Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:37]=[C:36]3[C:31]([CH:32]=[CH:33][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:37]=[C:36]4[C:31]([CH:32]=[CH:33][C:34]([C:38]([O:40][CH3:41])=[O:39])=[CH:35]4)=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: COC(=O)c1ccc2ccc(-c3ccc(O)cc3)cc2c1
Reactant: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2ccc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2c1
Temperature: 80 °C
Yield: 64.2 %

Procedure:
A solution of [3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.050 g, 0.16 mmol), methyl 7-(4-hydroxyphenyl)-2-naphthalenecarboxylate (0.045 g, 0.16 mmol), triphenyl phosphine (0.042 g, 0.16 mmol) and diisopropyl azodicarboxylate (0.043 mL, 0.16 mmol) in dichloromethane (1.6 mL) was placed in microwave reaction tube and heated to 80° C. for 20 minutes. The solution was concentrated and the residue was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.059 g, 64%). 1H NMR (DMSO-d6): δ 8.68 (s, 1H), 8.40 (s, 1H), 8.07-7.93 (m, 4H), 7.80 (d, J=7 Hz, 2H), 7.42 (d, J=8 Hz, 2H), 7.28-7.24 (m, 1H), 7.14 (d, J=7 Hz, 2H), 4.99 (s, 2H), 3.91 (s, 3H), 3.32-3.20 (2 m, overlapping H2O, total 3H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 574 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:16][C:17]#[CH:18]>>[N:19]1([CH2:15][CH2:16][C:17]#[C:18][C:2]2[N:7]=[C:6]([CH2:8][N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Brc1cccc(CN2CCOCC2)n1
Reactant: C#CCCN1CCCCC1
Product: C(#Cc1cccc(CN2CCOCC2)n1)CCN1CCCCC1
Yield: 19 %

Procedure:
The title compound (19%) was prepared in a manner similar to that described in Example 18, Step D, using 4-(6-bromo-pyridin-2-ylmethyl)-morpholine (0.278 g, 1.08 mmol) and 1-but-3-ynyl-piperidine (0.297 g, 2.16 mmol). MS (ESI): exact mass calcd. for C19H27N3O, 313.45; m/z found, 314.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.52 (t, J=7.8, 1H), 7.32 (dd, J=8.0, 1.1, 1H), 7.20 (dd, J=7.1, 1.1, 1H), 3.65 (t, J=4.6, 4H), 3.58 (s, 2H), 2.65-2.55 (m, 4H), 2.46-2.37 (m, 8H), 1.57-1.49 (m, 4H), 1.41-1.34 (m, 2H).
Reaction SMILES: [NH3:1].C(O[C:5](=[N+:13]1[CH2:21][CH:20]2[CH:15]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:18][C:19]2=[O:22])[CH2:14]1)[CH2:6][C:7]1[CH2:12][CH:11]=[CH:10][CH2:9][CH:8]=1)C>C(O)C.ClCCl>[C:7]1([CH2:6][C:5]([N:13]2[CH2:21][CH:20]3[CH:15]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:17][CH2:18][C:19]3=[O:22])[CH2:14]2)=[NH:1])[CH2:12][CH:11]=[CH:10][CH2:9][CH:8]=1
Reactant: N
Reactant: CCOC(CC1=CCC=CC1)=[N+]1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Solvent: CCO
Solvent: ClCCl
Product: N=C(CC1=CCC=CC1)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Temperature: -15 °C
Reaction time: 20 h

