Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:22][CH:23]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[C:24]([F:27])([F:26])[F:25])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2.Cl.O>O1CCOCC1>[NH2:14][CH:10]1[C:11]2[C:7](=[CH:6][C:5](/[CH:4]=[CH:3]/[C:2]([NH:22][CH:23]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[C:24]([F:25])([F:26])[F:27])=[O:1])=[CH:13][CH:12]=2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.2 g of tert-butyl {5-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-amino)prop-1-en-1-yl]-2,3-dihydro-1H-inden-1-yl}carbamate were dissolved in 40 ml of dioxane and admixed with 10 ml of semisaturated hydrochloric acid, and stirred at room temperature overnight. The reaction mixture was admixed with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 1.5 g of (2E)-3-(1-amino-2,3-dihydro-1H-inden-5-yl)-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]-ethyl}-acrylamide (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[C:7]([NH:9][CH2:10][CH2:11][OH:12])=[O:8].C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[C:7]([NH:9][CH2:10][CH2:11][O:12][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1)=[O:8]
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(Cl)cc1C(=O)NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)NCCOc1ccc(C=O)cc1

Procedure:
A mixture of 2-(N-(5-chloro-2-methoxybenzoyl)amino)ethanol (4.5 g), potassium carbonate (5 g) and 4-fluorobenzaldehyde (2.5 g, 2.16 ml) were heated at 100° C. in dry dimethylsulphoxide (50 ml) for 18 hours. The mixture was cooled, diluted with water and extracted with diethyl ether containing a little methanol. The organic layers were combined, dried (MgSO4) and evaporated. The residual oil was chromatographed on silica gel with 2% methanol in dichloromethane as solvent to afford the title compound as an oil.
Reaction SMILES: [O:1]=[C:2]([CH3:5])[CH:3]=[CH2:4].[CH3:6][NH:7][CH2:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[CH3:6][N:7]([CH2:8][CH2:9][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:4][CH2:3][C:2](=[O:1])[CH3:5]
Reactant: CNCCC(c1ccccc1)c1ccccc1
Reactant: C=CC(C)=O
Solvent: CCOCC
Product: CC(=O)CCN(C)CCC(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A solution of 3.72 ml of 3-oxo-but-1-ene was added dropwise, over a period of 20 minutes and such that the temperature did not exceed 2°-3° C., to a cooled solution of 7.87 g of N-methyl-3,3-diphenylpropylamine in 7 ml of diethyl ether. The solution thus obtained was evaporated in vacuo at room temperature to give 10.3 g of N-methyl-N-(3,3-diphenylpropyl)-4-aminobutan-2-one (100%) as free base, shown to be practically pure by TLC (chloroform: methanol 9:1 by volume) which could be used as such for further reactions. This compound could be transformed into the corresponding hydrochloride (m.p. 133°-135° C.) by treating the free base with hydrogen chloride in diethyl ether, and crystallizing the product thus obtained first from acetone: ethyl acetate: isopropanol then from acetone.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C@@H:5]([CH3:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:2].[CH3:12][Mg]Br.C1COCC1.C1(C)C=CC=CC=1>C1COCC1>[OH:2][CH:1]([CH3:12])[CH2:3][CH2:4][C@@H:5]([CH3:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C[C@H](C)CCC=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@H](C)CCC(C)O
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
To a solution of aldehyde from Step 1 (1.03 g, 6.5 mmol) in THF (20 mL) at -70° C. was added 1.4M methyl magnesium bromide in THF-toluene 1:3 (4.66 mL, 6.52 mmol). The mixture was stirred at -70° C. for 45 minutes, quenched with aqueous saturated NH4Cl and allowed to warm up to room temperature. It was diluted with ether, and the organic phase was washed twice with brine, dried over MgSO4 and evaporated down. The residue was chromatographed on silica gel, eluting with a 1:2 mixtue of ethyl acetate and hexane, to afford the desired compound (293 mg) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1([CH2:9][CH2:10][OH:11])[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH:1]([C:4]1([CH2:9][CH2:10][O:11][S:13]([CH3:12])(=[O:15])=[O:14])[O:8][CH2:7][CH2:6][O:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C1(CCO)OCCO1
Solvent: ClCCl
Product: CC(C)C1(CCOS(C)(=O)=O)OCCO1
Yield: 115.6 %

Procedure:
To a solution of 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethanol (11 g, 0.069 mol) and TEA (20.91 g, 0.207 mol) in dried CH2Cl2 (110 mL) was added MsCl (15.8 g, 0.138 mol) dropwise at 0° C. The mixture was stirred till the reaction was over. The reaction was quenched with water. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phase was dried over Na2SO4, and concentrated to give the crude methanesulfonic acid 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethyl ester (19 g, crude), which was used for the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C(Cl)Cl.B(Br)(Br)Br>C(OCC)(=O)C>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([CH:12]2[CH2:13][C:14]3[CH:15]=[CH:16][C:3]([OH:2])=[CH:4][C:5]=3[CH:6]3[CH:11]2[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:22][CH:21]=1
Reactant: COc1ccc(C2Cc3ccc(OC)cc3C3CCCCC23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1ccc(C2Cc3ccc(O)cc3C3CCCCC23)cc1
Reaction time: 1.5 h
Yield: 71.8 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (132.1 mg, 0.41 mmol), methylene chloride (4.0 mL), boron tribromide (0.16 mL, 1.64 mmol) at 0° C., and stir under a nitrogen atmosphere. After 1.5 hours, add ethyl acetate to reaction mixture, quench reaction with sat ammonium chloride solution (aq). Wash organic layer with brine, dry over sodium sulfate, and concentrate in vacuo. Flash chromatograph to yield the titled compound (86.7 mg, 72%) as a white solid. 1H NMR (DMSO): 9.15 (s, 1H), 9.00 (s, 1H), 7.08 (d, 2H, J=8.8 Hz), 6.93 (d, 1H, J=8.4 Hz), 6.70 (m, 3H), 6.52 (dd, 1H, J=8.4, 2.2 Hz), 3.05 (m, 3H), 2.65 (m, 1H), 2.34 (d, 1H, J=12.8 Hz), 1.88 (m, 1H), 1.55 (m, 2H), 1.37 (m, 1H), 1.05 (m, 4H); MS m/z 293 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:25]([O:27][CH2:28][CH2:29][NH2:30])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:25]([O:27][CH2:28][CH2:29][NH:30][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])[CH3:26]
Reactant: CCOCCN
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C

Procedure:
1-Methyl-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (33 mg) was prepared by following General Procedure F using 1-methyl-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (36 mg), 2-ethoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 431; and 1H NMR (DMSO-d6, 400 MHz): δ 8.26 (t, 1H), 7.80 (s, 1H), 7.65 (t, 1H), 7.56 (br, 2H), 7.48 (d, 1H), 7.18 (m, 1H), 7.14 (d, 1H), 3.54 (s, 3H), 3.46 (q, 2H), 3.38 (m 2H), 3.24 (t, 2H), and 1.08 (t, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([OH:37])[CH3:36])=[CH:31][C:30]=3[O:38][CH3:39])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)O)ccc1OCCCCN1CCC(c2noc3ccccc23)CC1
Temperature: 75 °C
Yield: 94.2 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g, 0.018 mol), K2CO3 (5.5 g, 0.04 mol), and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 0.018 mol), and dimethylformamide (60 ml) was stirred and heated at 75° C. for 16 hours. The reaction was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 7.2 g of a beige solid. Recrystallization (twice) from ethyl alcohol yielded 3.3 g (43%) of 1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]3-methoxyphenyl]ethanone, m.p.=99°-101° C.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[C:14](=[O:16])[N:13]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=2)[CH2:18][C:19](O)=[O:20])[CH2:12]3)=[O:5])[CH2:3][CH2:2]1.C1N=C[N:37](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:19]([CH2:18][CH:17]([N:13]1[C:14](=[O:16])[C:15]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH2:12]1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:30])[F:31])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=1)(=[O:20])[NH2:37]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 69.6 %

Procedure:
Cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by the procedure of example 6 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and NH4OH (0.25 ml. 3.4 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.56 g, 70%): mp, 179-181° C.; 1HNMR (CDCl3): δ 0.92 (m, 2H, c-CH2), 1.44 (t, J=6.8 Hz, 3H, OCH2CH3), 1.68 (m, 1H, c-CH), 2.99 (dd, J=5, 15 Hz, 1H, CH2), 3.44 (dd, J=10, 15 Hz, 1H, CH2), 4.08 (q, J=7.0 Hz, 2H, OCH2CH3), 4.20 (d, J=17.5 Hz, 1H, CH2N), 4.40 (d, J=17.5 Hz, 1H, CH2N), 5.42 (broad, 1H, NH2), 5.58 (m, 1H, CHN), 6.07 (broad, 1H), 6.56 (t, JH-F=75 Hz, 1H, CF2H), 6.98 (m, 3H, Ar), 7.15 (d, J=7.5 Hz, 1H, Ar), 7.46 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.49 (s, 1H, NHCO). 13CNMR (CDCl3): 8.31, 14.6, 16.2, 38.9, 48.6, 53.9, 64.8, 101.57, 102.3, 113.2, 116.7, 117.3, 117.8, 119.2, 122.9, 113.5, 137.3, 138.1, 141.4, 141.2, 150.9, 170.9, 171.4, 172.7; Anal. Calcd. for C24H25F2N3O5: C, 60.88; H, 5.32; N, 8.87. Found: C, 60.82; H, 5.11; N, 8.80.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[C:15](=[O:17])[CH3:16])[CH2:3][CH2:2]1.[Br:18]Br>C(Cl)(Cl)(Cl)Cl.CC(O)=O>[Br:18][CH2:16][C:15]([C:5]1[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1)=[O:17]
