Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=CC=CC=2)C=CC1.C1(=O)C2C(CC=CC=2)CCC1.[Br:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([CH3:35])([CH3:34])[CH2:28][CH2:29][C:30]2=O)=[CH:25][CH:24]=1.[C:36]1([SH:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:34][C:27]1([CH3:35])[C:26]2[C:31](=[CH:32][C:23]([Br:22])=[CH:24][CH:25]=2)[C:30]([S:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:29][CH2:28]1
Reactant: Sc1ccccc1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1=Cc2ccccc2CC1
Agent: O=C1CCCC2CC=CC=C12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC=C(Sc2ccccc2)c2cc(Br)ccc21

Procedure:
Reaction Scheme 3 provides further examples for the synthesis of compounds within the scope of Formula 5 where the linking group between the dihydronaphthalene moiety and the Y group is —CH═CH—. In the sequence of reactions described here the oxo function of a starting tetrahydronaphthalene-one moiety is modified before a Heck coupling reaction is performed. Specifically, in the example shown in the reaction scheme, 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) is reacted with thiophenol in the presence of titanium tetrachloride and triethylamine in tetrahydrofuran (THF), to provide the intermediate 4,4-dimethyl-7-bromo-1-phenylthio-3,4-dihydronaphthalene (Compound A35). A similar reaction can be performed with ethanethiol as a reagent instead of thiophenol, to yield 2-bromo-5,6-dihydro-5,5-dimethyl-8-ethylthio-naphthalene (Compound A36) and other analogous compounds which are not shown in the reaction scheme. Compound A35 is reacted in the Heck reaction to yield ethyl (E)4[2-(5,6-dihydro-5,5-dimethyl-8-phenylthio-naphthalenyl)ethenyl]benzoate (Compound A16). Compound A16 is saponified to yield the carboxylic acid, (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl] benzoic acid (Compound A18), and is oxidized with m-chloroperoxybenzoic acid (MCPBA) to provide the corresponding phenylsulfonyl compound, ethyl (E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(phenylsulfonyl)-naphthalenyl)ethenyl]benzoate (Compound A17). Compound A18 can also be oxidized under similar conditions to provide the free carboxylic acid (or salt thereof) of the phenylsulfonyl compound, (E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-phenylsulfonyl-naphthalenyl)ethenyl]benzoic acid (Compound A19).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.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.[CH2:47]([O:50][C:51]([C@H:53]1[CH2:58][CH2:57][C@H:56]([CH:59]([NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH2:60][NH2:61])[CH2:55][CH2:54]1)=[O:52])[CH2:48][CH3:49]>CN(C=O)C>[CH2:47]([O:50][C:51]([C@H:53]1[CH2:58][CH2:57][C@H:56]([CH:59]([NH:62][C:63]([O:65][C:66]([CH3:67])([CH3:69])[CH3:68])=[O:64])[CH2:60][NH:61][C:11]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[O:13])[CH2:55][CH2:54]1)=[O:52])[CH2:48][CH3:49]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCCOC(=O)[C@H]1CC[C@H](C(CN)NC(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)[C@H]1CC[C@H](C(CNC(=O)C2(c3ccc(Cl)cc3)CC2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-(4-Chlorophenyl)cyclopropanecarboxylic acid (527 mg, 2.68 mmol, 1.0 eq) was dissolved in anhydrous DMF (20 mL) in a 250 mL RB flask, under argon. HBTU (1.32 g, 3.48 mmol, 1.3 eq), and DIPEA (0.95 mL, 5.36 mmol, 2.0 eq) were added to this solution. The reaction mixture was stirred at RT for 15 minutes. To this mixture was charged cis-/trans-4-(2-Amino-1-tert-butoxycarbonylamino-ethyl)-cyclohexanecarboxylic acid propyl ester (1-7) (880 mg, 2.68 mmol, 1.0 eq) in anhydrous DMF (20 mL) solution. The reaction mixture was stirred at RT for 2 hours. LC/MS indicated the absence of the starting material. DMF was removed under vacuum. The residue was treated with 1:1 brine/EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×150 mL). The combined EtOAc extracts were washed with brine (1×150 mL), dried over Na2SO4 and the solvent evaporated to dryness. The crude product was purified on a silica gel column, eluting with EtOAc/Hexanes (20˜25%) to give 1.26 g (92% yield) of 1-9. The 1H NMR (DMSO-d6) data is depicted in FIG. 6.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[CH:9]=[O:10].BrCCC.OC1C=CC(C=O)=CC=1>>[CH2:1]([O:14][C:13]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:5][CH3:4])[CH3:2]
Reactant: CCI
Reactant: COc1cc(C=O)ccc1O
Agent: O=Cc1ccc(O)cc1
Solvent: CCCBr
Product: CCOc1ccc(C=O)cc1OC
Yield: 90 %