Procedure:
A 5.4N solution (0.7 cc) of ammonia in ethanol is added to a stirred suspension of (3aRS,7aRS)-2-[1-ethoxy-2-(cyclohexa-1,4-dien-1-yl)-ethylidene]-4-oxo-7,7-diphenyl-perhydroisoindolium tetrafluoborate (2 g) in anhydrous dichloromethane (30 cc), which is cooled to -15° C. After the temperature has returned to ambient temperature, the reaction mixture is stirred for 20 hours and then washed with a 20% aqueous potassium carbonate solution (2×35 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (5 cc). The crystals obtained are drained, washed with acetonitrile and dried. (3aRS,7aRS)-2-[-2-(cyclohexa-1,4-dien-1-yl)-1-iminoethyl]-7,7-diphenyl-4-perhydroisoindolone (0.6 g) is obtained in the form of white crystals. m.p.=190° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:20])[F:19])=[N:7][O:8][C:9]=1[NH2:10])=[O:4].[OH-].[Na+]>CO>[NH2:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:20])([F:21])[F:19])[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccccc2OC(F)(F)F)noc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Yield: 70 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylate (6.0 g, 19.85 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (4.00 g, 13.89 mmol, 70%) was obtained.
Reaction SMILES: [CH:1]1([CH2:5][NH:6][C:7]([C:9]2[C:10]([C:16]([F:19])([F:18])[F:17])=[N:11][C:12](Cl)=[N:13][CH:14]=2)=[O:8])[CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=1[NH2:23]>O1CCOCC1.CS(C)=O>[CH:1]1([CH2:5][NH:6][C:7]([C:9]2[C:10]([C:16]([F:19])([F:18])[F:17])=[N:11][C:12]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[CH3:20])=[N:13][CH:14]=2)=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: Cc1cc(Cl)ccc1N
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1Nc1ncc(C(=O)NCC2CCC2)c(C(F)(F)F)n1
Temperature: 180 °C
Yield: 53 %

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid cyclobutylmethyl-amide (50 mg) in 1,4-dioxan (1.0 ml) was added 2-methyl-4-chloroaniline (120 mg) and the solution heated at 180° C. under microwave irrdiation for 30×2 minutes. The residue was dissolved in 1:1 DMSO:methanol (11.0 ml) and purified by Mass Directed Auto-Purification to afford the title compound (36 mg).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>>[C:1]1([C:7]2[CH2:8][O:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:27])=[CH:19][CH:18]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1
Product: CS(=O)(=O)NC(=O)C=Cc1ccc(C2=C(c3ccccc3)COc3ccccc32)cc1

Procedure:
Prepared from the coupling of 3d and methylsulfonamide by the method described in Procedure 1, Method A. Yield (35%); ESI m/z: 430 (M−H−, 100%).
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:30](=[O:32])N)[CH2:10][C@H:11]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:14]([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=[O:37])C>C(O)C.O>[C:19]([O:18][C:16]([N:15]1[C@H:11]([CH2:10][CH:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:30]([OH:37])=[O:32])[CH2:12][CH2:13][C@H:14]1[C:23]([OH:25])=[O:24])=[O:17])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CC(NCc2ccccc2)C(N)=O)N1C(=O)OC(C)(C)C
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](CC(NCc2ccccc2)C(=O)O)CC[C@H]1C(=O)O

Procedure:
2.2 g of di-tert-butyl (2S,5S)-5-(2-benzylamino-2-carbamoylethyl)pyrrolidine-1,2-dicarboxylate were dissolved in 20 ml of ethanol and 5 ml of water. 1.2 g of solid sodium hydroxide were added thereto. The solution was then boiled under reflux for 36 h. For workup, it was cooled to room temperature and neutralized with acetic acid, and the ethanol was removed in vacuo. The residue was diluted with 20 ml of water and adjusted to a pH of 3 with acetic acid. The mixture was extracted 3 times with 30 ml of 5:1 ethyl acetate/butanol each time. The organic phases were combined and concentrated in vacuo. The residue was chromatographed on silica gel.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[O:21]([CH2:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C(Cl)Cl>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:29](=[O:30])[CH2:28][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=C(Cl)COc1ccccc1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(COc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
In a two neck round bottom flask, 1-(naphthalene-2-yl-sulfonyl)piperazine hydrochloride (compound 4, 0.639 moles, 0.200 g) and 2-phenoxyacetylchloride (0.639 moles, 0.109 g) were charged in DCM (20 mL). TEA (2.557 moles, 0.258 g) was added slowly to the reaction flask. The resulting mixture was stirred for 3 h at room temperature. After completion of the reaction, water (10 mL) was added and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (Silica gel 60-120, 4:6, Ethyl acetate/Hexane) to obtain the title compound (0.200 g, 76.33%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=2)[N:22]=[C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:20]=1[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].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>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]>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[CH:8][CH:9]=2)[N:4]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=3)[N:22]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:20]=2[CH3:36])[CH2:3]1
Reactant: CC1(C)CNc2cc(-c3ccncc3)ccc21
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(-c3ccncc3)cc21

