Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[F:3][C:4]([F:19])([F:18])[C:5]1[C:10]([F:11])=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:6]=1B(O)O.S([O-])(O)=[O:21].[Na+]>C1COCC1>[F:3][C:4]([F:19])([F:18])[C:5]1[C:10]([F:11])=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:6]=1[OH:21]
Reactant: CCOc1ccc(B(O)O)c(C(F)(F)F)c1F
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(O)c(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
16.2 g (104.4 mmol) of an aqueous 30% hydrogen peroxide was dropped to 13.8 g (52.2 mmol) of the crude 2-trifluoromethyl-3-fluoro-4-ethoxyphenyl boronic acid obtained in the third step dissolved in 100 ml of THF, and further stirred at a room temperature for 2 hours. The solution was poured into 300 ml of an aqueous saturated sodium hydrogen sulfite solution and extracted with 200 ml of ethyl acetate. The organic layer was washed with 300 ml of an aqueous saturated sodium hydrogen sulfite solution, with 300 ml of water, and then with 200 ml an aqueous saturated sodium chloride solution successively and, after drying over anhydrous magnesium sulfate, concentrated under a reduced pressure. The residue was purified by distillation and further recrystallized twice from a heptane/ethanol mixed solvent to obtain 5.67 g of pure 2-trifluoromethyl-3-fluoro-4-ethoxyphenol.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C>[N:24]1([CH2:23][CH2:22][CH2:21][O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: ClCCCN1CCOCC1
Reactant: CCOC(=O)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 2-hydroxybenzoate (2.4 ml, 16.38 mmol), K2CO3 (4.98 g), and DMF (30 ml) was added N-(3-chloropropyl)morpholine hydrochloride (3.93 g). The mixture was stirred at room temperature for 30 minutes, then was warmed on a steam bath overnight. The reaction mixture was cooled, filtered and stripped to afford a liquid which was partitioned between EtOAc (350 ml) and water. The organic layer was separated, washed with water (2×200 ml), dried over MgSO4 and stripped to afford ethyl 2-[3-(4-morpholinyl)propoxy]benzoate.
Reaction SMILES: [BH4-].[Na+].[Te].[Br:4][C:5]1[CH:6]=[C:7]([CH:11]2[N:15]([CH3:16])[C:14](=[O:17])[C:13](Br)(Br)[CH2:12]2)[CH:8]=[N:9][CH:10]=1.C(OCC)(=O)C>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH:11]2[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:8]=[N:9][CH:10]=1
Reactant: CN1C(=O)C(Br)(Br)CC1c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [Te]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1C(=O)CCC1c1cncc(Br)c1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
Sodium borohydride (862 mg, 22.8 mmol) was dissolved in ethanol (20 mL) and tellurium metal powder (1.45 g, 11.4 mmol) was added in portions. The mixture was heated under reflux for 0.25 h and 5-bromo-3-(3,3-dibromo -1-methyl-5-pyrrolidin-2-onyl)pyridine (775 mg, 1.9 mmol) was added to the solution at 25° C. After stirring for 2 h, ethyl acetate (50 mL) was added and the solution was filtered through Celite and concentrated in vacuo. 