Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:30])(=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(C)nc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and purified by HPLC. 1H NMR (CDCl3) δ 9.66 (br s, 1H, NH), 8.34 (d, 1H, J=2.2 Hz), 7.75 (d, 1H, J=8.8 Hz), 7.72 (d, 1H, J=8.0 Hz, J=2.2 Hz), 7.56 (d, 2H, J=8.4 Hz), 7.51 (dd, 1H, J =8.8 Hz, J=2.2 Hz), 7.32 (d 1H, J=2.2 Hz), 7.26 (d, 1H, J=7 Hz), 7.09 (d, 2H, J=8.4 Hz), 3.65 (s, 3H), 2.97(t, 2H, J=7.6 Hz), 2.66 (s, 3H), 2.51 (t, 2H, J=7.6 Hz). MS: m/z 473 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:27])([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: CC(C)(N)c1ncco1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=370.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11]#[N:12])=[CH:5][NH:6]2.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:24]([O:23][C:13](=[O:22])[CH:14]=[C:15]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:11]#[N:12])=[CH:5][NH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: N#Cc1c[nH]c2cccc(Br)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of 4-bromo-1H-indole-3-carbonitrile LVII (2 g, 9.05 mmol), ethyl cinnamate (3.19 g, 18.1 mmol), tetrabutylammonium bromide (582 mg, 1.81 mmol), TEA (2.52 ml, 18.1 mmol) and palladium-dichloro-[bis-(tri-ortho-tolyl)phosphine] (357 mg, 0.453 mmol) in a sealed vial was stirred at 110° C. for 20 hours. The reaction mixture was cooled to room temperature, partitioned between H2O and DCM, and the aqueous layer was extracted with DCM. The organic extracts were combined, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII as a yellow solid (1.57 g, 55% yield).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH2:14]1[CH:18]2[CH2:19][NH:20][CH2:21][CH:17]2[CH2:16][N:15]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(O)(C)C>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:20]2[CH2:19][CH:18]3[CH2:14][N:15]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][CH:17]3[CH2:21]2)=[CH:7][CH:8]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC2C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-[(2S)-Oxiranylmethoxy]benzonitrile (4.36 g, 0.025 mol; prepared as described in International Patent Application WO 99/31100) and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (6.2 g, 0.025 mol; see Preparation A above) were mixed in isopropanol and stirred at 60° C. overnight. The solvent was evaporated and the product was purified by flash chromatography on silica, eluting with ethyl acetate, 10% MeOH. This gave 1.2 g (88%) of the sub-title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13](=[O:16])[NH:12][C:11]4([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[NH:10][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[C:22]1([CH2:28][C:29](O)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:22]1([CH2:28][C:29]([N:19]2[CH2:20][CH2:21][C:11]3([NH:10][C:9]4[CH:8]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:15][C:14]=4[C:13](=[O:16])[NH:12]3)[CH2:17][CH2:18]2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1NC2(CCNCC2)Nc2cc(-c3ccncc3)sc21
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC2(CCN(C(=O)Cc3ccccc3)CC2)Nc2cc(-c3ccncc3)sc21
Reaction time: 8 h
Yield: 21.2 %

Procedure:
To a stirred solution of 6′-(pyridin-4-yl)-1′H-spiro [piperidine-4,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (0.050 g, 0.17 mmol) in DMF (5 mL) were added phenylacetic acid (0.030 g, 0.22 mmol), N,N-diisopropylethylamine (0.12 mL, 0.68 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.050 g, 0.26 mmol) and hydroxybenzotriazole (0.035 g, 0.26 mmol). The mixture was allowed to stir overnight. Then, the reaction was poured into saturated NaHCO3 (75 mL) and the mixture was extracted with 3:1 tetrahydrofuran/ethyl acetate (3×75 mL). The combined organic layers were concentrated and the residue was diluted with water (5 mL) and sonicated for 1 min. Then, the solids were collected by filtration to give the title compound (0.0151 g, 21%) as a yellow solid:
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[C:8](=[O:9])[N:7]([CH:21]([CH3:23])[CH3:22])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CC(C)I
Reactant: CCC1Oc2cc(C(=O)OC)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1Oc2cc(C(=O)OC)ccc2N(C(C)C)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
To a solution of 2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (10.00 g) in dimethylformamide (200 ml) were added 60% sodium hydride (in oil) (1.87 g) and 2-iodopropane (7.80 g) and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 2-ethyl-7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (4.43 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:9])([O-])=O.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:19][C:18]3[CH:17]=[CH:16][C:6]([NH:7][C:8](=[O:9])[C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccncc1
Reactant: CN(C)c1ccc(C=O)cc1
Product: CN(C)c1ccc(-c2nc3cc(NC(=O)c4ccncc4)ccc3[nH]2)cc1

