Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][C:25]([NH:24][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:23])([CH3:29])[CH3:28]
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)(C)CO)nn1
Yield: 82 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.64 mmol) was converted, using 2-amino-2-methyl-propanol instead of ethanolamine, to the title compound (SiO2, heptane:ethyl acetate=95:5 to 50:50, 202 mg, 82%) which was obtained as a white foam. MS: m/e=383.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:36].IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][C@@H:10]([CH3:36])[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of (S)-1-t-butoxycarbonyl-5-t-butyldiphenylsiloxymethyl-pyrrolidine-2-one (15 g, 33 mmol) in THF (250 mL) at -78° C. a 1M solution of LiN(SiMe3)2 (35 mL, 35 mmol) was slowly added. After stirring for 1 hr, iodomethane (6.2 mL, 100 mmol) was added. The reaction mixture was allowed to stir for another 2 hr at -78° C. and then quenched with acetic acid. The mixture was concentrated into half volume, diluted with water (200 mL) and extracted with ethyl acetate (EtOAc). The combined extracts were washed with water, brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue purified by flash column chromatography on silica gel, eluted with EtOAc:Hexane (1:2.5). The desired (2S,5R) isomer was eluted first from the column and crystallized in hexanes to give 7.3 g (47%) of product as white crystals. mp=84°-85° C. 1H NMR (200 MHz, CDCl3): δ 7.62 (m, 5H), 7.40 (m, 5H), 4.12 (m, 1H), 3.85 (dd, J=10.3, 4.7 Hz, 1H), 3.72 (dd, J=10.3, 2.8 Hz, 1H), 2.82 (m, 1H), 2.31 (dd, J=12.7, 8.9 Hz, 1H), 1.75 (m, 1H), 1.42 (s, 9H), 1.20 (d, J=7.0 Hz, 3H), 1.02 (s, 9H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[N:12]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][N:14]=[CH:13]1>>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:20][CH2:19][CH2:18][CH2:17][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: NCCCn1ccnc1
Product: O=[N+]([O-])c1ccc(NCCCn2ccnc2)c(F)c1
Temperature: 96 °C
Yield: 68.1 %

Procedure:
Starting with 31.8 g (0.2 mol) of 1,2-difluoro-4-nitrobenzene and 37.5 g (0.3 mol) of 3-imidazol-1-ylpropylamine, and after purification by recrystallization from refluxing 96° C. ethanol, 36.0 g of orange-yellow crystals melting at 144° C. (Kofler) were obtained, the elemental analysis of which, calculated for C12H13N4O2F, was:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:21][C:22]1[C:23](=[O:38])[O:24][CH:25]([CH2:35][CH2:36]O)[C:26]=1[O:27]CC1C=CC=CC=1)C1C=CC=CC=1>CCOCC>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([O:1][CH2:36][CH2:35][CH:25]2[O:24][C:23](=[O:38])[C:22]([OH:21])=[C:26]2[OH:27])=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Solvent: CCOCC
Product: O=C1OC(CCOc2ccc(-c3ccccc3)cc2)C(O)=C1O
Yield: 32 %

Procedure:
Mitsunoble coupling of 0.20 g (1.2 mmol) of 4-hydroxy-1,1'-biphenyl with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 100 mg (32% yield) of 5-[2-((1,1'-biphenyl)-4-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone as a white powder after trituration with ether and hexanes: 1H NMR (acetone-d6) δ 7.71-7.02 (m, 9H), 4.97 (dd, J=4.9, 8.7 Hz, 1H), 4.25 (dd, J=2.6, 4.7 Hz, 2H), 2.58-2.41 (m, 1H), 2.10-1.92 (m, 1H). Anal Calcd for C18H16O5 +1H2O: C, 67.49; H, 5.66. Found: C, 67.34; H, 5.42.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:40][CH:41]([F:43])[F:42])(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:40][CH:41]([F:43])[F:42])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(CC(F)F)C4)CC2)no1
Temperature: 70 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.130 mmol), cesium carbonate (84.9 mg, 0.261 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (41.8 mg, 0.195 mmol) in acetonitrile (1.3 ml) was heated at 70° C. for 20 h. After cooling to room temperature the reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with three 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (13 mg, 21%) as off-white solid. MS m/e: 448 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[CH:23]4)=[CH:18][C:17]=3[N+:27]([O-])=O)[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1.[H][H]>[Pd].C(O)C>[CH3:1][N:2]([CH3:30])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[CH:23]4)=[CH:18][C:17]=3[NH2:27])[CH:12]=[CH:13][CH:14]=2)=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: CN(C)c1ncc(-c2cccc(Nc3ccc(-n4cccc4)cc3[N+](=O)[O-])c2)cn1