Procedure:
When the EtI and 3-methoxy-4-hydroxybenzaldehyde was substituted for 1-bromopropane and 4-hydroxybenzaldehyde respectively in Example 49, Step A, the identical process afforded the title compound in 90% yield, as light yellow oil. 1H-NMR (CDCl3) 1.49 (tr, 3H, J=6.98 Hz); 3.91 (s, 3H); 4.17 (q, 2H, J=14, 7 Hz); 6.94 (d, 1H, J=8.09 Hz); 7.38-7.43 (m, 2H); 9.02 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[N:27]1[CH:32]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])[CH:30]=[N:29][CH:28]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 66 using 5-bromo-6-(pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 67.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (Condition 3) tR=1.07 min, m/z=430.4 [M+H]+, m/z=428.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.94 (m, 4H) 3.15 (t, J=6.15 Hz, 4H) 7.37 (d, J=8.78 Hz, 2H) 7.86 (d, J=8.91 Hz, 2H) 8.11 (d, J=2.01 Hz, 1H) 8.80 (d, J=1.88 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](I)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])[CH3:2].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(I)c2nc(-c3ccccc3)sc2c1OCc1ccccc1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1nc(N2CCCCC2)c2nc(-c3ccccc3)sc2c1OCc1ccccc1
Temperature: 130 °C
Yield: 15.8 %

Procedure:
A mixture of 7-benzyloxy-4-iodo-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (165 mg, 0.32 mmole), piperidine (95 μl, 0.96 mmole) and triethylamine (89 μl, 0.64 mmole) in ethanol (1.6 ml) was heated at 130° C. in a CEM microwave synthesizer for 30 min before it was cooled to room temperature, concentrated and purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a green oil (24 mg). MS: (+) m/z 474.55 (M+1).
Reaction SMILES: [BH4-].[Li+].CO[C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][C:13]2[CH:15]=[C:16]([CH:19]([OH:27])[CH2:20][CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH:17]=[CH:18][C:12]=2[O:11]1.CC[O:31]CC>>[OH:27][CH:19]([C:16]1[CH:17]=[CH:18][C:12]2[O:11][CH:10]([CH:9]([OH:31])[CH2:8][CH2:7][CH2:6][CH3:5])[O:14][C:13]=2[CH:15]=1)[CH2:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOCC
Reactant: COC(=O)CCCCC1Oc2ccc(C(O)CCc3cccs3)cc2O1
Agent: [BH4-]
Agent: [Li+]
Product: CCCCC(O)C1Oc2ccc(C(O)CCc3cccs3)cc2O1
Reaction time: 1 h
Yield: 98 %

