Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.[NH2:5][CH2:6][C:7]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:8]=1[CH2:9][CH:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:11]([F:13])[F:12].[C:28]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37](O)=[O:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:8]([CH2:9][CH:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:11]([F:13])[F:12])=[C:7]([CH:26]=1)[CH2:6][NH:5][C:37](=[O:38])[C@@H:36]1[CH2:40][CH2:41][CH2:42][N:35]1[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CN)C(F)F)cc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Yield: 72.3 %

Procedure:
EDC (0.402 g, 2.10 mmol) was added to a stirred mixture of N-{1-[2-(aminomethyl)-4-chlorobenzyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.550 g, 1.61 mmol), N-Boc-L-proline (0.347 g, 1.61 mmol) and HOAT (0.286 g, 2.10 mmol) in DMF (2.8 mL). After 18 h the mixture was partitioned between EtOAc and water. The organic phase was washed with 1 M citric acid, saturated aqueous NaHCO3 and brine, dried (Na2SO4) and evaporated in vacuo to give N-(5-Chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-1-tert-butoxycarbonyl-L-prolinamide (0.626 g) as an oil; MS m/z=538.4.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[CH3:8][C:7]1[O:6][C:5](=[O:9])[O:4][C:3]=1[CH2:2][S:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Sc1ccccc1
Reactant: Cc1oc(=O)oc1CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1oc(=O)oc1CSc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
In 40 ml of dichloromethane was dissolved 2.0 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and 1.5 g of benzenethiol was added. Then, 1.4 g of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1. The eluate was concentrated under reduced pressure to give 2.3 g of the captioned compound as a colorless liquid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([Br:10])[S:8][CH:9]=1)=O.[NH3:11]>CO>[Br:10][C:7]1[S:8][CH:9]=[C:5]([C:3]([NH2:11])=[O:2])[N:6]=1
Reactant: N
Reactant: COC(=O)c1csc(Br)n1
Solvent: CO
Product: NC(=O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
2-Bromothiazole-4-carboxylic acid methyl ester (50 mg) was dissolved in a solution of saturated ammonia in methanol (4 ml). The reaction solution was stirred overnight at room temperature. The solvent was removed under reduced pressure to give 2-bromothiazole-4-carboxylic acid amide (46 mg, yield 100%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 8.11 (s, 1H). LC-MS calcd for C4H3BrN2OS (m/e) 205.91, obsd 207 and 209 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:10]=1)[C:5]([OH:7])=O.[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH2:28])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.O>C(Cl)Cl>[Br:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH:28][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:2]([F:1])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(F)cc(N2CCOCC2)c1
Reactant: Nc1ccc(Br)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(Br)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a solution of 3-fluoro-5-morpholin-4-ylbenzoic acid (1.01 g, 4.4 mmol) in methylenechloride (30 ml) is added DMC (0.908 g, 5.4 mmol) and the mixture is stirred for 10 minutes. To this mixture is added 4-bromonaphthalen-1-amine (1.0 g, 4.50 mmol) and Hunig's base (3.21 ml). The mixture is stirred vigorously overnight at room temperature. The mixture is poured into water (200 ml) and extracted with EtOAc (2×100 ml). The organic layers are combined, dried over Na2SO4, filtered and concentrated. The residue is recrystallized from EtOH (50 ml) to give N-(4-bromo-naphthalen-1-yl)-3-fluoro-5-morpholin-4-yl-benzamide as white crystals (1.26 g, 65%). Mp: 187-189° C. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.18 (d, J=6.3 Hz, 1H), 8.02 (d, J=6.0 Hz, 1H), 7.93 (d, J=5.7 Hz, 1H), 7.72 (t, J=5.1Hz, 1H), 7.67 (t, J=5.4 Hz, 1H), 7.51 (d, J=5.7 Hz, 1H), 7.45 (s, 1H), 7.24 (d, J=6.3 Hz, 1H), 7.04 (d, J=9.3 Hz, 1H), 3.74 (t, J=3.3 Hz, 4H), 3.24 (t, J=3.9 Hz, 4H). MS 429 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.Cl.Cl.[NH:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:27][O:28][C:29]1[C:30]([C:35]([NH2:37])=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C.Cl>ClCCl.C(OCC)(=O)C.CN(C)C=O>[F:12][C:2]([F:1])([F:13])[C@@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([N:22]2[CH2:26][CH2:25][CH2:24][C@@H:23]2[CH2:27][O:28][C:29]2[C:30]([C:35]([NH2:37])=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: O=C(O)[C@H]1CC[C@@H](C(F)(F)F)CC1
Reactant: NC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@@H](C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To an ice-cold solution of cis-4-(trifluoromethyl)cyclohexanecarboxylic acid (267 mg, 1.36 mmol) in dichloromethane (5 mL), oxalyl chloride (0.18 mL, 2.04 mmol) and several drop of N,N-dimethylformamide were added. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo to give a waxy solid. The residual solid was dissolved with dichloromethane (3 mL) and added to the mixture of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (200 mg, 0.68 mmol, EXAMPLE 1 Step 3) and triethylamine (0.48 mL, 3.40 mmol) in dichloromethane (5 mL) at 0° C. After being stirred at 0° C. for 2 h, the mixture was dissolved with ethyl acetate and 2 N hydrochloric acid. The aqueous layer was washed with ethyl acetate, and basified with aq. ammonia. The mixture was extracted with ethyl acetate twice, and washed with brine. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give an amber oil. The residual oil was purified by preparative TLC (methanol/dichloromethane 1:10) to afford 160 mg of the title compound as a colorless viscous oil.
Reaction SMILES: BrBr.[F:3][C:4]([F:14])([F:13])[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[S-:15][C:16]#[N:17].[K+].N>C(O)(=O)C.O>[NH2:17][C:16]1[S:15][C:11]2[CH:12]=[C:6]([O:5][C:4]([F:13])([F:14])[F:3])[CH:7]=[CH:8][C:9]=2[N:10]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: N
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of 77 g of bromine in 220 ml of acetic acid is added drop by drop, in a period of one hour, to a solution of 84 g of 4-trifluoromethoxy-aniline and 187 g of potassium thiocyanate in 500 ml of acetic acid. The mixture is stirred overnight at the ambient temperature. The reaction mixture is then poured into 2 liters of water. The resulting mixture is cooled in an icebath and neutralized by addition of ammonia. The insoluble material is separated by filtration, washed with water, then recrystallized in an ethanol-water mixture (50--50). 77 g of 2-amino-6-trifluoromethoxy-benzothiazole, which melts at 119° C., are thus obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([NH:13]C(OC(C)(C)C)=O)=[CH:8][C:7]=1[Cl:21])(=[O:3])[CH3:2].C[Si](I)(C)C>CC#N>[C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([NH2:13])=[CH:8][C:7]=1[Cl:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)cc(NC(=O)OC(C)(C)C)cc1Cl
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC(=O)OCc1c(F)cc(N)cc1Cl
Reaction time: 0.25 h