Procedure:
Compound 207 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(pyridin-4-oyl)aniline and 4-dimethylaminobenzaldehyde. 1H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.83 (d, J=6 Hz, 2H), 8.40 (s, 1H), 8.10 (d, J=9 Hz, 2H), 7.98 (d, J=6 Hz, 2H), 7.81 (dd, J=2, 9 Hz, 1H), 7.75 (d, J=9 Hz, 1H), 6.97 (d, J=9 Hz, 2H), 3.09 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]3=2)[C:5](=[O:25])[N:4]([C@@H:26]2[C@@H:31]([OH:32])[CH2:30][O:29][CH2:28][CH2:27]2)[CH2:3]1.Cl.Cl[CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([CH:42]([F:44])[F:43])[CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:43][CH:42]([F:44])[C:38]1[CH:37]=[C:36]([CH2:35][C:8]2[CH:7]=[C:6]3[C:11](=[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=24)[N:2]([CH3:1])[CH2:3][N:4]([C@@H:26]2[C@@H:31]([OH:32])[CH2:30][O:29][CH2:28][CH2:27]2)[C:5]3=[O:25])[CH:41]=[CH:40][N:39]=1
Reactant: FC(F)c1cc(CCl)ccn1
Reactant: CN1CN([C@H]2CCOC[C@@H]2O)C(=O)c2cc(B3OC(C)(C)C(C)(C)O3)c3ccccc3c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CN1CN([C@H]2CCOC[C@@H]2O)C(=O)c2cc(Cc3ccnc(C(F)F)c3)c3ccccc3c21
Temperature: 100 °C

Procedure:
A solution of 1,5-anhydro-2,3-dideoxy-3-[1-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydrobenzo[h]quinazolin-3(2H)-yl]-L-threo-pentitol (47 mg, 0.11 mmol), 4-(chloromethyl)-2-(difluoromethyl)pyridine hydrochloride (23 mg, 0.11 mmol), cesium carbonate (98 mg, 0.30 mmol), and PdCl2(dppf)-CH2Cl2 adduct (12 mg, 0.017 mmol) in THF (0.85 mL) and water (0.10 mL) was purged subsurface with nitrogen, then capped and heated at 100° C. overnight. The reaction was diluted with water and saturated, aqueous NaHCO3, then extracted 2× with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, concentrated, and dried. The residue was purified via silica gel chromatography, eluting with 20-100% ethyl acetate in hexanes to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 454.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=4.8 Hz, 1H), 8.28-8.31 (m, 1H), 7.92 (s, 1H), 7.76 (dd, J=7.6, 1.6 Hz, 1H), 7.52-7.61 (m, 2H), 7.47 (s, 1H), 7.12 (d, J=4.8 Hz, 1H), 6.58 (t, J=55.2 Hz, 1H), 4.70 (dd, J=32.8, 12.4 Hz, 2H), 4.62-4.69 (m, 1H), 4.40 (s, 2H), 4.17 (dd, J=10.8, 5.2 Hz, 1H), 4.06 (dd, J=7.6, 4.4 Hz, 1H), 3.73-3.82 (m, 1H), 3.51-3.58 (m, 1H), 3.25-3.30 (m, 1H), 3.02 (s, 3H), 2.62 (d, J=7.2 Hz, 1H), 1.86-2.04 (m, 2H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].I[CH2:10][CH2:11][CH2:12][CH3:13]>[Ag]=O.CCOCC>[CH2:10]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCI
Reactant: CCOC(=O)[C@H](C)O
Agent: O=[Ag]
Solvent: CCOCC
Product: CCCCO[C@@H](C)C(=O)OCC
Reaction time: 72 h
Yield: 44 %

Procedure:
Silver oxide (77.5 g, 0.3 mol) was added to a mixture of ethyl L-(+)-lactate (49.4 g, 0.4 mol) with 1-iodobutane (100 g, 0.5 mol) over 2 hours, followed by allowing the mixture to stand at room temperature for 3 days, adding ether (30 ml) to dilute it, filtering, distilling off ether, washing the residue with 2N-NaOH aqueous solution, drying it over anhydrous magnesium sulfate and distilling it to obtain ethyl (S)-2-butyloxypropionate (30.7 g) (b.p. 64° C./7 mmHg), adding to this product, 5N-NaOH aqueous solution (50 ml), agitating the mixture at room temperature for 5 hours, pouring it in 6N-HCl (75 ml), adding ether, agitating the mixture, washing the resulting organic layer with water and distilling off ether to obtain (S)-2-butyloxypropionic acid (21.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.[C:11]1(=[O:18])[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.BrC1C=CC=CC=1CCN1C(=O)CN(C)C1=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][N:16]1[C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: OCCc1ccccc1Br
Reactant: O=C1CCCC(=O)N1
Agent: CN1CC(=O)N(CCc2ccccc2Br)C1=O
Product: O=C1CCCC(=O)N1CCc1ccccc1Br