Procedure:
Lithium borohydride (2.1 mg, 0.096 mmol) was added to a solution of (±)-methyl-5-[[6-(1-hydroxy-3-(2-thienyl)propyl]-1,3-benzodioxolyl]pentanoate (Compound F, 36.0 mg, 0.096 mmol) in Et2O (2.0 mL) at 23° C. After 12 hours the reaction was quenched with 1N NaOH, stirred 1 hour, and extracted with EtOAc. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 2:1 hex/EtOAc) provided 32.6 mg (98%) of the title compound. 1H NMR (300 MHz, CDCl3) δ7.14 (d, J=5.5 Hz, 1H), 7.01 (s, 1H), 6.93 (dd J=3.3, 5.5 Hz, 1H), 6.84 (d, J=3.3 Hz, 1H), 6.61 (s, 1H), 5.92 (s, 2H), 4.88-4.92 (m, 1H), 3.63 (t, J=5.7 Hz, 2H), 2.97-3.03 (m, 2H), 2.43-2.49 (m, 2H), 1.84-2.20 (m, 3H), 1.26-1.59 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:15][CH2:14][CH2:13][Br:12])[CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: BrCCCBr
Reactant: Fc1ccc2c(c1)OCCN2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)OCCN2CCCBr
Temperature: 70 °C
Yield: 47.3 %

Procedure:
A mixture of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.3 g, 1 eq, 8.49 mmol) obtained in step (iii) above, 1,3-dibromo propane (8.6 ml, 10 eq, 84.9 mmol) and anhydrous sodium carbonate (2.7 g, 3 eq, 25.4 mmol) in dry DMF (85 ml) was heated at 70° C. for 16 h. The reaction was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound (1.1 g, yield 47%) as viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.Cl.[CH3:13][O:14][NH:15][CH3:16].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([N:15]([O:14][CH3:13])[CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ncc(Br)cc1F
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ncc(Br)cc1F

Procedure:
A solution of crude 5-bromo-3-fluoropyridine-2-carboxylic acid (40.65 g, 184.8 mmol), O,N-dimethylhydroxylamine hydrochloride (21.63 g, 221.7 mmol), 1-ethyl-(3-dimethyl-aminopropyl)-carbodiimide hydrochloride (70.85 g, 369.6 mmol), 1-hydroxy-7-azabenzotriazole (2.497 g, 18.48 mmol), and triethylamine (16.48 mL, 118.3 mmol) in 200 mL DMF was stirred at room temperature overnight. The solution was partially concentrated in vacuo and partitioned between ethyl acetate and 10% aqueous sodium bicarbonate. The aqueous layer was extracted 4× with ethyl acetate, and the combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum to provide 5-bromo-3-fluoro-N-methoxy-N-methylpyridine-2-carboxamide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 263.01 for M+H+(79Br).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OCC)(OCC)(OCC)[CH3:26].C(OC1C=C2C(C(N)=C(NCC(C)C)C=N2)=CC=1)C1C=CC=CC=1>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:25]([CH3:26])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: CC(C)CNc1cnc2cc(OCc3ccccc3)ccc2c1N
Solvent: CCOCC
Product: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Temperature: 160 °C

Procedure:
The preparation of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine is described in Parts A-F of Example 1. Under a nitrogen atmosphere, triethyl orthoacetate (4.59 mL, 25.0 mmol) was added to a solution of 7-benzyloxy-N-(2-methylpropyl)quinoline-3,4-diamine (8.05 g, 25.0 mmol) in xylenes (130 mL), and the resulting solution was heated at reflux (160° C.) overnight. The solvent volume was reduced to 70 mL using a Dean-Stark trap. Over a period of a few days, a precipitate formed. Diethyl ether was added, and the precipitate was isolated by filtration and washed with diethyl ether to provide 6.81 g of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a light-brown powder.
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:19]2[O:20][CH2:21][CH2:22][N:23]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16][N:15]=1.Cl[C:31]([O:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])=[O:32]>C(Cl)Cl>[CH3:12][S:9]([C:7]1[CH:8]=[CH:3][C:4]([NH:13][C:14]2[C:19]3[O:20][CH2:21][CH2:22][N:23]([CH:24]4[CH2:25][CH2:26][N:27]([C:31]([O:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])=[O:32])[CH2:28][CH2:29]4)[C:18]=3[N:17]=[CH:16][N:15]=2)=[CH:5][CH:6]=1)(=[O:11])=[O:10]
Reactant: CC(OC(=O)Cl)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c2OCCN3C2CCNCC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Product: CC(OC(=O)N1CCC(N2CCOc3c(Nc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1)C(F)(F)F
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-yl chloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1 H), 8.31 (brs, 1 H), 8.14 (s, 1 H), 7.59-7.78 (m, 2 H), 5.18-5.34 (m, 1 H), 4.78-4.93 (m, 1 H), 4.22-4.41 (m, 4 H), 3.47-3.55 (m, 2 H), 3.04 (s, 3 H), 2.88-3.07 (m, 2 H), 1.79 (m, 2 H), 1.60-1.75 (m, 2 H), 1.42 (d, J=6.60 Hz, 3 H).). LRMS (ESI) 548 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].C1(C)C=CC=CC=1>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=3[CH2:9][O:10]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: OCc1ccc(CO)c(CO)c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2OCc3ccc(CO)cc3CO2)cc1
Yield: 62.6 %