Procedure:
Prepared according to procedure T using 3,3-dimethyl-6-(pyridin-4-yl)indoline (0.026 g, 0.116 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.032 g, 0.116 mmol), cesium carbonate (0.076 g, 0.232 mmol), Pd2(dba)3 (0.011 g, 0.012 mmol) and (±) BINAP (0.011 g, 0.017 mmol) in toluene (3 mL). After purification by HPLC 4-(3,3-dimethyl-6-(4-pyridinyl)-2,3-dihydro-1H-indol-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained. 1H NMR (400 MHz, MeOH) δ ppm 8.75 (1H, d, J=4.7 Hz), 8.68 (2H, m), 8.12-8.23 (3H, m), 8.07 (1H, dd, J=9.4, 5.9 Hz), 7.96 (1H, d, J=7.8 Hz), 7.83 (1H, dd, J=9.8, 2.7 Hz), 7.65 (1H, dd, J=7.6, 4.9 Hz), 7.50 (2H, m), 7.42 (1H, m), 6.62 (1H, s), 4.05 (1H, d, J=9.0 Hz), 3.90 (1H, d, J=9.4 Hz), 2.28 (3H, s), 1.65 (3H, s), 1.57 (3H, s). Mass Spectrum (ESI) m/e=462 (M+1).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH:16]1[C:20]([Br:21])=[C:19]([Br:22])[NH:18][C:17]=1[C:23]([OH:25])=[O:24].[NH2:26][C@H:27]([C:35]([NH:37]N)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N[C@@H:40]([C:48]([NH:50][C@H:51]([C:56]([NH:58][C@H:59]([C:64]([NH2:66])=[O:65])[CH2:60][CH2:61][S:62][CH3:63])=[O:57])[CH2:52][CH:53]([CH3:55])[CH3:54])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH:16]1[C:20]([Br:21])=[C:19]([Br:22])[NH:18][C:17]=1[C:23]([OH:25])=[O:24].[NH2:26][C@H:27]([C:35]([NH:37][C@@H:40]([C:48]([NH:50][C@H:51]([C:56]([NH:58][C@H:59]([C:64]([NH2:66])=[O:65])[CH2:60][CH2:61][S:62][CH3:63])=[O:57])[CH2:52][CH:53]([CH3:54])[CH3:55])=[O:49])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NNC(=O)[C@@H](N)Cc1ccccc1
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1ccccc1)C(N)=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: O=C(O)c1cc(Br)c(Br)[nH]1
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1)C(N)=O
Yield: 51 %