1M HCl (10 mL) was added to the residue and the solution was adjusted to pH 11 with solid potassium carbonate. After extraction with ethyl acetate (50 mL) the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic phases were washed with brine (30 mL), dried (MgSO4) and concentrated. This material was chromatographed on silica gel with ethyl acetate:hexane (1:1) as eluant to afford 5-bromo-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine as a solid (329 mg, 68%). M.p. 85°-87° C.; 1H NMR (CDCl3, 300 MHz): δ8.66 (d, J=2 Hz, 1H), 8.42 (d, J=2 Hz, 1H), 7.68 (t, J=2 Hz, 1H), 4.56 (t, J=7 Hz, 1H), 2.71 (s, 3H), 2.45-2.65 (m, 2H), 1.80-1.95 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8][CH3:9])[N:7]=1.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:14]([NH2:21])[C@H:13]1[OH:22].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH2:10]([C:3]1[C:2]([NH:21][C@@H:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][C@@H:13]2[OH:22])=[N:7][C:6]([CH2:8][CH3:9])=[CH:5][N:4]=1)[CH3:11]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1cnc(CC)c(Cl)n1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Temperature: 100 °C
Yield: 64.9 %

Procedure:
A solution of 3-chloro-2,5-diethylpyrazine (171 mg, 1.0 mmol), (1R,2S)-(+)-cis-1-amino-2-indanol (298 mg, 2.0 mmol), tris(dibenzylideneacetone)dipalladium (0) (28 mg, 0.03 mmol), and 2-(di-tertbutylphosphino)biphenyl (18 mg, 0.06 mmol) in toluene (2.0 mL) was purged with nitrogen and treated with sodium tertbutoxide (135 mg, 1.4 mmol). The resulting brown suspension was heated to 100° C. for 2 hours. At this time, the reaction was quenched with a saturated water solution of NaHCO3 and extracted twice with ethyl acetate (20 mL). The combined organics were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated to give a black solid. This material was purified by biotage MPLC (40 g column, 25% ethyl acetate/heptane) to afford 184 mg (65%) of the title compound as a light purple solid. IR (diffuse reflectance) 3435, 3241, 2962, 2935, 2912, 2873, 1581, 1547, 1500, 1453, 1184, 1163, 1047, 744, 733 cm−1; OAMS supporting ions at: ESI+ 384.0; MS (CI) m/z 284 (MH+); HRMS (FAB) calcd for C17H21N3O+H1 284.1763, found 284.1754. [α]25D=12 (c 0.55, methylene chloride); Anal. Calcd for C17H21N3O: C, 72.06; H, 7.47; N, 14.83. Found: C, 72.15; H, 7.53; N, 14.42.
Reaction SMILES: [OH:1][C@@H:2]([CH3:10])[C@@H:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].I(O[CH3:15])(=O)=O.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:15][O:1][C@@H:2]([CH3:10])[C@@H:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CO[I+2]([O-])[O-]
Reactant: CCOC(=O)[C@H](C)[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)[C@H](C)OC
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Ethyl (2R, 3S)-3-hydroxy-2-methylbutyrate (8.20 g) and methyl iodate (78.0 g) were dissolved in N,N-dimethylformamide (150 ml). To this solution was added sodium hydride (about 60% in oil, 2.46 g) little by little with ice cooling and the mixture was stirred for 1 hour with ice cooling. The reaction mixture was poured into ethyl acetate (300 ml) and the mixture was stirred for 10 minutes. Insoluble materials were filtered off and the filtrate was washed 3 times with water. The organic layer was dried, concentrated and distilled under reduced pressure (b.p. 80° C./30 mmHg) to obtain ethyl (2R, 3S)-3-methoxy-2-methylbutyrate (6.87 g).
