Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19].C1C=CC=CC=1>O>[CH2:16]([N:20]=[C:1]=[C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH2:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: CCOC(=O)COc1ccc(C=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCN=C=C1C=CC(OCC(=O)OCC)=CC1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Ethyl (4-formylphenoxy)acetate (104.1 g, 0.5 mole), butylamine (36.6 g, 0.5 mole) and benzene (400 ml) were united and refluxed in a flask equipped with a Dean-Stark water separator. After one hour, water ceased to separate. The heating was terminated after 6 hours and the mixture distilled. There was obtained 108.6 g of product boiling at 178°-181° C. at 0.5 mm Hg pressure.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([NH2:16])=[O:15])[N:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH:22]=[N:16][C:14]([C:3]1[N:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:15])[CH3:21]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cc2c(cn1)[nH]c1ccccc12
Product: CN(C)C=NC(=O)c1cc2c(cn1)[nH]c1ccccc12
Temperature: 115 °C

Procedure:
A mixture of 1.0 g of beta-carboline-3-carboxamide and 3 ml of dimethyl-formamide-dimethylacetal is heated for 3 h at about 115° C. in an oil bath. After cooling, the crystals are collected on a glass frit and washed with 1 ml of dimethylformamide and then with 20 ml of ether. 1.2 g of N-[(dimethylamino)methylene]-beta-carboline-3-carboxamide with a m.p. of 307°-317° C. is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[C:11]2=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:12]2[CH2:13][CH2:14][CH2:15][N:10]([CH2:9][C:8]3[CH:27]=[CH:28][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)[C:11]2=[O:26])=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(CN2CCCN(Cc3ccc([N+](=O)[O-])cc3)C2=O)cc1
Solvent: CO
Product: CC(C)(C)c1ccc(CN2CCCN(Cc3ccc(N)cc3)C2=O)cc1

Procedure:
To a solution of 1-(4-tert-butylbenzyl)-3-(4-nitrobenzyl)tetrahydropyrimidin-2-one (K) (500 mg, 1.31 mmol) in abs. MeOH (50 mL) palladium on charcoal (5%, 600 mg) was added. The reaction mixture was subjected to a hydrogen pressure of 2 bar for 20 min at RT. The catalyst was separated by filtration through Celite and the filtrate was concentrated in vacuo. The desired product 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-tetrahydropyrimidin-2-one (L) was obtained as a colorless oil (364 mg, 79% of theory).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:34])[CH:15]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:14]2[C:21]([CH3:33])=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:23]([CH3:26])=[C:24]([CH3:25])[C:13]=2[O:12]1.[ClH:35]>C(OCC)(=O)C>[ClH:7].[ClH:35].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:30]2[CH2:31][CH2:32][N:27]([C:22]3[C:23]([CH3:26])=[C:24]([CH3:25])[C:13]4[O:12][C:11]([CH3:34])([CH3:10])[CH:15]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[C:14]=4[C:21]=3[CH3:33])[CH2:28][CH2:29]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C)c(N2CCN(Cc3ccc(F)cc3)CC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Yield: 25 %

Procedure:
Using 4-fluorobenzyl chloride and (2,2,4,6,7-pentamethyl-3-pyrrolidinyl-2,3-dihydro-1-benzofuran-5-yl)piperazine obtained in Example 134, the free base was obtained in the same manner as in Example 2. The free base was treated with 4N hydrogenchloride in ethyl acetate (10 mL) to obtain the title compound. Yield 25% mp. 227–232° C. (decomposition) (ethanol-ethyl acetate).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][N:9]=1)=[O:7].Cl.[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN1CCCC1=O>[ClH:1].[Cl:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([N:26]3[CH2:27][CH2:28][CH:29]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]4[C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[S:10][N:9]=4)=[O:7])[CH2:30][CH2:31]3)=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: Clc1ccc2c(N3CCCCC3)noc2c1
Reactant: O=C(NCCCCl)c1nsc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN1CCCC1=O
Product: O=C(NCCCC1CCN(c2noc3cc(Cl)ccc23)CC1)c1nsc2ccccc12
Temperature: 180 °C
Reaction time: 36 h
Yield: 29.8 %