Procedure:
Condensation of each of BocPro-LBpa-PheNHNH2 (1.20 g.) and BocPro-DBpa-PheNHNH2 (0.450 g.) with HDPhe-Leu-MetNH2 hydrochloride salt (Example 23, 1.02 g., 0.445 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-LBpa-Phe-DPhe-Leu-MetNH2 in 51% yield and BocPro-DBpa-Phe-DPhe-Leu-MetNH2 in 44% yield. De-t-butoxycarbonylation of BocPro-LBpa-Phe-DPhe-Leu-MetNH2 (0.500 g.) and BocPro-DBpa-Phe-DPhe-Leu-MetNH2 (0.250 g.) using hydrogen chloride in dioxane gave HPro-LBpa-Phe-DPhe-Leu-MetHN2, which was isolated as the amorphous white solid dihydrochloride salt hydrate (2:9) in 53% yield, and HPro-DBpa-Phe-DPhe-Leu-MetNH2, which was isolated as the dihydrochloride salt hexahydrate in 59% yield.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:20][C:21]([C:23]2[O:27][N:26]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=2)=O)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[CH:8][CH:9]=1)([O-])=O>C(O)(=O)C.[Fe]>[C:28]([C:25]1[CH:24]=[C:23]([C:21]2[NH:1][C:4]3[C:5]([N:20]=2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[CH:8][CH:9]=3)[O:27][N:26]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)ccc2[N+](=O)[O-])on1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2nc3nc(-c4ccccc4C(F)(F)F)ccc3[nH]2)on1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (78.0 mg, 0.180 mmol, prepared as described in the previous step) in acetic acid (5 mL) was treated with iron powder (50.1 mg, 0.898 mmol) and heated to 100° C. for 2 h. The volume of acetic acid was reduced to 2 mL by concentrating in vacuo, and saturated aqueous NaHCO3 (50 mL) was added. The resulting mixture was extracted twice with EtOAc (60 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 4-g SEPRA Si 50 SPE column (Isco system: Flow rate=10 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 5 min, then 1:99 to 1:9 v/v over 40 min) to yield 2-(3-tert-butyl-isoxazol-5-yl)-5-(2-trifluoromethyl-phenyl)-1H-imidazo[4,5-b]pyridine as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 10.06 (br. s., 1H), 8.16 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.52-7.60 (m, 2H), 7.46 (d, J=8.3 Hz, 1H), 7.07 (s, 1H), 1.42 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C20H17F3N4O: 387.1 (M+H). Measured: 387.1.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]1[C:20]([C:21](=[O:32])[C:22](=[CH:28]N(C)C)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][C:18]2[C:13](=[C:14]([F:35])[C:15]([F:34])=[C:16]([F:33])[CH:17]=2)[N:12]=1>ClC(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:11]2[N:12]=[C:13]3[C:14]([F:35])=[C:15]([F:34])[C:16]([F:33])=[CH:17][C:18]3=[CH:19][C:20]=2[C:21](=[O:32])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Reactant: Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
5.2 g of 2,4-difluoroaniline were added, at a temperature around 20° C., to a solution of 7.7 g of ethyl 3-(2-chloro-6,7,8-trifluoro-3-quinolyl)-2-dimethylaminomethylene-3-oxopropionate in 50 cm3 of trichloromethane and the reaction mixture was left stirring at this temperature for 8 hours. The trichloromethane was concentrated under reduced pressure (20 kPa) at a temperature around 40° C. 120 cm3 of ethanol and 4.5 cm3 of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to the mixture, which was heated at a temperature around 80° C. for approximately 1 hour. After cooling to a temperature around 10° C., the product was filtered off and washed 2 times with 50 cm3 of ethanol and 2 times with 50 cm3 of isopropyl ether. 5 g of ethyl 1-(2,4-difluorophenyl)-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow solid melting at about 304-306° C., which solid was used without additional purification in the subsequent stages.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10])(=[O:3])[CH3:2].CC(=CC)C.P([O-])([O-])(O)=[O:21].[Na+].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]([OH:21])=[O:10])(=[O:3])[CH3:2]
Reactant: O=P([O-])([O-])O
Reactant: CC(=O)OCOc1ccccc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)OCOc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
21.79 g (112.2 mmol) of 2-acetoxymethoxy-benzaldehyde and 100 ml (900 mmol) of 2-methyl-2-butene are diluted in 400 ml of tert-butanol. A solution containing 41 g (337 mmol) of sodium hydrogen phosphate and 35 g (393 mmol) of sodium chlorite in 100 ml of water is added dropwise to the reaction mixture, which is stirred for 2 hours at room temperature. The mixture is evaporated under reduced pressure and the residue is dissolved in dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated. The white solid obtained is precipitated in heptane at 0° C. The precipitate is filtered, then rinsed with heptane and dried. 14.8 g of 2-acetoxymethoxy-benzoic acid is obtained in the form of white powder at a yield of 63%.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C#N)cc3)ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(OCc3ccc(CN)cc3)ccc21