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)-2-chloro-6-fluorobenzyl acetate (8.5 g, 24 mmol) in CH3CN (300 mL) was added trimethylsilyl iodide (4.12 mL, 28 mmol) at 0° C. under N2.2 After stirring 15 min, the reaction mixture was quenched with 5% Na2S2O3 (10 mL) in ice-bath, concentrated in vacuo, and extracted with EtOAc. The combined extracts were washed with H2O and brine successively, dried over anhyd MgSO4, concentrated and purified by column chromatography (Hex/DCM=1:1) to afford 4-amino-2-chloro-6-fluorobenzyl acetate as yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.55-6.49 (m, 1H), 6.33-6.27 (m, 1H), 5.15 (d, 2H), 3.97 (d, 2H), 2.07 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C(N(CC)CC)C.C(#N)C.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>O>[C:27]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[CH:15][CH:16]=1)(=[O:30])[CH:28]=[CH2:29]
Reactant: C=CC(=O)Cl
Reactant: O=Cc1ccc(OCCCCCCO)cc1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCOc1ccc(C=O)cc1
Temperature: 0 °C

Procedure:
8.9 g (0.04 mol) of 4-(6-hydroxyhexyloxy)benzaldehyde, 6.8 ml of triethylamine and 100 ml of acetonitrile were put in a three-neck flask equipped with a thermometer and a stirrer and cooled to 0° C. To this mixture was dropwise added a solution comprising 4.0 g (0.044 mol) of acryloyl chloride and 10 ml of acetonitrile with stirring at 0° C. to 5° C. After the addition, the whole mixture was stirred for one hour at 0° C. and poured into water containing ice. The crystals which precipitated out after a while were taken out by filtration, washed with water and dried by airing to obtain the intended compound. The yield of the product was 3.94 g (35.7%). The product had a melting point of 30° C. or lower.
Reaction SMILES: [CH2:1]([C:3]12[CH2:17][CH:7]3[NH:8][CH:9]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=41)[CH:4]2[CH2:5][CH:6]3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Li].[CH3:32][S:33][CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>>[CH2:1]([C:3]12[CH2:17][CH:7]3[NH:8][CH:9]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=41)[CH:4]2[CH2:5][C:6]3([C:37](=[O:38])[CH2:36][CH2:35][CH2:34][S:33][CH3:32])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2]
Reactant: CSCCCC(=O)Cl
Reactant: CCOC(=O)C1CC2C3Cc4ccccc4C2(CC)CC1N3
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Product: CCOC(=O)C1(C(=O)CCCSC)CC2C3Cc4ccccc4C2(CC)CC1N3