Procedure:
A mixture of N-(3-chloropropyl)-1,2-benzisothiazole-3-carboxamide (5.0 g), 1-(6-chloro-1,2-benzisoxazol-3-yl)piperidine hydrochloride (5.40 g), potassium carbonate (5.40 g), and sodium iodide (100 mg) in dry N-methylpyrrolidinone (100 ml), was heated to 180° C., with stirring, under nitrogen. After 36 hr, the reaction mixture was allowed to cool to room temperature and partitioned between ethyl acetate/water. The organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated in vacuo. The residue was chromatographed on silica using ethyl acetate as the eluent. The appropriate fractions were collected and concentrated. The filtrate was treated with hydrogen chloride in ether. The salt was recrystallized from methanol/dichloromethane/ether to provide 2.87 g (29.4%) of product, mp 221°-223° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:8]=1[C:9](OCC)=[O:10]>>[CH2:1]([NH:5][C:9](=[O:10])[C:8]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[N:17][C:7]=1[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C
Reactant: CCCCN
Product: CCCCNC(=O)c1cc([N+](=O)[O-])cnc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To n-butylamine (5 ml.) was added ethyl 2-methyl-5-nitronicotinate (1 g.) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by a silica gel dry column chromatography to give 0.9 g. of the desired pale orange crystals. mp 98° - 99° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: COc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ncccc1N
Yield: 91.5 %

Procedure:
10% palladium-activated carbon (2.5 g) was added to a solution of commercially available 2-methoxy-3-nitropyridine (50.5 g) in methanol (500 mL), and the mixture was stirred for four hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give 2-methoxypyridin-3-amine as a yellow powder (37.2 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[NH:11][CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: C[C@@H]1CN[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Yield: 76.3 %

Procedure:
A mixture of (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (14.58 g, 63 mmol), benzaldehyde (7.39 g, 70 mmol), sodium triacetoxyborohydride (16.0 g, 76 mmol) and 1,2-dichloroethane (100 mL) was stirred at 20° C. then quenched with saturated aqueous sodium hydrogen carbonate (500 mL). The mixture was extracted with DCM (3×100 mL) and the combined organic extracts dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-25% EtOAc in 40-60 petroleum ether) gave the title compound (15.4 g, 76%) as an oil. MS: [M+H]+=321. 1H NMR (CDCl3): 7.42-7.12 (5H, m), 4.12-3.88 (2H, m), 3.85-3.55 (4H, m), 3.27 (1H, dd), 2.91-2.79 (1H, m), 2.73 (1H, dd), 2.63 (1H, s), 2.33 (1H, dd), 1.49 (9H, s), 1.21 (3H, d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19](S(O)(=O)=O)=[CH:18][CH:17]=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:26]([N:11]1[CH2:12][CH:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OC1(c2cccc(Br)c2)CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc(C2=CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
A solution of 28.2 g (81.4 mmol) of 4-(3-bromophenyl)-piperidin-4-ol in 600 ml of toluene was treated with 30 g (157 mmol) of p-toluenesulphonic acid monohydrate and heated to reflux on a water separator for 4 hours. Subsequently, the reaction mixture was cooled to room temperature and adjusted to pH 10 with 3N sodium hydroxide solution. Thereafter, it was firstly extracted three times with 500 ml of methylene chloride. The combined organic phases were washed three times with 200 ml of water each time, dried over magnesium sulphate and then evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of methylene chloride and hexane as the eluent. There were obtained 9.5 g (36% of theory) of 1-benzyl-4-(3-bromophenyl)-1,2,3,6-tetrahydro-pyridine as a light yellow oil; MS: 327, 329 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Reactant: CC(C)C(=O)Cl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(=O)C(C)C
Yield: 53.6 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 19, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline (150 mg, 0.36 mmol), (prepared as described for the starting material in Example 12), was reacted with isobutyryl chloride (45 μl, 0.43 mmol). The product was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-{[(2S)-1-isobutyrylpyrrolidin-2-yl]methoxy}-6-methoxyquinazoline (95 mg, 54%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][N:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:14]=1[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[F:21][C:18]1[CH:19]=[CH:20][C:13]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH:10]=2)=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(F)ccc1F
Reactant: Cc1noc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1noc2cc(Oc3ccc(F)cc3C#N)ccc12
Temperature: 100 °C
Yield: 58 %