Reactant: BrBr
Reactant: CC(=O)c1c(-c2ccccc2)noc1C1CC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)c1c(-c2ccccc2)noc1C1CC1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 1-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-ethanone (3.34 g, 14.6 mmol) in carbontetrachloride (9.7 mL) and AcOH (0.4 mL) at 48° C. was added a solution of bromine (0.79 mL, 14.6 mmol) in carbontetrachloride (7.8 mL) over 10 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (50 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate: 100:0 to 80:20) afforded the title compound (4.29 g, 95%) which was obtained as an off-white solid. MS m/e (EI): 305.0/307.0 [M].
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[C:2]#[CH:3].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)([CH3:23])[CH3:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:14])=[O:10])=[CH:7][CH:6]=1)[C:2]#[CH:3].[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:14])=[O:10])=[CH:7][CH:6]=1)[C:2]#[CH:3].[OH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=2)([CH3:23])[CH3:22])=[CH:19][CH:20]=1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 4-propargyloxybenzoyl chloride (17.86 grams, 0.092 moles) in 110 milliliters chloroform is added at room temperature over a 2 hour period to a solution of bisphenol A (9.13 grams, 0.040 moles) and triethylamine (15.0 milliliters, 0.018 moles) in 75 milliliters chloroform. After an additional 1.5 hours, the solution is washed with 5 percent aqueous sodium bicarbonate, then with 1N hydrochloric acid. The organic solution is dried and the solvent is removed by evaporation. The product is purified by recrystallization from a 1:1 solution of toluene in heptane. About 21 grams of product are obtained, reflecting a yield of about 96 percent. Nuclear magnetic resonance spectra confirm the identity of the product, and establish its purity. A dynamic scanning calorimetry run shows a melt endotherm at about 144° C. and a polymerization exotherm with a maximum at about 296° C. The heat of polymerization is about 713 joules/gram.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:24]2[C:25]3=[C:26]4[C:21](=[CH:22][CH:23]=2)[CH:20]=[CH:19][CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[CH:13][CH:12]=1.[Br:27]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:27][C:18]1[C:17]2[C:26]3=[C:25]4[C:14](=[CH:15][CH:16]=2)[CH:13]=[CH:12][C:11]([C:2]2[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=2)=[C:24]4[CH:23]=[CH:22][C:21]3=[CH:20][CH:19]=1
Reactant: c1ccc2cc(-c3ccc4ccc5cccc6ccc3c4c56)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2ccc3c(-c4ccc5ccccc5c4)ccc4ccc1c2c43
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 21.5 %

Procedure:
Next, a mixed solution of 7.5 g of 1-(2-naphthyl)pyrene, 4.1 g of N-bromosuccinimide and 115 ml of dimethylformamide was heated with stirring under a nitrogen gas flow at 50° C. for 7.5 hours. After cooling the solution to room temperature, 100 ml of water was injected, followed by stirring at room temperature for 0.5 hours. The precipitated solid was collected by filtration, washed twice with 100 ml of water and then washed twice with 100 ml of methanol. The solid was washed three times with 50 ml of 1,2-dimethoxyethane and then vacuum-dried to obtain 2.0 g of 1-bromo-6-(2-naphthyl)pyrene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][CH:29]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: COCCOc1ccc(CNc2ccc(C(C)C)cc2)cn1