Reaction SMILES: [N:1]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18]C)=[O:17])=[CH:8][CH2:7]2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[C:23]([O:22][C:20]([N:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH2:7]2)[CH2:3][CH2:2]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)C1=CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC=C(C(=O)O)c3ccccc32)CC1

Procedure:
A solution of the methyl ester (B1) (1.59 g, 4.66 mmol) in MeOH (20 ml) was heated with 6N NaOH (2 ml) at 65° C. for 2 h. The reaction mixture was cooled with in an ice-bath, its pH was adjusted to ca. 5 with 0.5N HCl, and extracted with dichloromethane three times. The combined extracts were dried with sodium sulfate, filtered and concentrated to give 1′-(tert-butoxycarbonyl)-2H-spiro[naphthalene-1,4′-piperidine]-4-carboxylic acid. LC-MS: m/e=344.0 (M+H), 288.0 (M+H—C(CH3)3), 244.0 (M+H−Boc). Rt=3.29 min. 1H-NMR (500 MHz, DMSO-d6): 8.05 (dd, 1 H), 7.80 (d, 1 H), 7.68 (t, 1 H), 7.46 (t, 1 H), 6.74 (s, 1H), 4.03 (m, 2 H), 3.71 (s, 2H), 3.4 (m, 2H), 2.21 (td, 2H), 1.46 (s, 9H), 1.45 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[NH:4][N:3]=1.C[O-].[Na+].Cl[CH2:12][C:13](=[O:15])[CH3:14]>CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[CH3:1][C:2]1[O:6][C:5](=[O:7])[N:4]([CH2:12][C:13](=[O:15])[CH3:14])[N:3]=1
Reactant: Cc1n[nH]c(=O)o1
Reactant: CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[O-]
Agent: [Br-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Cn1nc(C)oc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
To a solution of 5-methyl-3H-1,3,4-oxadiazol-2-one (5.509 g, 55.0 mmol) in MeOH (40 mL) is added 25 wt % NaOMe solution in methanol (12.7 mL, 58.8 mmol). The mixture is stirred at rt for 15 min and then concentrated in vacuo. The residue is added to a solution of tetrabutylammonium bromide (0.358 g, 1.08 mmol) and chloro-acetone (4.6 ml, 54.9 mmol) in CHCl3 (33 mL), and the mixture is heated to reflux for 5 h under N2. The mixture is cooled to rt and stirred overnight. The resulting slurry is filtered, and the filtrate is concentrated in vacuo. The residue is purified on a pad of silica gel, eluting with 2:1:1/heptane:EtOAc:DCM to afford 5-methyl-3-(2-oxo-propyl)-3H-1,3,4-oxadiazol-2-one (7.32 g, 86%) as a crystalline solid. MS: 157 (M+H); 1H NMR (300 MHz, CDCl3) δ 4.46 (s, 2H), 2.27 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:31]C)=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2/[CH:23]=[CH:24]\[CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CN(C)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:31])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2/[CH:23]=[CH:24]\[CH2:25][N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])(=[O:14])=[O:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(O)c1C(=O)OC
Yield: 66.4 %

Procedure:
A solution of methyl 3-bromo-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylmethyl]-2-methoxybenzoate (Intermediate 69, 3.9 g) and N,N-dimethylaniline (9.00 g) in DCM (150 mL) was cooled to 0° C. and aluminium chloride (3.00 g) was added in three portions. The resultant mixture was stirred at room temperature for 2 hours. The mixture was cooled in an ice bath and quenched with brine. The layers were separated and the organic phase was dried (MgSO4), filtered and the filtrate was concentrated in vacuo. Cyclohexane was added to the residual gum and then decanted off. The residual oil was dissolved in DCM and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-15% to give methyl 3-bromo-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylmethyl]-2-hydroxybenzoate (2.52 g) as a blue glass.
Reaction SMILES: [NH:1]([C:8]1[O:9][CH2:10][C:11](=O)[C:12]=1[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:2]1([NH:1][C:8]([C:12]2[C:13](=[O:15])[O:14][CH2:10][C:11]=2[NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1=C(Nc2ccccc2)OCC1=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)C1=C(Nc2ccccc2)COC1=O

Procedure:
The title derivative was obtained by a procedure similar to that described in Example 8 starting with 2-anilino-4-oxo-3-furoic acid (7.01 grams, 0.032 mol), triethylamine (8.98 ml, 0.064 mol), BOP-Cl (8.15 grams, 0.032 mol) and aniline (2.95 ml, 0.32 mol) dissolved in 100 ml methylene chloride. Yield: 7.37 g, mp 175°-176° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:33]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]([O:43]C)=[O:42])=[CH:37][CH:36]=4)[C:32]4[CH:45]=[CH:46][CH:47]=[CH:48][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].O.[OH-].[Li+].O1CCCC1.O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]([C:29]3[N:33]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([C:41]([OH:43])=[O:42])=[CH:39][CH:40]=4)[C:32]4[CH:45]=[CH:46][CH:47]=[CH:48][C:31]=4[N:30]=3)=[O:28])[CH2:25][CH2:26]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COC(=O)c1ccc(Cn2c(C(=O)C3CCN(CCC4(c5ccccc5)CCN(C(=O)c5cc(OC)c(OC)c(OC)c5)C4)CC3)nc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(C(=O)O)cc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 72 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1-(4-methoxycarbonyl-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (0.68 g, 0.92 mmol) and lithium hydroxide hydrate (0.12 g, 2.75 mmol) in 4/1 tetrahydrofuran/water (45 mL). After 72 hours, dilute the reaction mixture with water and evaporate in vacuo to remove most of the tetrahydrofuran. Acidify to pH 2 using 1 M hydrochloric acid solution to obtain a solid. Collect the solid by filtration. Suspend the solid in diethyl ether (150 mL) and stir. Collect the solid by filtration and dry to give the title compound: mp; 173.0-190.0° C.