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ncc(-c2cccc(Nc3ccc(-n4cccc4)cc3N)c2)cn1

Procedure:
To a suspension of 3f (0.2g, 0.5mmol) in abs. ethanol is added palladium catalyst (5% Pd on activated carbon) and the mixture is hydrogenated at ambient pressure until the hydrogen uptake has ceased. The mixture is filtered through celite and the filtrate is concentrated under reduced pressure. This crude product is used directly for the next step. See Example 11.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([B:15]([OH:17])O)[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH2:19]1[CH2:29][O:28][C:27]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=2[O:20]1>>[CH2:19]1[CH2:29][O:28][C:27]2[CH:26]=[CH:25][C:23]([NH:24][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([BH:15][OH:17])[CH:10]=4)[C:5]([F:18])=[CH:4][N:3]=3)=[CH:22][C:21]=2[O:20]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: OB(O)c1cccc(Nc2nc(Cl)ncc2F)c1
Product: OBc1cccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)c1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to produce N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxyborylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.46 (bs, 1H), 9.11 (bs, 1H), 8.05 (d, 1H, J=4.2 Hz), 7.95 (bs, 1H), 7.88 (s, 1H), 7.78 (d, 1H, J=7.5 Hz), 7.52 (d, 1H, J=7.5 Hz), 7.29 (t, 1H, J=7.5 Hz), 7.16 (s, 1H), 7.02 (d, 1H, J=8.7 Hz), 6.65 (d, 1H, J=8.7 Hz), 3.40 (s, 4H); LCMS: purity: 98%; MS (m/e): 383 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:14]=3[N:15]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([O:20][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=4)=[CH:16][C:14]=3[N:15]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(Nc2nc3cc(O)ccc3s2)c1
Reactant: CC(=O)Nc1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Oc2ccc3sc(Nc4cccc(C(C)C)c4)nc3c2)ccn1
Reaction time: 0.25 h

Procedure:
The mixture containing 2-(3-isopropylphenylamino)benzo[d]thiazol-5-ol (1 eq), N-(4-chloropyridin-2-yl)acetamide (1.4 eq), potassium bis(trimethylsilyl)amide (4 eq) and potassium carbonate (1.2 eq) in dimethylformamide was subjected to the microwave at 200° C. for 15 minutes. The reaction was then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to give the crude product. Purification on HPLC to yield N-[4-({2-[(3-isopropylphenyl)amino]-1,3-benzothiazol-5-yl}oxy)pyridin-2-yl]acetamide. HPLC=4.87 min; MS: MH+=419.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C@H:3]1[F:15].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([CH:34]=O)[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl.CCO>[F:15][C@H:3]1[CH:2]([NH:1][CH2:34][C:31]2[CH:32]=[CH:33][C:27]3[S:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=3[CH:30]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCCl
Product: O=C1CSc2ccc(CNC3CCNC[C@H]3F)cc2N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of cis-4-amino-1-tert-butoxycarbonyl-3-fluoropiperidine (5a) (340 mg, 1.60 mmole) in ClCH2CH2Cl (8 mL) and EtOH (0.8 mL) was treated with anhydrous Na2SO4 (450 mg) and 3-oxo-3,4-dihydro-2-benzo[1,4]thiazine-6-carboxaldehyde (1n) (330 mg, 1.80 mmole). The resulting solution was stirred at room temperature for 6 hr, then sodium triacetoxy borohydride (500 mg, 2.40 mmole) was added. The resulting slurry was stirred at room temperature for a further 10 hr, then was quenched by the addition of water (2 mL) and the volatiles were removed in vacuo. The residue was partitioned between EtOAc (2×50 mL) and brine (20 mL). The organic phases were combined, dried (MgSO4), and concentrated in vacuo. The residue was passed through a column of silica gel (100% ethyl acetate), the eluant was concentrated in vacuo and the residue was disolved in 10 mL of CH2Cl2 and treated with 1.25 mL of 4N HCl in dioxane for 2 h. The volitiles were removed in vacuo and the residue was dissolved in 10 mL of CH3OH. MP-carbonate resin (1.08 g) was added and stirred at rt for 1 h. The reaction was filtered to remove the resin and concentration under reduced pressure gave the desired compound as a white solid:
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][C:11]2[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=2)[O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:23])[C:20](=[NH:22])[NH2:21])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[S:27](Cl)Cl>CN(C=O)C>[NH2:22][C:20]1[C:19]([NH:18][CH2:17][CH2:16][CH2:15][O:14][C:13]2[CH:24]=[CH:25][CH:26]=[C:11]([CH2:10][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:12]=2)=[N:23][S:27][N:21]=1
