)CBr
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC(=O)O)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 80 °C
Yield: 62 %

Procedure:
A mixture of solution of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (600 mg, 1.38 mmol), bromo acetic acid (289 mg, 2.08 mmol) and K2CO3 (575 mg, 4.16 mmol) in acetone (10 ml) was heated at 80° C. for 3 hrs. The reaction mixture was filtered through celite and washed with acetone. The organic layer was concentrated and the residue obtained was purified by column chromatography to obtain {4-[2,6-dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-pyrazol-1-yl}-acetic acid (420 mg, 61%) as white solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.F[C:12]1[CH:13]=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([NH2:18])[CH:17]=1>>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:12]3[CH:13]=[CH:14][C:15]([N+:19]([O-:21])=[O:20])=[C:16]([NH2:18])[CH:17]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CC2(CCN1)OCCO2
Product: Nc1cc(N2CCC3(CC2)OCCO3)ccc1[N+](=O)[O-]

Procedure:
The title compound was synthesized as described in Method 10, Step 2 from 1,4-dioxa-8-aza-spiro[4.5]decane and 5-fluoro-2-nitrophenylamine. LC/MS (m/z) 280.3 (MH+), Rt 2.41 minutes.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C:7]1[CH:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:28]([CH:29]([F:40])[C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[C:27]([CH:41]4[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]4)[C:26]4[CH:25]([O:49]CC5C=CC(OC)=CC=5)[CH2:24][C:23]([CH3:60])([CH3:59])[CH2:22][C:21]=4[N:20]=3)[CH2:15][CH2:14]2)=[N:11][CH:12]=1)([OH:6])=O>>[F:47][C:44]1([F:48])[CH2:43][CH2:42][CH:41]([C:27]2[C:26]3[CH:25]([OH:49])[CH2:24][C:23]([CH3:60])([CH3:59])[CH2:22][C:21]=3[N:20]=[C:19]([CH:16]3[CH2:17][CH2:18][N:13]([C:10]4[N:9]=[CH:8][C:7]([C:4](=[O:6])[N:2]([CH3:3])[CH3:1])=[CH:12][N:11]=4)[CH2:14][CH2:15]3)[C:28]=2[CH:29]([F:40])[C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=2)[CH2:46][CH2:45]1
Reactant: CNC
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(=O)O)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Product: CN(C)C(=O)c1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of the second step of Reference Example 25 and Example 38 were performed except for using dimethylamine aqueous solution instead of methylamine aqueous solution, and from 70 mg of the crude product of 2-[1-(5-Carboxypyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared in the first step of Reference Example 25, 30 mg of the title compound was obtained as a white solid (yield: 56%).