Reaction SMILES: [C:1]([C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)(=O)[CH2:2][CH2:3][CH3:4].[CH:17]1([C:20]2[CH:21]=[N:22][N:23]([C:25]3[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[CH:24]=2)[CH2:19][CH2:18]1.[B][B][B][B][B][B][B][B][B][B]>CO>[CH:17]1([C:20]2[CH:21]=[N:22][N:23]([C:25]3[N:30]=[CH:29][C:28]([NH:31][CH:1]([C:6]4[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=4)[CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=3)[CH:24]=2)[CH2:19][CH2:18]1
Reactant: CCCC(=O)c1ccc(C(=O)OCC)cc1
Reactant: Nc1ccc(-n2cc(C3CC3)cn2)nc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.7 %

Procedure:
To a solution of ethyl 4-butyrylbenzoate (121 mg, 0.549 mmol) and 6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-amine (0.110 g, 0.549 mmol) in methanol (1.3 ml) was added decaborane (27 mg, 0.22 mmol). The reaction was stirred for 12 hours at ambient temperature. The reaction mixture was quenched with aqueous 1.0M hydrochloric acid and concentrated in vacuo. The crude material was purified via ISCO MPLC (SiO2, 0-100% ethyl acetate in heptane) to yield the product (26 mg, 12%) as an oil. 1H NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.67 (br. s., 1H), 7.62 (d, J=9.0 Hz, 1H), 7.44 (s, 1H), 7.40 (d, J=8.2 Hz, 2H), 6.90 (d, J=6.8 Hz, 1H), 4.37 (q, J=7.2 Hz, 3H), 1.76-1.90 (m, 2H), 1.72 (tt, J=8.4, 5.1 Hz, 1H), 1.41-1.52 (m, 2H), 1.38 (t, J=7.1 Hz, 3H), 0.96 (t, J=7.3 Hz, 3H), 0.86 (ddd, J=8.2, 5.9, 3.9 Hz, 2H), 0.56 (dt, J=5.9, 4.1 Hz, 2H).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39]CN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]([CH3:57])[CH2:47][CH2:48][O:49][C:50]1[CH:56]=CC(N)=[CH:52][CH:51]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:52]=[CH:51][C:50]([O:49][CH2:48][CH2:47][N:46]([CH3:57])[CH3:45])=[CH:56][CH:30]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:39])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(OCCN(C)C)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(2-(dimethylamino)ethoxy)aniline as the aniline component. (23%, MS=557.3 (M+H))
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:21][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2
Reactant: BrBr
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
6.0 g (23.7 mmol) of 9-phenylanthracene was dissolved into 80 mL of carbon tetrachloride, and a solution in which 3.80 g (21.1 mmol) of bromine was dissolved in 10 mL of carbon tetrachloride was dropped into the reaction solution using a dropping funnel. After dropping, the solution was stirred for 1 hour at a room temperature. After the reaction, an aqueous sodium thiosulfate solution was added to stop the reaction. An organic layer was washed with an aqueous sodium hydroxide (NaOH) solution and a saturated sodium chloride solution and dried with magnesium sulfate. The mixture was naturally filtered, and a compound obtained by concentrating the filtrate was dissolved into toluene and filtered through florisil, Celite®, and alumina. The filtrate was concentrated and recrystallized with dichloromethane and hexane, thereby obtaining 7.0 g of objective 10-bromo-9-phenylanthracene as a light-yellow solid with a yield of 89%.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21](CC)[CH2:22][CH3:23])[CH3:20].ClC(OCC(C)C)=O.C(NCC)C>CN(C)C=O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][N:10]=1)[CH3:20]
Reactant: O=C(O)CCCCc1nnnn1-c1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCCCc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
5-(1-Phenyl-1,2,3,4-tetrazol-5-yl)valeric acid (2.5 g) is dissolved in dimethylformamide (50 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring diethylamine (0.9 g) at room temperature, and the mixture is stirred for 2 hours. After distilling off dimethylformamide under reduced pressure, acetone is added to the resulting residue, and the insoluble materials are filtered off. The mother liquor is concentrated and then purified by column chromatography (Kieselgel 60, made by Merck & Co.). By eluting with chloroform, there is obtained N,N-diethyl-5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeramide (1.2 g), colorless liquid, nD25 =1.5303.