Procedure:
3-Methyl-benzo[d]isoxazol-6-ol (1v) (reference for synthesis, see Indian J. Chem. Sect. B; 19:571-575 (1980)) (1.58 g, 10.6 mmol) and 2,5-difluoro-benzonitrile (2v) (1.47 g, 10.6 mmol) were combined with potassium carbonate (1.46 g. 10.6 mmol) in 15 mL of dry DMA. The reaction was heated in a 100° C. bath for 6 hours. The reaction was cooled and diluted with EtOAc (200 mL) and washed three times with water, NH4Cl, NaHCO3, and brine. The organic solution was dried over MgSO4 and concentrated. The crude residue was purified by column chromatography (silica, 70-80% CH2Cl2/hexane) to provide compound (3v) (1.65 g, 58% yield). 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8.6 Hz, 1H), 7.44-7.41 (m, 1H), 7.33-7.26 (m, 1H), 7.10-7.06 (m, 2H), 7.03 (dd, J=8.2, 4.7 Hz, 1H), 2.59 (s, 3H); MS (ESI+) m/z 269 (M+H) detected.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[CH:15]=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:10]([C:11](O)=[O:12])=[CH:9][C:8]=2[C:24]([OH:26])=O)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]2[CH2:16][C:14]3[C:10]([C:11](=[O:12])[C:18]=2[CH:19]=1)=[CH:9][C:8]1[C:24](=[O:26])[C:27]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:28]=2)[CH2:6][C:7]=1[CH:15]=3
Reactant: Cc1ccc(Cc2cc(Cc3ccc(C)cc3)c(C(=O)O)cc2C(=O)O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)C(=O)c1cc3c(cc1C2)Cc1ccc(C)cc1C3=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 14.1 grams of 4,6-bis(4-methylbenzyl)isophthalic acid was added 75 mL of trifluoroacetic acid followed by 48 grams of trifluoromethanesulfonic acid. After stirring for 3 days at room temperature, the mixture was poured over 200 g of ice, and the resulting solid was collected by filtration. The solid was washed with 400 mL of saturated aqueous sodium bicarbonate solution, followed by 1100 mL of water until the filtrate was neutral to pH paper. The solid was washed with heptane and dried to give 3,9-dimethylpentacene-5,7(12H,14H)-dione.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)(=[O:10])[CH3:9]>>[C:8]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: Oc1ccccc1
Product: CC(=O)Oc1ccccc1

Procedure:
Phenol was acetylated with a 1.5 times molar excess of acetyl chloride at room temperature, the excess acetyl chloride being removed by evaporation under reduced pressure. A very high yield of phenyl acetate was produced. To this reaction product a 2.4 times molar excess of acetic anhydride was added with stirring, followed by a 1.5 times molar excess of sulphuric acid added dropwise at 50° C. over 30 minutes. After stirring for a further 60 minutes, the mixture was neutralised using a 1.5 time molar excess of sodium acetate in glacial acetic acid solution. Trituration of the reaction mixture with ether followed by filtration resulted in a dry yellow solid. This was recrystallised from methanol and washed with sodium carbonate solution. A 99% conversion to sodium sulphonatophenyl acetate was achieved.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOCC>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:29][C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)=[N:3][CH:4]=1
Reactant: Cn1ccc(N)n1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), 1-methyl-1H-pyrazole-3-amine (0.058 g, 0.595 mmol) and p-toluenesulfonic acid monohydrate (0.006 g, 0.030 mmol) in 1,4-dioxane (2.0 mL) was stirred in a microwave reactor at 120° C. for 3 hours. The reaction mixture was adsorbed onto SiO2 and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-5% MeOH in DCM) to give a gummy solid. The solid was suspended in a mixture of Et2O and petroleum benzine 40-60° C. (1:1) and sonicated for 10 minutes. The precipitate was isolated by vacuum filtration and dried to give the title compound 28 as a yellow solid (0.014 g, 12%). LCMS-D: rt 3.26 min; m/z 397 [M+H]+.
Reaction SMILES: Cl[C:2](=[N:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:16]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)=[CH2:17].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[CH:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][C:2]([C:3]([O:5][CH3:6])=[O:4])=[N:7]2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cl)=NNc1ccc(Cl)cc1
Reactant: C=Cc1ccco1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccco2)C1

Procedure:
The compound of Example 1 (2.0 g) was suspended in benzene (20 ml) and heated to reflux in the presence of 2-vinylfuran (2.5 ml). Triethylamine was added and the mixture was allowed to reflux for 1 hour longer. The mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and concentrated. Chromatography on silica gel (5:1 hexanes/ethyl acetate) gave the title compound (1.8 g). NMR (CDCl3) 7.3 to 6.9 (m, Ar-H, 5H); 6.2 (m, Furan-H, 2H); 5.5 (dd, CH, 1H); 3.9 (s, OCH3, 3H); 3.6 (m, CH, 1H); 3.4 (m, CH3, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].C([O:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)C>CC(O)C>[N:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:13][CH2:14][CH:9]([C:7]([NH:2][NH2:3])=[O:6])[CH2:10][CH2:11]1
Reactant: NN
Reactant: CCOC(=O)C1CCN(c2ccccn2)CC1
Solvent: CC(C)O
Solvent: O
Product: NNC(=O)C1CCN(c2ccccn2)CC1
Temperature: 25 °C