Procedure:
A suspension of 3 g (9.4 mmol) of 4-cyanobenzyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether in 60 ml of ether was added dropwise under nitrogen to a suspension of I g (26 mmol) of lithium aluminum hydride in 50 ml of dry ether at 25° C. The mixture was then stirred under reflux for 3 h, cooled and hydrolyzed cautiously with water and sodium sulfate solution. The mixture was extracted three times with ether, and the combined ether extracts were washed with water, dried over Na2SO4 and concentrated. 3 g of the title compound of melting point 77°-79° C. remained.
Reaction SMILES: C1(C2C=CC(C(Cl)=O)=C(OCC)C=2)CC1.BrC1C=CC(C(O)=O)=C(O)C=1.ICC.C1(B(O)O)CC1.[Cl-].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2([CH3:70])[C:48]([C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=3)([CH3:49])[NH:47][C:46]([C:57]3[CH:62]=[CH:61][C:60]([C:63](C)([CH3:65])[CH3:64])=[CH:59][C:58]=3[O:67][CH2:68][CH3:69])=[N:45]2)=[CH:40][CH:39]=1>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2([CH3:70])[C:48]([C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=3)([CH3:49])[NH:47][C:46]([C:57]3[CH:62]=[CH:61][C:60]([CH:63]4[CH2:65][CH2:64]4)=[CH:59][C:58]=3[O:67][CH2:68][CH3:69])=[N:45]2)=[CH:40][CH:39]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Agent: CCOc1cc(C2CC2)ccc1C(=O)Cl
Agent: O=C(O)c1ccc(Br)cc1O
Agent: OB(O)C1CC1
Solvent: CCI
Product: CCOc1cc(C2CC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1

Procedure:
rac-(4S*,5R*)-4,5-Bis-(4-chloro-phenyl)-2-(4-cyclopropyl-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was prepared from 4-cyclopropyl-2-ethoxy-benzoyl chloride (prepared from 4-bromo-2-hydroxy-benzoic acid by alkylation with iodoethane, Suzuki coupling with cyclopropyl boronic acid, then saponification and conversion to the chloride) and meso-2,3-bis-(4-chlorophenyl)-2,3-butanediamine (example 1) in an analogous manner as described in example 2 (method 1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[BrH:7].[CH3:8][N:9]1[CH2:15][CH2:14][C:13]2=[CH:16][C:17](=[O:21])[C:18](=[O:20])[CH:19]=[C:12]2[CH2:11][CH2:10]1>CO>[BrH:7].[OH:21][C:17]1[C:18]([OH:20])=[CH:19][C:12]2[CH2:11][CH2:10][N:9]([CH3:8])[CH2:15][CH2:14][C:13]=2[C:16]=1[S:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1ccco1
Reactant: CN1CCC2=CC(=O)C(=O)C=C2CC1
Agent: Br
Solvent: CO
Product: CN1CCc2cc(O)c(O)c(Sc3ccco3)c2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.1 g. (0.0011 mole) of 2-furanthiol in 200 ml. of methanol is added portionwise 2.3 g. (0.0084 mole) of 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione hydrobromide. After stirring for 1 hour at room temperature the reaction mixture is filtered and the filtrate concentrated in vacuo to give 7,8-dihydroxy-6-(2-furylthio)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: OCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(OCCCCCCCCO)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 62.5 %

Procedure:
20.0 g (150 mmol) of (4-hydroxyphenyl)acetonitrile and 29.5 g (179 mmol) of 8-chlorooctan-1-ol are dissolved in 400 mL of N,N-dimethylformamide. 41.5 g (300 mmol) of potassium carbonate and 5.0 g (30 mmol) of potassium iodide are added and the suspension is heated to 80° C. After 48 h, the excess of potassium carbonate is filtered off and the resulting filtrate is poured to icy water. The aqueous layer is extracted twice with ethyl acetate. Combined organic layers are washed with brine and evaporated to dryness. The crude is purified twice on column chromatography (SiO2, Heptane/ethyl acetate: 7/3) and dried overnight at 40° C. 24.5 g of {4-[(8-hydroxyoctyl)oxy]phenyl}acetonitrile are obtained as a yellow solid (62% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.