Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[O:33][C:34]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])=[CH:35][N:36]=1)[CH3:31].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>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:34]6[O:33][C:32]([CH2:30][CH3:31])=[N:36][CH:35]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:22])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCc1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cnc(CC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (167 mg; compound C10), 1-[(2-ethyl-1,3-oxazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B34), HBTU (175 mg), DIPEA (0.29 ml) and DCM (3 ml). Purification by flash column chromatography [amino phase silica gel, eluent: EtOAc/methanol, 97.5/2.5 (v/v)] and afterwards by preparative HPLC gives the title compound as a solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[I:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: O=C1Cc2cc(I)ccc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(I)cc21
Yield: 77.2 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 130 mg 5-iodo-2-oxindole, and 75 L piperidine in 2 mL ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 162 mg (77%) of the title compound as a brown solid.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].[F:19][C:20]([F:39])([F:38])[C:21]1[CH:22]=[C:23]([C:31]2[O:35][N:34]=[C:33]([CH2:36]Cl)[N:32]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>CCOC(C)=O>[F:39][C:20]([F:19])([F:38])[C:21]1[CH:22]=[C:23]([C:31]2[O:35][N:34]=[C:33]([CH2:36][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[N:32]=2)[CH:24]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:26]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
A mixture of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.040 g, 0.16 mmol), 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole (0.058 g, 0.17 mmol), Cs2CO3 (0.057 g, 0.17 mmol) and CH3CN (4 mL) was stirred at 75° C. for 1.5 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), and brine (15 mL). The organic portion was dried (MgSO4), filtered, and concentrated. The concentrated material was treated with 10% Et2O in hexanes (10 mL) and stirred for 2 h. The resulting solid was filtered, rinsed with hexanes, and dried to afford the title compound (0.070 g, 81%) as a light tan solid: 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 8.50 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.59 (s, 1H), 5.90 (s, 2H), 2.90 (t, J=7.5 Hz, 2H), 1.79-1.70 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS m/z 547 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([O:16][CH3:15])[CH:18]=1
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2c(C#N)cnc3ccc(I)cc23)c1

Procedure:
Prepared from 1.00 g of 4-chloro-6-iodoquinoline-3-carbonitrile and 0.469 g of 3-methoxyaniline in the same manner as EXAMPLE 377. The crude product was filtered through silica gel with 20% EtOAc in CH2Cl2, evaporated and dried in vacuo (50° C.). The yield of 6-iodo-4-(3-methoxyphenylamino)quinoline-3-carbonitrile was 1.09 g as yellow crystals: mass spectrum (electrospray, m/e): M+H 401.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH2:16].C1(C)C=CC=CC=1>C(O)C>[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH:16][C:11]([NH:10][C:8](=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[S:12]
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 52%).
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH:3]([CH2:7][C:8](Cl)=[O:9])[C:4](Cl)=[O:5].[Br:13][C:14]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:16]([C:17]([O:19]C(C)(C)C)=O)[C:15]=1[OH:28].[H-].[Na+]>O1CCCC1.FC(F)(F)C(O)=O>[Br:13][C:14]1[CH:26]=[C:25]([Br:27])[CH:24]=[C:16]([CH2:17][O:19][C:1](=[O:11])[CH2:2][CH:3]([CH2:7][C:8]([O:19][CH2:17][C:16]2[C:15](=[C:14]([Br:13])[CH:26]=[C:25]([Br:27])[CH:24]=2)[OH:28])=[O:9])[C:4]([O:19][CH2:17][C:16]2[C:15](=[C:14]([Br:13])[CH:26]=[C:25]([Br:27])[CH:24]=2)[OH:28])=[O:5])[C:15]=1[OH:28]