Procedure:
Hydrazine hydrate (61.4 ml, 1.265 mol) was charged to a propan-2-ol solution of 3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (0.253 mol, 5 ml/g)(see reference Farmaco, 1993, 48(10), 1439), before heating under reflux for 18 hours. The mixture was cooled to room temperature and then to 10° C. and the product, a white solid, was collected by filtration (44.5 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)([NH2:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[S:35])[CH:30]=[CH:31][CH:32]=1>O1CCOCC1>[Cl:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH:15][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[S:35])[CH:30]=[CH:31][CH:32]=1
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: NC(Cc1ccccc1)(c1cccc(C(F)(F)F)c1)c1ccccn1
Solvent: C1COCCO1
Product: FC(F)(F)c1cccc(C(Cc2ccccc2)(NC(=S)Nc2cccc(Cl)c2)c2ccccn2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(Pyridin-2-yl)-1-(3-(trifluoromethyl)phenyl)-2-phenylethanamine was dissolved in dioxane (40 uL, 0.5 M in dioxane, 20 umol) and 3-chlorophenylisothiocyanate was added (200 uL, 0.2 M in dioxane, 40 umol, 2.0 eq). The reaction mixture was agitated at room temperature for 18 h The solvent was evaporated and the residue was redissolved in 1 mL of MeOH and purified by reverse phase preparative HPLC using MeOH:water:TFA system. 1-(3-chlorophenyl)-3-(2-phenyl-1-(pyridin-2-yl)-1-(3-(trifluoromethyl)phenyl)ethyl)thiourea was obtained a colorless oil (13.9 umol, 69% yield). LCMS: M+calc=511.11; found=511.98.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:33]5[CH:45]=[CH:44][C:36]([C:37]([O:39]C(C)(C)C)=[O:38])=[CH:35][C:34]=5[CH3:46])[CH:29]=[N:30][C:31]=4[CH3:32])=[CH:24][N:23]=[C:22]([N:47]4[CH2:50][CH:49]([F:51])[CH2:48]4)[N:21]=3)[C@H:14]2[CH3:52])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:33]5[CH:45]=[CH:44][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=5[CH3:46])[CH:29]=[N:30][C:31]=4[CH3:32])=[CH:24][N:23]=[C:22]([N:47]4[CH2:50][CH:49]([F:51])[CH2:48]4)[N:21]=3)[C@H:14]2[CH3:52])[CH:4]=[C:3]([C:2]([F:54])([F:53])[F:1])[CH:8]=1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1cnc(C)c(-c2cnc(N3CC(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)O)ccc1-c1cnc(C)c(-c2cnc(N3CC(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 25 mL round bottom flask was added tert-butyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methylpyridin-3-yl}-3-methylbenzoate (Step A, 40 mg, 0.053 mmol) and TFA (4 mL). The mixture was stirred at room temperature for 10 minutes. Volatiles were removed. The residue was purified on silica gel chromatography (0 to 100% acetone/hexane), affording the title compound as white solid. LCMS (M+H)+: 704.1. RTA IC50: 26 nM.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[N:23]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C=O)C.CO>[CH3:21][N:22]1[CH2:26][CH2:25][C:24]([C:27]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:28])=[N:23]1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: Cn1ccc(C(=O)O)n1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (58 mg, 0.21 mmol, example 30, step 1) in DMF (1 mL) was added 1-methyl-1H-pyrazole-3-carboxylic acid (Fluorochem, 34 mg, 0.27 mmol), 1-hydroxybenzo-triazole hydrate (42 mg, 0.27 mmol), and N-((isopropylimino)methylene)propan-2-amine (66 μL, 0.42 mmol). The resulting mixture was then stirred at RT for 16 h. Then, the mixture was filtered and the filtrate was purified by preparative HPLC to give the target compound. The product was dissolved in MeOH and passed through PL-HCO3 MP resin and the resin was washed with MeOH (2×0.3 mL). The combined filtrates were concentrated and dried under vacuum to give the title compound as a light-yellow solid. MS (ESI, positive ion) m/z: 386 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[CH2:12][C:13]#[N:14].[CH2:15](N)[CH2:16][NH2:17]>C(=S)=S>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1
Reactant: CC1=C(CC#N)CCc2ccccc21
Reactant: NCCN
Solvent: S=C=S
Product: CC1=C(CC2=NCCN2)CCc2ccccc21
Temperature: 120 °C

Procedure:
To a mixture of 60 g (0.33 mole) of 3,4-dihydro-1-methyl-2-naphthaleneacetonitrile and 30 ml of ethylenediamine was added 3 ml of carbon disulfide. The reaction mixture was stirred under nitrogen and heated in an oil bath at 120° C. for 21 hours, and then cooled to room temperature and concentrated in vacuo to remove volatile substances. The solid material was collected, dissolved in 600 ml of chloroform and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was triturated with ether and dissolved in ethanol. The ethanol solution was acidified with ethanolic hydrogen chloride and ether was added until the solution became cloudy. The solid product which crystallized was collected and dried in vacuo to give 28.7 g of 2-[(3,4-dihydro-1-methyl-2-naphthalenyl)methyl]-4,5-dihydro-1H-imidazole in the form of its mono-hydrochloride salt, m.p. 223°-224° C. A recrystallization from the same solvent mixture gave a sample with m.p. 226°-229° C.