Reaction SMILES: [CH2:1]([O:8][P:9]([CH2:18][C@H:19]([OH:43])[CH2:20][NH:21][C:22](=[O:42])[C@@H:23]([NH:27][C:28](=[O:41])[C@@H:29]([NH:33]C(OC(C)(C)C)=O)[CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:26])[CH3:25])([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]([NH:54][C@H:55]([C:59]([OH:61])=O)[CH:56]([CH3:58])[CH3:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>>[CH2:1]([O:8][P:9]([CH2:18][C@H:19]([OH:43])[CH2:20][NH:21][C:22](=[O:42])[C@@H:23]([NH:27][C:28](=[O:41])[C@@H:29]([NH:33][C:59](=[O:61])[C@@H:55]([NH:54][C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])[CH:56]([CH3:57])[CH3:58])[CH:30]([CH3:31])[CH3:32])[CH:24]([CH3:25])[CH3:26])([CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1)C(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1)C(C)C)C(C)C

Procedure:
The resulting product from Step 1 was deprotected in a similar manner as Example 1, step 3, and the compound was used immediately and coupled to N-Cbz-L-valine in accordance with the procedures set forth in Example 12, Method B. The crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a RediSep disposable column. 1H NMR (CD3Cl, 300 MHz): δ 7.45-7.25 (m, 10H), 6.0-5.85 (m, 1H), 5.18-4.92 (m, 4H), 4.50-4.33 (m, 2H), 4.31-4.04 (m, 2H), 3.43-3.26 (m, 2H), 2.25-2.03 (m, 3H), 2.02-1.70 (m, 8H), 1.37-1.10 (m, 4H), 1.04-0.82 (m, 20H). LCMS m/z: [M+H]+=757.9.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:28][NH2:29]>>[CH3:28][NH:29][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccnc4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cccc(-c3cccnc3)c2O1

Procedure:
The title compound was prepared (0.367 g, 70%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.730 g, 1.91 mmol) and methylamine (1.14 g, 36.7 mmol). mp 212-215° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[CH2:12][CH2:13][C:14]#[N:15].O.[OH-].[Na+]>CCOCC>[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: N#CCCC1OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCCCC1OCCO1

Procedure:
50.1 g (1.32 mol) of lithium aluminium hydride are suspended in 500 ml of ether. Added dropwise to this suspension is a solution of 111.9 g (0.88 mol) of 3-[1,3]-dioxolan-2-yl-propionitrile. The mixture is subsequently heated at reflux for 2.5 hours. After cooling, 50 g of water, 50 g of 10% strength sodium hydroxide solution and a further 150 g of water are added. The mixture is then filtered and the filtrate is dried over calcium chloride and concentrated. The orange oil obtained is subsequently distilled under reduced pressure (overhead temperature=46° C., p=0.016 mbar). This gives 68.4 g of 3-[1,3]-dioxolan-2-yl-propylamine.