Reactant: O=C(Cl)CC(CC(=O)Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(CC(CC(=O)OCc1cc(Br)cc(Br)c1O)C(=O)OCc1cc(Br)cc(Br)c1O)OCc1cc(Br)cc(Br)c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Tricarballylic trichloride (0.01 mol) (see Emery, Ber., 22:2921 (1989)) in dry tetrahydrofuran (THF) (10 ml) was added dropwise to three equivalents of tert-butyl 3,5-dibromosalicylate (see Delaney et al, Arch. Biochem. Biophys., 28:627 (1984)) previously been treated with a stoichiometric amount of NaH in THF. The mixture was stirred for 5 hours at room temperature, and the solvent was then removed under reduced pressure. The residue was dissolved in diethyl ether and extracted several times with water. The extract was dried over MgSO4, filtered and concentrated. Recrystallization from ethanol gave a pure product; m.p. 100-102° C. The resulting product (2 mmol) was dissolved in anhydrous trifluoroacetic acid (10 ml) and allowed to stand at room temperature. After 30 minutes, the solvent was removed under reduced pressure and the precipitate recrystallized from trifluoroacetic acid; m.p. 186° C. (see Razynska et al, supra).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:27][C:26]4[CH2:28][CH2:29][CH2:30][CH2:31][C:25]=4[N:24]=3)[CH2:18]2)[N:3]=1.[NH2:32][NH2:33]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]3[C:11]([C:12]([NH2:13])=[N:32][NH:33]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][C:25]4[CH2:31][CH2:30][CH2:29][CH2:28][C:26]=4[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc5c([nH]4)CCCC5)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc4c([nH]3)CCCC4)C2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 129.5 %

Procedure:
A mixture of 4-{2-amino-6-[2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (150 mg, 0.358 mmol) and hydrazine (1.13 mL, 35.8 mmol) in ethanol (4 mL) was heated at 120° C. under microwave conditions with stirring for 1 hour. The solvent was evaporated to get 200 mg of residue, which was purified by preparative HPLC to afford the title compound (42 mg) as a yellow powder. LC-MS (ES) m/z=432 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.71 (s, 4H), 2.42 (s, 2H), 3.12-2.99 (m, 2H), 3.66 (dt, J=11.6 Hz, 2.4 Hz, 1H), 4.00 (dd, J=11.6 Hz, 2.0 Hz, 1H), 4.33-4.30 (m, 1H), 4.44 (dd, J=10.8 Hz, 2.4 Hz, 1H), 4.62 (bs, 1H), 5.28 (s, 2H), 6.18 (s, 2H), 6.66 (s, 1H), 7.61 (dd, J=8.4 Hz, 0.8 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 11.51 (s, 1H), 11.68 (s, 1H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.[OH:11][CH2:12][CH2:13][O:14][C:15]1[C:20]2[N:21]=[C:22]([NH2:24])[O:23][C:19]=2[CH:18]=[CH:17][CH:16]=1>>[Cl:10][C:9]1[C:4]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]3[N:21]=[C:22]([NH2:24])[O:23][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: Clc1nccnc1Cl
Reactant: Nc1nc2c(OCCO)cccc2o1
Agent: [H-]
Agent: [Na+]
Product: Nc1nc2c(OCCOc3nccnc3Cl)cccc2o1

Procedure:
The title compound was prepared according to the procedure of Example 4, Step 1, except that 4 equiv of both NaH and 2,3-dichloropyrazine were used, starting from the product of Step 1 The reaction temperature was 90° C. The crude product was used directly in the next step.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:17])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:4]1.[OH:24]S(O)(=O)=O>>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:17])=[O:24])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:4]1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Product: NC(=O)c1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Temperature: 70 °C
Yield: 78 %

Procedure:
Solid 126 (500 mg, 1.48 mmol), was added to 90% H2SO4 (5 μL) and heated to 70° C. for 1 h. After cooling to room temperature, the mixture was poured into ice-water and extracted with EtOAc (3×50 mL). The extracts were dried and concentrated under reduced pressure. Chromatography of the residue on silica gel (EtOAc/petroleum ether, from 1:1 to 1:0) gave 1-(chloromethyl)-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-carboxamide (128) (410 mg, 78%) as a white solid: mp (EtOAc/petroleum ether) 190-193° C.; 1H NMR (CDCl3) δ 8.54-8.45 (m, 2H), 7.89 (d, J=5.8 Hz, 1H), 7.69 (dd, J=7.1, 1.1 Hz, 1H), 7.59 (dd, J=8.4, 7.1 Hz, 1H), 5.91 (br, 2H), 4.69-4.61 (m, 1H), 4.48-4.40 (m, 1H), 4.25-4.17 (m, 1H), 3.97-3.89 (m, 1H), 3.58-3.50 (m, 1H; 13C NMR δ 170.7, 153.8 (q, JC-F 38.0 Hz), 140.5, 134.6, 129.7, 128.6, 126.5, 125.6, 125.4, 124.8, 118.4, 115.4 (q, JC-F 288 Hz), 53.4, 45.4, 43.0. Anal. (C16H12ClF3N2O2) C, H, N, Cl.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.Cl.[CH:41]12[NH:47][CH:44]([CH2:45][CH2:46]1)[CH2:43][CH2:42]2>>[CH:44]12[N:47]([CH2:1][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]4[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=4[C@@H:21]4[CH2:30][CH2:29][C:28]5[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=5[CH2:22]4)=[CH:38][CH:39]=3)[CH:41]([CH2:46][CH2:45]1)[CH2:42][CH2:43]2
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: C1CC2CCC1N2
Agent: Cl
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN3C4CCC3CC4)cc2)c1
Yield: 6 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 7-azabicyclo[2.2.1]heptane hydrochloride (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (1.1 mg) was obtained.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:13]([NH:31][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCCCCCCCN
Product: CCCCCCCCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
In the first process step, glucose (a) is reacted with octadecylamine (b) to give N-octadecyl-β-D-glucopyranosylamine (c) which, in the second process step is acylated with oleyl chloride to give N-octadecyl-N-oleyl-β-D-glucopyranosylamine (I).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.C([O-])(O)=O.[Na+].[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32](Cl)=[O:33])=[CH:26][CH:25]=1>O.C(OCC)(=O)C>[NH:1]([C:32]([O:31][CH2:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1)=[O:33])[C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Tyr(3-tBu)-OMe (1.1 g) in H2O (10 ml), 0.7 g (6.57 mmol) of NaHCO3 and 0.92 ml (6.57 mmol) of Z-Cl were added under cooling with ice and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=1:2) to give Z-Tyr(3-t-Bu)-OMe in the amount of 1.44 g (85%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1
Yield: 73.6 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (200 mg) and 4-piperidinecarboxylic acid, ethyl ester (280 mg). Purification (SiO2, ethyl acetate:isohexane 25:75 as eluant) gave the sub-title compound as an oil (200 mg).
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:49]([OH:51])=[O:50])[CH2:20][CH2:21][C:22](=[O:48])[NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([P:40]([CH2:45][CH:46]=[CH2:47])([CH2:42][CH:43]=[CH2:44])=[O:41])[P:32]([CH2:37][CH:38]=[CH2:39])([CH2:34][CH:35]=[CH2:36])=[O:33])=[CH:26][CH:25]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[CH2:37]([P:32]([CH:31]([P:40]([CH2:42][CH:43]=[CH2:44])([CH2:45][CH:46]=[CH2:47])=[O:41])[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:22](=[O:48])[CH2:21][CH2:20][C@@H:19]([C:49]([OH:51])=[O:50])[NH2:18])=[CH:25][CH:26]=1)([CH2:34][CH:35]=[CH2:36])=[O:33])[CH:38]=[CH2:39]
Reactant: C=CCP(=O)(CC=C)C(Cc1ccc(NC(=O)CC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1)P(=O)(CC=C)CC=C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C=CCP(=O)(CC=C)C(Cc1ccc(NC(=O)CC[C@H](N)C(=O)O)cc1)P(=O)(CC=C)CC=C
Reaction time: 2.5 h

Procedure:
Fmoc-protected compound 105 (431 mg, 0.51 mmol) was treated with a 5% v/v solution of piperidine in DMF (2.5 mL). After stirring for 2.5 h, the reaction mixture was concentrated to dryness and purified by silica gel chromatography on a Biotage™ flash chromatography system using a gradient of 0-10% methanol in CH2Cl2. Compound 106 was obtained as a colorless oil (246 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.82-1.91 (m, 1H), 2.16-2.24 (m, 1H), 2.45-2.60 (m, 2H), 2.71 (tt, J=23.9, 6.2 Hz, 1H), 3.24 (dt, J=16.6, 6.2 Hz, 2H), 4.42 (dd, J=8.8, 4.5 Hz, 1H), 4.47-4.61 (m, 8H), 5.19-5.22 (m, 4H), 5.29-5.35 (m, 4H), 5.83-5.94 (m, 4H), 7.21 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 8.57 (bs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=[NH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([N:35]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N=C(c3ccccc3)c3ccccc3)c(F)c2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.57 g) and benzophenone imine (1.15 ml) in toluene (40 ml) was added sodium tert-butoxide (691 mg). The reaction mixture was purged with argon for 10 min. (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (280 mg) and tris(dibenzylideneacetone)dipalladium(0) (120 mg) were added and the reaction mixture was heated to 100° C. and stirred for 1 h. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 30% EtOAc in hexanes) to afford (RS)-2-[4-(benzhydrylidene-amino)-3-fluoro-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (2.215 g, quant.) as a yellow viscous oil. MS (ISP): 461.3 ([M+H]+), 405.4 ([M+H—C4H8]+), 361.3 ([M+H—C4H8—CO2]+).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[N:12](OCCCC)=[O:13]>COCCO>[N:12](=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[OH:13]
Reactant: O=C1CCc2ccccc21
Reactant: CCCCON=O
Agent: Cl
Solvent: COCCO
Product: O=C1C(=NO)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 134.5 %

Procedure:
1-Indanone (100 g, 0.757 mol) was dissolved in 2-methoxyethanol (600 mL) in a 2 L round bottom flask equipped with a overhead mechanical stirrer. The mixture was cooled over an ice bath, and concentrated aqueous HCl (200 mL) was added. Butyl nitrite (50 mL, 0.428 mol) was added, and after 1 minute when precipitate began to form, more butyl nitrite (50 mL, 0.428 mol) was added. The mixture was stirred for 15 min. more and then poured into ice water (8 L). The solid was filtered on a sintered funnel and rinsed with 8 L water. The solid was dissolved in 2.5 L hot methanol, seeded with pure oxime, then allowed to cool to room temperature then over an ice bath. The yellow crystals were collected on a sintered funnel, rinsed with cold methanol, then dried overnight under vacuum to yield 2-oximino-1-indanone (92.8 g, 76% yield). The finely ground oxime (80 g, 0.496 mol) was suspended in 35% formaldehyde solution (160 mL) and concentrated HCl (320 mL) in a 2 L round bottom flask equipped with an overhead mechanical stirrer. The temperature was maintained initially at 15° C. with an ice bath, then the bath was removed and the reaction mixture was stirred vigorously for 30 min. The mixture was poured onto 2 L ice, the solid filtered and then rinsed with water. The yellow powder was dried in a vacuum oven to yield 55.0 g product, which was recrystallized from ether (5 L, 3 crops) to afford after oven drying pure diketone (37.3 g, 51% yield). The aqueous mother liquor yielded crystals of the oxime (9.5 g, 12% recovered starting material).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(OC)cc2)c1C(=O)OC
Yield: 116.4 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.1 g, 5.2 mmol) in acetone (45 mL) and potassium carbonate (2.2 g, 15.7 mmol), was added 1-bromomethyl-4-methoxy-benzene (0.79 mL, 5.5 mmol). The mixture was refluxed for six hours. The solvent was evaporated in vacuo, and the residue was partitioned between water (50 mL) and ethyl acetate (80 mL). The organic layer was washed with water (2×50 mL), dried, concentrated in vacuo, and purified by flash column chromatography (Silica Gel. EtOAc/Hexane, 0% gradient to 100% 30 min) to give 3-(4-methoxy-benzyloxy)-phthalic acid dimethyl ester (2.0 g, 115% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)=[CH:4][CH:3]=1.[S:16]1[CH2:22][C:20](=[O:21])[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:17]1=[S:18].[Cl-].[NH4+].N>C(O)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[S:8][CH:9]=[C:10]([CH:12]=[C:22]3[S:16][C:17](=[S:18])[N:19]([CH2:23][C:24]([OH:26])=[O:25])[C:20]3=[O:21])[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(Nc2ccc(F)cc2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(Nc3ccc(F)cc3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 1 g of 2-(p-fluoroanilino)thiazole-4-carbaldehyde, 0.85 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia, and 10 ml of ethanol, giving the title compound as an orange powder.