Reactant: ClSCl
Reactant: N=C(N)C(=N)NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1nsnc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of N-[3-(3-piperidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride (854 mg; 2 mmoles) in 6 mL of DMF under N2 in an ice bath was added SCl2 (206 mg; 2 mmoles) in 2 mL of DMF. The reaction mixture was stirred at ambient temperature and the title compound was produced.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]#[N:11])=[CH:4][CH:3]=1.[CH2:12]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](O)=[O:24])[CH2:19][CH2:18]1)[CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:10]([C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]2)=[O:24])=[CH:7][CH:6]=1)#[N:11]
Reactant: N#CC#Cc1ccc(O)cc1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C#CC#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
A mixture of 143 mg of (p-hydroxyphenyl)propiolonitrile, 218 mg of trans-4-pentylcyclohexanecarboxylic acid, 227 mg of N,N'-dicyclohexylcarbodiimide and 12.2 mg of 4-(dimethylamino)pyridine in 15 ml of methylene chloride was stirred at room temperature for 105 minutes in a round flask under argon gasification. The yellow heterogeneous mixture was subsequently poured into 30 ml of water and extracted twice with 30 ml of methylene chloride each time. The organic phases were washed in sequence twice with 30 ml of water each time, twice with 30 ml of 5% acetic acid each time and twice with 30 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.4 bar) of the residue (383 mg) on silica gel with 3% ethyl acetate/petroleum ether gave 270 mg (84%) of trans-4-pentylcyclohexanecarboxylic acid p-(2-cyanoethynyl)phenyl ester as colourless crystals. A single crystallization from hexane yielded 219 mg of the ester as colourless platelets (purity 99.7%); m.p. (C-N) 76.8° C., cl.p. (N-I) 153.2° C.
Reaction SMILES: COC1C=CC(C2CC3C(=CC(OC)=CC=3)OC2(C)C)=C(N)C=1.Cl.[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.N1(CCOC2C=C[C:57]([CH2:58][NH:59][C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[CH:68]3[CH2:77][C:76]4[C:71](=[CH:72][C:73]([O:78][CH3:79])=[CH:74][CH:75]=4)[O:70][C:69]3([CH3:81])[CH3:80])=CC=2)CCCCCC1>>[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([CH2:39][N:59]([CH2:58][CH3:57])[C:60]3[CH:65]=[C:64]([O:66][CH3:67])[CH:63]=[CH:62][C:61]=3[CH:68]3[CH2:77][C:76]4[C:71](=[CH:72][C:73]([O:78][CH3:79])=[CH:74][CH:75]=4)[O:70][C:69]3([CH3:80])[CH3:81])=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc(C2Cc3ccc(OC)cc3OC2(C)C)c(NCc2ccc(OCCN3CCCCCC3)cc2)c1
Agent: COc1ccc(C2Cc3ccc(OC)cc3OC2(C)C)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1Cc2ccc(OC)cc2OC1(C)C

Procedure:
Synthesized from 5-methoxy-2-(7-methoxy-2,2-dimethylchroman-3-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][5-methoxy-2-(7-methoxy-2,2-dimethylchroman-3-yl)phenyl]amine (493 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[5-methoxy-2-(7-methoxy-2,2-dimethylchroman-3-yl)phenyl]amine (504 mg). This compound (502 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (380 mg).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH:4]=1)#[N:2].C(N1C=CN=C1)([N:25]1C=CN=C1)=O.N.O>O1CCCC1>[C:1]([C:3]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:5]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:25])=[O:20])=[CH:21][CH:22]=2)[CH:4]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1cn(-c2ccc(C(=O)O)cc2)cc1-c1ccccc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cn(-c2ccc(C(N)=O)cc2)cc1-c1ccccc1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of 4-(3-cyano-4-phenylpyrrole-1-yl)benzoic acid (0.14 g) in tetrahydrofuran (2 5 mL) was added 1,1′-carbonyldiimidazole (0.16 g). After stirring for 30 minutes, to this reaction mixture was added aqueous ammonia (28% solution 0.75 mL), and this mixture was stirred 2 hours. To this reaction mixture was added water (10 mL), the precipitated white solid was collected by filtration, and wash with methanol, dried to give the title compound (0.13 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:23][C:24]([C@H:26]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:27][C@@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](Cl)=[O:30])=[O:25])[CH3:22]>O>[CH2:21]([O:23][C:24]([C@H:26]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:27][C@@H:28]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:29]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:30])=[O:25])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)Cl