Procedure:
10 g of (3,4-bis-hydroxymethylphenyl)methanol (59.4 mmol) (prepared according to Nakazaki, M.; Yamamoto, K. And Miura, Y.; J. Org. Chem., 43(6), (1978), 1041-1044), 100 ml of toluene, 8.98 g of 4-nitrobenzaldehyde (59.4 mmol) and 0.6 g of Montmorillonite KSF (10 mg/mmol) are introduced into a flask equipped with a Dean-Stark. The mixture is heated under reflux for 2 hours 30 minutes. The montmorillonite is filtered off and the reaction medium is allowed to return to room temperature, with stirring. The reaction product crystallizes. After filtration and drying under vacuum at 50° C., 11.2 g of [7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl]methanol are obtained.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>O1CCCC1>[Br:1][C:2]1[S:3][C:4]([C:8]([NH:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (10.00 g, 45.00 mmol) and 4-methylmorpholine (6.5 mL, 59.0 mmol) in tetrahydrofuran (150 mL) was added isobutyl chloroformate (6.5 mL, 49.6 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour then 3-(aminomethyl)pyridine (5.2 mL, 51.4 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 hours, then concentrated in vacuo. The residue was purified by column chromatography to afford 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide in 52% yield (7.3 g): 1H NMR (300 MHz, CDCl3) δ 8.39-8.80 (m, 2H), 7.80-7.72 (m, 1H), 7.40-7.35 (m, 1H), 6.47 (br s, 1H), 4.60 (d, J=6.0 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 312.1, 314.1 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].COC.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:13]=[O:14])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: O=Cc1ccccc1B(O)O
Agent: COC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=Cc1ccccc1-c1ccc(Br)c2ccccc12
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Under an argon atmosphere, 230 g of 1,4-dibromonaphthalene, 121 g of 2-formylphenylboronic acid and 18.5 g of tetraxis(triphenylphosphine)palladium(0) were placed in a flask. 2.4 L of dimethyl ether (DME) and 1.2 L of a 2M aqueous sodium carbonate solution were added to this flask, and the resultant was refluxed with stirring while heating for 8 hours. After cooling to room temperature, an aqueous phase was removed. An organic phase which had been separated was washed with water, and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by means of silica gel column chromatography, whereby 170 g (yield: 67%) of 1-bromo-4-(2-formylphenyl) naphthalene was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:29]([C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[C@H:30]([C:32]([NH:34][C@H:35]([C:37](ON1C(=O)CCC1=O)=[O:38])[CH3:36])=[O:33])[CH3:31]>CN(C=O)C.C(OCC)(=O)C>[NH:29]([C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[C@H:30]([C:32]([NH:34][C@H:35]([C:37]([NH:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:38])[CH3:36])=[O:33])[CH3:31]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The tripeptide Z-Ala-Ala-Asn(Trt)-OH (2) was prepared according to the following procedure: To a stirred solution of H-Asn(Trt)-OH (4.97 g, 13.28 mmol, obtained from Bachem) in dry DMF (25 ml) a solution of Z-Ala-Ala-OSu (5.2 g, 13.28 mmol) in dry DMF (20 ml) was added and stirred for 14 h at room temperature. The solvent was evaporated in vacuo by using an oil pump. The obtained crude compound was dissolved in ethyl acetate (100 ml), washed with 1 N HCl (2×30 ml) and water (30 ml). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the tripeptide as a white solid (7.95 g, 92%) of m.p. 196° C. The peptide was used without further purification.—1H NMR (500 MHz, DMSO-d6): δ=1.18 (d, 3 H, J=7.1 Hz, CH3), 1.22 (d, 3 H, J=7.0 Hz, CH3), 2.62-2.88 (m, 2 H, CHCH2), 4.06-4.12 (m, 1 H, CH), 4.31-4.37 (m, 1 H, CH), 4.46-4.50 (m, 1 H, CH), 4.98-5.04 (m, 2 H, CH2O), 7.15-7.35 (m, 20 H, aryl-H). —MS(EI) m/z (%): 651 [M+H+], 673 [M+Na+], 689 [M+K+].
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][S@:12](=[O:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[N:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([C:32]3[O:33][CH:34]=[CH:35][C:36]=3[CH3:37])=[O:31])[CH:24]=2)[CH:18]=[N:17][CH:16]=1)(C(C)(C)C)(C)C.[F-].C([NH3+])(C)(C)C>C1COCC1.CCOC(C)=O>[OH:8][CH2:9][CH2:10][CH2:11][S@:12](=[O:45])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[N:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([C:32]3[O:33][CH:34]=[CH:35][C:36]=3[CH3:37])=[O:31])[CH:24]=2)[CH:18]=[N:17][CH:16]=1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCO[Si](C)(C)C(C)(C)C)c3ccccc3)c2)c1
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCO)c3ccccc3)c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of (S)-N-[(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide (2.2 g, 3.43 mmol) in anhydrous THF (60 mL) at 0° C. was added dropwise tert-butylammonium fluoride (7.2 mL, 1 M in THF) and the reaction was stirred at 0° C. for 1 hour. The yellow reaction solution was then concentrated at room temperature to give a red oil. The oily residue was diluted with EtOAc, which was washed with saturated aqueous NaHCO3 (2×), brine (1×), and then dried (anhydrous Na2SO4). The organic layer was decanted, concentrated, and the resulting oily residue was chromatographed (MeOH—CH2Cl2: from 1:100 to 1:50) yielding the title compound as a clear oil which turned into white foam in-vacuo (1.72 g, 95%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][C:10]=2[N:9]=[CH:8]1.[H-].[Na+].I[CH2:28][CH3:29]>CN(C=O)C>[CH2:28]([N:17]([CH2:16][C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:8]=[N:9][C:10]=2[CH:15]=1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)ncn2C1CCCCO1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(Cc1ccc2c(c1)ncn2C1CCCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 55.3 %