Procedure:
Following a procedure similar to that described in Examples 1 or 2, it is contemplated that reaction of ethyl 5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate with lithium diisopropylamide, followed by reaction of the resulting lithium salt with γ-methylmercaptobutyryl chloride and treatment of the resulting product with dilute mineral acid affords ethyl 5α-ethyl-3-(γ-methylmercaptobutyryl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate, which, on heating with trimethylammonium formate, affords 6(eq)-ethyl-11(eq)-(6-methylmercapto-3-oxohexyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:30]2[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: OC1CCNCC1
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CCC(O)CC2)n(C)c(=O)c1OCc1ccccc1

Procedure:
A solution of 5-Benzyloxy-2-methanesulfonyl-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.725 g, 2 mmol) and 4-hydroxypiperidine (1 g, 10 mmol) in THF (20 mL) was stirred for 16 h at ambient temperature. Then, the reaction mixture was taken up in EtOAC (100 mL), washed with 1N aq HCl (2×10 mL) and brine (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated to give the desired product as a pale yellow paste (0.608 g, 79%) which was used in the subsequent reaction without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.46 (d, J=7.0 Hz, 2H), 7.36–7.28 (m, 3H), 5.14 (s, 2H), 4.30 (q, J=7.0 Hz, 2H), 3.92–3.87 (m, 1H), 3.50 (s, 3H), 3.44–3.39 (m, 2H), 3.01–2.95 (m, 2H), 2.79 (br s, 1H), 2.02–1.98 (m, 2H), 1.71–1.64 (m, 2H), 1.28 (t, J=7.0 Hz, 3H). LRMS (M+H) calcd for C20H26N3O5: 388.44. found: 388.20
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:51]=[CH:50][C:39]([O:40][CH2:41][CH2:42][CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:38][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[N:44]1([CH2:43][CH2:42][CH2:41][O:40][C:39]2[CH:50]=[CH:51][C:36]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([N:11]4[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)=[O:19])=[CH:12]4)(=[O:10])=[O:9])[CH:3]=3)=[CH:37][CH:38]=2)[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: CC1(C)OB(c2ccc(OCCCN3CCOCC3)cc2)OC1(C)C
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1)NOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2cccc(-c3ccc(OCCCN4CCOCC4)cc3)c2)c1)NOC1CCCCO1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
(E)-3-[1-(3-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (4.6 g) and 4-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propyl}-morpholine (3.9 g) are dissolved in DME (200 mL). Under an inert gas atmosphere are added are added (Ph3P)3PdCl2 (1.4 g) and 2M Na2CO3-solution (31 mL). The mixture is heated to 100° C. for 2 h. After filtration and extraction, the crude product from the organic phase is purified by silica gel flash chromatography. 4.7 g of the title compound are obtained as brownish oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:4][CH:3]=1.[NH2:19][CH:20]1[CH:27]2[CH2:28][C:23]3([OH:30])[CH2:24][CH:25]([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH:19][CH:20]2[CH:21]3[CH2:29][CH:25]4[CH2:24][C:23]([OH:30])([CH2:28][CH:27]2[CH2:26]4)[CH2:22]3)=[O:13])=[CH:17][CH:18]=1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: O=C(O)c1cccc(OCc2ccc(F)cc2)c1
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)c1cccc(OCc2ccc(F)cc2)c1

Procedure:
Prepared from 3-(4-fluoro-benzyloxy)-benzoic acid and 4-amino-1-hydroxyadamantane. LC-MS (m/z): 296 (M+1).
Reaction SMILES: C(OC([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][CH:17]=3)=[CH:12][C:9]=2[C:10]=1[CH3:11])=O)C.Br>C(O)(=O)C>[CH3:11][C:10]1[C:9]2[CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)[CH:14]=[CH:15][C:8]=2[O:7][CH:6]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc3oc(C(=O)OCC)c(C)c3c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1coc2ccc(-c3ccc(CC(=O)O)cc3)cc12
Temperature: 0 °C

Procedure:
A solution of 17 g. of the product of step A in 100 ml. of acetic acid with 35 ml. of 48 percent hydrobromic acid is heated at reflux for three hours, then poured into ice water. This mixture is extracted into dichloromethane, and the extracts are dried to provide 4-(3-methylbenzofuran-5-yl)phenylacetic acid. This intermediate is esterified by heating with a trace of sulfuric acid in ethanol. The product is purified by chromatography on silica gel, eluting with 20 percent dichloromethane in carbon tetrachloride to provide ethyl 4-(3-methylbenzofuran-5-yl)phenylacetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[C:11]([CH:13]([OH:27])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)#[CH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:27][CH:13]([C:11]#[CH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:8]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CC(OC(=O)C1C(C)(C)C1(C)C)c1cccc(Oc2ccccc2)c1
Reaction time: 16 h