Product: COCCOc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 46.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and (4-isopropylphenyl)([6-(2-methoxyethoxy)pyridin-3-yl]methyl)amine (0.60 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-([6-(2-methoxyethoxy)pyridin-3-yl]methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.52 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][CH2:12]N(CC)CC.ClC(OCC)=O.CCO>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromopicolinic acid from Step 1 (92 g, 0.455 mol) and Et3N (69 g, 0.68 mol) in THF (1.1 L) at 0° C. there was slowly added ethyl chloroformate (61.6 g, 0.57 mol). The resulting suspension was stirred at 0° C. for 15 min., EtOH (250 mL) was added, and the mixture was stirred at r.t. overnight. After filtration, the filtrate was evaporated down, the residue was taken up in ET2O (1 L) and filtered again. The filtrate on evaporation of the solvents afforded the title compound as an oil which was immediately used as such.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:7]=1.C([Li])CCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1(C)C=CC=CC=1>[F:19][C:3]1[C:2]([B:25]([OH:30])[OH:26])=[CH:7][C:6]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(COCc2cnc(F)c(Br)c2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(COCc2cnc(F)c(B(O)O)c2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
3-Bromo-2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridine (1.615 g, 4.952 mmol) was dissolved in PhMe (25.0 mL) and the reaction flask was cooled under nitrogen in a dry ice/acetone bath. Then, n-butyllithium solution (Fluka, Buchs, Switzerland, 1.6 M in hexane, 3.7 mL, 5.9 mmol) was added via syringe, turning the solution yellow. The reaction was stirred at −78° C. for 45 minutes and then triisopropyl borate (Alfa Aesar, Ward Hill, Mass. 98+%, 1.7 mL, 7.2 mmol) was added via syringe. The reaction was allowed to slowly warm up to room temperature, and after 90 minutes, the dry ice/acetone bath was removed. After another 25 minutes, the reaction was quenched with water and diluted with 10:1 DCM/MeOH. The biphasic solution was treated with 5 N HCl to lower the pH of the aqueous phase from 9 to about 4, and the aqueous phase extracted with 10:1 DCM/MeOH. The organic extracts were concentrated and dried under high vacuum in water bath (about 45° C.-60° C.), and then the solid was washed with Et2O and dried again under high vacuum at room temperature over the weekend to afford 2-fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-ylboronic acid (1.389 g, 68% purity, 66% yield). MS (ESI pos. ion) m/z 292 (M+H)+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[N:19][C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:11])=[CH:3][CH:4]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=N[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
A mixture of p-anisaldehyde (11.24 g, 82.5 mmol) and (S)-α methyl benzyl amine (10.0 g, 82.5 mmol) in toluene (100 mL) was heated to reflux with removal of water by a Dean-Stark apparatus. After cooling to ambient temperature, the mixture was concentrated to provide 20.15 g (100%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.75-7.68 (m, 2H), 7.45-7.15 (m, 5H), 4.50 (q, 1H, J=6.6 Hz), 3.82 (s, 3H), 1.58 (d, 3H, J=6.6 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][CH3:31])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:40]2[CH:52]=[CH:51][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:40]2[CH:41]=[CH:42][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:51][CH:52]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][CH3:31])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(propyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (0.2 g, 0.412 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (0.148 g, 0.488 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.108 g, 1.01 mmol) was added and reaction mixture purged with argon for 15 min. Pd(PPh3)4 (0.048 g, 0.042 mmol) was then added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and solvent removed under reduced pressure to afford crude product which was purified by column chromatography over silica gel to afford the title compound (0.20 g, 83.68%). LCMS: 587.40 (M+1)+; HPLC: 98.68% (@254 nm) (Rt; 4.257; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H, J=4.8 Hz), 7.56 (d, 2H, J=8 Hz), 7.38 (t, 3H, J=8 Hz), 7.19 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.82-3.85 (m, 2H), 3.57 (m, 4H), 3.48 (s, 2H), 3.23 (t, 2H, J=10.8 Hz), 2.94-3.02 (m, 3H), 2.36 (bs, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.56-1.65 (m, 4H), 1.20-1.25 (m, 2H), 0.76 (t, 3H, J=6.8 Hz).