Procedure:
To a solution of 202 (600 mg, 1.81 mmol) in DMF (4.5 mL) at 0° C. was added NaH (101 mg, 2.54 mmol, 60% in oil). The reaction was warmed to RT and stirred for 25 min, then re-cooled to 0° C. and iodoethane (0.27 mL, 3.26 mmol) was added. The reaction was warmed to RT and stirred for 5 h. The reaction mixture was partitioned between EtOAc and H2O. The EtOAc extract was washed thrice with water, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography to afford 360 mg (55%) of tert-butyl ethyl((1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)carbamate (208): MS (ESI) m/z=360.3 [M+1]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1)#[N:2].[NH3:13]>C(O)C.[Ni]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH2:13])=[O:11])[CH:4]=1
Reactant: N
Reactant: COC(=O)c1cc(C#N)ccn1
Agent: [Ni]
Solvent: CCO
Product: NCc1ccnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
830 mg of methyl 4-cyanopyridine-2-carboxylate was dissolved in 20.0 mL of ethanol and 20.0 mL of aqueous ammonia, and 160 mg of Raney nickel was added thereto, followed by stirring at room temperature for 4 hours under a hydrogen atmosphere. The reaction liquid was filtered through Celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 410 mg of 4-(aminomethyl)pyridine-2-carboxamide.