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3.3g of O-benzyl-(S)-serine and 1.8 g of sodium carbonate in 30 ml of water at 0° is added to 2.2 g of 4-ethoxycarbonyl-(S,S)-2,4-dibenzylbutyryl chloride and the mixture is stirred at room temperature for 4 hours. The mixture is extracted with ether, and the aqueous layer is acidified with 2N hydrochloric acid. The acidic solution is extracted with ethyl acetate, washed with saturated brine, dried (magnesium sulfate), filtered and concentrated to yield N-[4-ethoxycarbonyl-(S,S)-2,4-di-benzylbutyryl]-O-benzyl-(L)-serine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([Cl:11])[C:3]=1Br.O.CCOC(C)=O.C(Cl)Cl.[CH3:23][N:24](C=O)C>>[C:8]([C:5]1[C:4]([Cl:11])=[C:3]([C:23]#[N:24])[C:2]([NH2:1])=[CH:7][CH:6]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)c(Br)c1Cl
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(N)c(C#N)c1Cl
Reaction time: 0.25 h

Procedure:
A mixture of 4'-amino-3'-bromo-2'-chloroacetophenone (17 g, 58 mmol) and cuprous cyanide (5.2 g, 58 mmol) is warmed in DMF (85 mL) to 80°-100° C. for 6 hours, then poured into H2O (1.5 L), stirred for 15 minutes and filtered. The brown solid was washed with H2O (200 mL) and then boiled in EtOAc (500 mL) and filtered. This extraction is repeated. The EtOAc filtrate is washed twice with 20% NH4Cl (500 ml), twice with H2O (500 mL), dried with Na2SO4, and evaporated to give a brown solid. After flash column chromatography (SiO2, EtOAc-CH2Cl2, 1:20), the product is isolated as a yellow solid; yld. 5.5 g (48%); m.p. 189°-193° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[N:27]=3)[CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Reactant: FC(F)(F)c1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ccccc3c2=O)cnc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 60 mg (0.22 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one, 10 mg (0.26 mmol) of 60% sodium hydride, 62 mg (0.26 mmol) of 2-bromomethyl-6-trifluoromethyl-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 29 mg of a white solid: LC-MSD, m/z for C24H18F3N3O2 [M+H]+=438.1; HPLC retention time: 1.4 min.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][N:32]=2)=[CH:27][CH:26]=1>COC(C)(C)C>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([CH:37]=[CH:2][O:3][CH3:4])=[CH:33][N:32]=2)=[CH:29][CH:30]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-c2ccc(Br)cc2)nc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: COC=Cc1ccc(-c2ccc(Br)cc2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 29.0 g of methoxymethyl-triphenylphosphonium chloride in 200 ml of t-butyl methyl ether in a sulphonation flask fitted with a mechanical stirrer is treated while gassing with argon at -10° C. within 3 minutes with 9.7 g of potassium t-butylate. The orange suspension is stirred at about 0° C. for a further 1 hour, then treated dropwise at -10° C. within 10 minutes with a solution of 14.76 g of 2-(p-bromophenyl)-5-pyridinecarboxaldehyde in 90 ml of t-butyl methyl ether and stirred at 0° C. for a further 45 minutes. The reaction mixture is subsequently partitioned three times in diethyl ether/water. The organic extracts are washed twice with water, dried over magnesium sulphate, filtered and evaporated. In order to separate triphenylphosphine oxide, the residue is dissolved in ethyl acetate and the solution is diluted with petroleum ether, filtered and evaporated. Purification of the residue by chromatography on silica gel gives 2-(p-bromophenyl)-5-(2-methoxyvinyl)pyridine.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.[C:32]1([CH3:42])[CH:37]=[CH:36]C(S(Cl)(=O)=O)=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:21][S:22]([C:25]2[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=2)(=[O:24])=[O:23])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cn2c3c(c(OS(C)(=O)=O)c(F)cc3c1=O)CCN2C
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cn2c3c(c(OS(=O)(=O)c4ccc(C)cc4)c(F)cc3c1=O)CCN2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
304 mg of the compound (168) obtained in Example 45 was added to 2 ml of pyridine, and 260 mg of p-toluene-sulfonyl chloride was added to the solution. The solution was stirred for 2 hours at room temperature. 50 ml of chloroform was added to the solution, and the solution was washed with water and aqueous 5% citric acid solution. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with isopropyl ether to obtain 220 mg of the subject compound (169).