Procedure:
2-Bromophenethyl alcohol (402 mg, 2 mmol) and glutarimide (317 mg, 2.8 mmol) were treated as described in the preparation of compound 436. Purification was done by flash chromatography (petroleum ether/ethyl acetate 2:1) to provide the title compound as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].Br[C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:5][C:4]([F:7])([F:6])[C:3]([CH2:2][NH:1][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)([OH:21])[CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN)C(F)(F)F
Reactant: COc1ccc(-n2ncc3c(Br)cc(C)cc32)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)cc1
Temperature: 120 °C
Yield: 59.3 %

Procedure:
To a mixture of 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (Intermediate 18, 200 mg, 0.65 mmol) and 4-bromo-6-methyl-1-[4-(methyloxy)phenyl]-1H-indazole (Intermediate 15, 190 mg, 0.6 mmol) in toluene (3 mL) were added tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol), racemic-BINAP (37 mg, 0.06 mmol) and sodium tert-butoxide (85 mg, 0.84 mmol). The mixture was heated in a microwave at 120° C. for 30 min and then cooled and partitioned between ethyl acetate (60 mL) and 1M hydrochloric acid (60 mL). The organic layer was separated, washed sequentially with aqueous sodium bicarbonate (30 mL) and brine (30 mL), passed through a hydrophobic frit and evaporated under reduced pressure. The residue was dissolved in dichloromethane (1.5 mL) and loaded onto a silica SPE cartridge and eluted with a gradient of ethyl acetate:petroleum ether (1:9 to 1:4) to give the title compound (194 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:40]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1NCc1c(-c2ccc(OC(=O)c3ccccc3)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Reaction time: 0.5 h
Yield: 65 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 25.0 mg, 0.0581 mmol) was dissolved in methylene dichloride (0.5 mL), and then triethylamine (16.2 μL, 0.116 mmol) and benzoyl chloride (8.7 μL, 0.075 mmol) were added thereto successively under ice cooling. The reaction mixture was stirred under ice cooling for 30 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (13.0 mg) as a colorless amorphous product. (Yield 65%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-[3-(4-chlorophenyl)-ureido]-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (33%, off-white crystals). HPLC-MS m/z=396.1 (M+1), Rt: 4.40 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@@H:14]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@H:16]([CH2:17][C@H:18]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[C@@H:19]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C@H:24]([CH3:29])[CH2:25][CH2:26][CH2:27][OH:28])[CH2:15]1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.O>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][C@@H:14]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@H:16]([CH2:17][C@H:18]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[C@@H:19]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C@H:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[O:28])[CH2:15]1
Reactant: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@@H](OC4CCCCO4)C[C@@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](OC4CCCCO4)C[C@@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
To a solution of oxalyl chloride (8.17 g; 64.35 mmoles) in methylene chloride (140 ml) kept at -70° C. under magnetic stirring and nitrogen atmosphere, dimethylsulfoxide (11.00 g; 141.15 mmoles) diluted in methylene chloride (10 ml) was added in about 10 min. The reaction mixture was left to stand for 10 min., then a solution of compound (3) (29.60 g; 54.15 mmoles) in methylene chloride (20 ml) and dimethylsulfoxide (20 ml) was dropped therein in about 20 min. 15 Min. after, triethylamine (29.73 g; 294.4 mmoles) was added and the resulting mixture was kept under stirring for 10 min. The reaction mixture was warmed to r.t., diluted with water (200 ml), the organic phase was separated and the aqueous one was extracted with methylene chloride (3×50 ml). The combined organic phases were washed with saturated water (1×50 ml), dried over sodium sulfate and concentrated under vacuum. The residue (31.50 g) was subjected to flash chromatography on SiO2 (φ 5.5 cm, h=25 cm): eluting with 4/6 ethyl ether/petroleum ether, 25.6 g of compound (4) were obtained, (87%); max (CHCl3): 1725 cm-1 (C=O); 1H-NMR (CDCl3)δ 0,7 (s, 3H, 18-CH3); 0,9-0,95 (m, 6H, 19-CH3, 21-CH3); 3,1-4,1 (m, 6H, 3-CH-, 7-CH- e 2x-OCH2 -); 4,35-4,7 (m, 2H, 2x-O-CH-O-); 9,6 (s, 1H, --CHO).
Reaction SMILES: O[C:2]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2[C:12]3=[C:17]4[C:5]([CH2:6][CH2:7][C:8]4=[CH:9][CH:10]=[CH:11]3)=[CH:4][C:3]1=2.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:18][C:2]1[C:3]2[CH:4]=[C:5]3[C:17]4[C:8](=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]=2[CH2:14][CH2:15][CH:16]=1)[CH2:7][CH2:6]3
Reactant: CC1(O)CCCc2c1cc1c3c(cccc23)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1=CCCc2c1cc1c3c(cccc23)CC1
Yield: 92.2 %