Procedure:
2,2,3,3-Tetramethylcyclopropanoyl chloride (3.05 g) was added with stirring to a solution of α-ethynyl-3-phenoxybenzylalcohol (4.8 g) and triethylamine (2.16 g) in dry toluene (70 ml) at 10°C. The solution was allowed to attain room temperature and stirred for 16 hours. The mixture was filtered and the solvent removed from the filtrate under reduced pressure. The residue was washed with 5% sulphuric acid, followed by saturated sodium bicarbonate solution and finally purified by chromatography on silica gel using toluene as eluent to give the desired product as an oil nD2μ 1.5455.
Reaction SMILES: [Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([Cl:23])[C:17]([F:24])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(Cl)Cl.Cl.[NH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([Cl:23])[C:17]([F:24])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CCN
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 2 h

Procedure:
38 g of ethoxy acrylate from Example 1 are initially introduced into 150 ml of methylene chloride. An aqueous solution of 15.4 g of ethyl 3-aminopropionate hydrochloride is added to this. A solution of 8.4 g of NaHCO3 in water is added dropwise to the two-phase system with vigorous stirring. After completion of the dropwise addition, the mixture is stirred for a further 2 hours, and the phases are subsequently separated. The organic phase is washed with water, dried over Na2SO4, and concentrated. The solid residue is slurried in diethyl ether and subsequently isolated. Yield: 38 g, melting point 107°-8° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:43])[C:35]5[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N+:36]=5[O-:42])=[C:30]([C:44]([F:47])([F:46])[F:45])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:11][CH:12]([CH3:15])[CH3:13])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:43])[C:35]5[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N+:36]=5[O-:42])=[C:30]([C:44]([F:47])([F:45])[F:46])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(C(F)(F)F)c2)CCN3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(C(F)(F)F)c2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 184.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) and isobutylaldehyde (0.22 ml) were dissolved in 1,2-dichloroethane (25 ml), and to the solution, triacetoxy sodium borohydride (0.48 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 20) (0.3 g) as yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:36])/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)C=Cc1ccccc1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)/C=C/c3ccccc3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.106 g, 0.384 mmol) was reacted with N-(2-azidoethyl)cinnamamide (0.083 g, 0.384 mmol) following the general click procedure to give (E)-tert-butyl 2-amino-4-(5-(1-(2-cinnamamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), δ 7.51 (d, J=11.1 Hz, 1H), δ 7.28 (m, 6H), δ 6.45 (t, J=14.1 Hz, 2H), δ 6.08 (s, 2H), δ 4.47 (s, 2H), δ 3.79 (s, 2H), δ 2.57 (s, 2H), δ 2.23 (s, 2H), δ 1.50 (bs, 13H), δ 1.28 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 166.9, 150.4, 149.5, 148.3, 141.2, 138.9, 134.9, 129.9, 128.9, 128.0, 122.1, 120.8, 106.5, 84.8, 53.7, 49.5, 39.9, 31.1, 29.3, 28.9, 28.3, 28.2, 25.6 ppm; HRMS (ESI) calcd for C26H35N7O3(M+) 493.2801. found 493.2800, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)cinnamamide hydrochloride (0.097 g, 59% yield). 1H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), δ 7.49 (s, 3H), δ 7.32 (s, 3H), δ 6.30 d, J=10.8 Hz, 1H), δ 6.39 (s, 1H), δ 4.66 (s, 2H), δ 3.83 (s, 2H), δ 2.73 (s, 2H), δ 2.40 (s, 2H), δ 1.57 (s, 2H), δ 1.55 (s, 2H), δ 1.36 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 167.8, 160.5, 150.2, 147.3, 141.1, 134.8, 130.7, 129.9, 128.8, 127.8, 127.6, 124.9, 23 9, 120.2, 108.5, 108.3, 53.1, 39.3, 36.5, 30.6, 28.4, 28.1, 27.6, 26.5, 24.2, 24.1, 23.7 ppm; HRMS (ESI) calcd for C21H27N7O (M+) 393.2277. found 393.2273.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][OH:10]>C(OCC)(=O)C.C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10]
Reactant: OCC#Cc1ccccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCCc1ccccn1

Procedure:
A solution of 3-(2-pyridyl)-2-propyn-1-ol (540 mg, 4.06 mmol) in ethyl acetate (15 ml) and ethanol (3 ml) was hydrogenated over 10% palladium on carbon at room temperature for 13 h. The mixture was filtered through celite and the filtrate on evaporation gave an oil, which was flash chromatographed on silica using 3% methanol/dichloromethane. Fractions with Rf of about 0.09 on evaporation gave the title alcohol as a yellow oil.