Procedure:
A solution of 7-hydroxy-7-methyl-7,8,9,10-tetrahydroacephenanthrene (0.15 g, 0.64 mmol) and camphorsulfonic acid (0.02 g, 0.064 mmol) in toluene (20 mL) was heated at reflux for 1 h. The reaction was allowed to cool and was diluted with ethyl acetate (20 mL). The organic solution was washed with saturated aqueous sodium carbonate solution (3×15 mL) and water (3×15 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The reaction product was purified by flash chromatography to give 0.13 g (92%) of the product: MS (CI) m/e (%) 221 (M+H+, 100); 1H NMR (CDCl3, 300 MHz) δ 7.69 (d, 1H, J=8.4 Hz), 7.44 (dd, 1H, J=7.0, 8.4 Hz), 7.32 (s, 1H), 7.21 (d, 1H, J=6.9 Hz), 5.94 (m, 1H), 3.38 (s, 4H), 3.09 (t, 2H, J=8.5 Hz), 2.52 (m, 2H), 2.16 (m, 3H).
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[NH:14])[NH2:13])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])(=O)=O.CS(O)(=O)=O.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[NH:14])[NH2:13])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1[N+](=O)[O-]
Agent: CS(=O)(=O)O
Product: CC(=O)Oc1ccc(C(=N)N)cc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
To a suspension of 3.0 g of 4-amidino-2-nitrophenol methanesulfonate in 15 ml of acetic anhydride, was added 0.5 ml of methanesulfonic acid. The mixture was refluxed with stirring for 10 to 20 minutes. The crystals dissolved slowly, forming a clear yellow solution. Upon standing at room temperature, colorless crystals separated out of the solution. The crystals were ashed with ethyl ether and recrystallized from ethanol to obtain 3.0 g of colorless needle crystals of 4-amidino-2-nitrophenyl acetate methanesulfonate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[CH:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: Ic1ccccc1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
Iodobenzene (135 μl, 1.2 mmols), 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (209 mg, 1 mmols) and triethylamine (167 μl, 1.2 mmols) were dissolved in acetonitrile (6 ml). Dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmols) and Cul (10 mg, 0.05 mmols) were added, and reaction mixture was stirred at room temperature overnight and continued to stir at 50 C. for two more hours before partitioning between ethyl acetate and water. Organic layer was isolated, washed with 1 N HCl, brine and dried (MgSO4). Solvents were removed and residue was purified by column chromatography on silica gel using solutions of ethyl acetate in hexanes (1:4; 1:2) to yield the title compound (74 mg). LCMS m/e (230, M−t-Bu+2H)
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8](Cl)[CH:7]=1)([CH3:3])[CH3:2].[Br-].[CH2:16]([CH:18]([Zn+])[CH2:19][CH3:20])[CH3:17].C1COCC1>O1CCOCC1>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([CH:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CCC([Zn+])CC
Reactant: Cc1cc(C(=O)OC(C)C)cc(Cl)n1
Agent: [Br-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C(=O)OC(C)C)cc(C)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 2-chloro-6-methyl-isonicotinic acid isopropyl ester (2.0 g, 9.36 mmol) in dioxane (75 mL) is degassed and put under argon before Pd(dppf) (229 mg, 0.281 mmol) is added. At rt, a 0.5 M solution of 1-ethyl-propylzinc bromide in THF (46.8 mL, 23.4 mmol) is added dropwise to the mixture. The mixture is stirred at 80° C. for 16 h before the reaction is quenched by adding ice-cold water (200 mL). A precipitate forms and the mixture is diluted with EA (200 mL) and filtered through celite. The filtrate is transferred into a separatory funnel. The org. phase is collected and the aq. phase is extracted with EA (120 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to 4:1 to give 2-(1-ethyl-propyl)-6-methyl-isonicotinic acid isopropyl ester (1.6 g) as a yellow oil; LC-MS: tR=0.79 min, [M+1]+=250.14; 1H NMR (D6-DMSO): δ 0.70 (t, J=7.3 Hz, 6 H), 1.33 (d, J=6.3 Hz, 6 H), 1.58-1.70 (m, 4 H), 2.51 (s, 3 H), 2.55-2.63 (m, 1 H), 5.15 (hept, J=5.8 Hz), 7.39 (s, 1 H), 7.49 (s, 1 H).