Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)CC(O)C.CO>[CH3:39][O:38][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][C:22]=1[NH:21][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:4][N:3]=1)[C:26]([NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:27]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CN1C(=O)CCN(C2CCCC2=O)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1=O)CCC(=O)N2C
Temperature: 150 °C
Yield: 11.1 %

Procedure:
10-chloro-6-methyl-2-(2-oxocyclopentyl)-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 261; 58 mg, 0.19 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 53 mg, 0.20 mmol) and p-toluene sulphonic acid monohydrate (80 mg, 0.42 mmol) were dissolved in 4-methyl-2-pentanol (2 mL) and heated by microwave irradiation at 150° C. for 30 minutes. After cooling, the reaction mixture was dissolved in methanol (5 mL) and water (5 mL) and poured directly onto an SCX-3 cartridge (5 g). The cartridge was washed with methanol (50 mL), before elution of products with 2M ammonia in methanol (50 mL). The ammoniacal fraction was evaporated and the residue was purified by base modified reverse phase preparative HPLC to yield the title compound as a yellow solid (11 mg, 7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:27]1([CH:33]([NH2:41])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:41][CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NC(Cc3ccccc3)c3ccccc3)ncc2[N+](=O)[O-])CC1
Reaction time: 18 h
Yield: 77.4 %

Procedure:
trans-{4-[(2-Chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (100 mg, 0.26 mmol) was dissolved in DCM (5 mL). 1,2-Diphenylethylamine (154 mg, 0.78 mmol) was added in one portion. After 18 h, the solution was partitioned between DCM (15 mL) and 2% AcOH (aq; 10 mL). The layers were separated and the aqueous layer was extracted with DCM (20 mL). The combined organic fraction were washed with saturated sodium carbonate (10 mL) and water, dried over MgSO4, filtered and concentrated to yield a pale yellow solid. Chromatography (silica, 10%-50% Hex/EtOAc) yielded 110 mg of (4-{[2-(1,2-diphenyl-ethylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester as a pale yellow solid, m/z 547.4 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:11]=2[N:10]=1.[C:28](O)([C:30](F)(F)F)=[O:29]>>[CH:23]1([N:12]2[C:11]3[N:10]=[C:9]([C:8]4[CH:7]=[CH:6][N:5]=[CH:4][C:3]=4[CH2:2][NH:1][C:28](=[O:29])[C:30]4[CH:6]=[CH:7][CH:8]=[CH:3][CH:2]=4)[N:18]=[CH:17][C:16]=3[N:15]([CH3:19])[C:14](=[O:20])[C@H:13]2[CH2:21][CH3:22])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C1CCCC1
Reactant: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNC(=O)c3ccccc3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 102, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 105) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91). LCMS (0.05% TFA): 471.3 m/z (M+H)+; 1H-NMR (CDCl3, 500 MHz): δ: 9.03 (bs, 1H), 8.83 (bs, 1H), 8.38 (bs, 1H), 8.03 (bs, 1H), 7.78 (d, 2H, J=9 Hz), 7.50 (t, 1H, J=9.0 Hz), 7.42 (t, 2H, J=9.0 Hz), 5.02 (s, 2H), 4.49 (m, 1H), 4.39 (m, 1H), 3.42 (s, 3H), 2.16-1.68 (m, 10H), 0.91 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH:1]1[C:6]([C:7](O)=O)=C[C:4]([C:10]2[C:20]3[CH:21]=[CH:22][C:23](O)=[CH:24][C:19]=3OC3C=2C=CC(C=3)=O)=[C:3]([C:26](O)=O)[CH:2]=1.O[N:30]1C(=O)CC[C:31]1=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:52]([N:54]([CH2:57][CH3:58])[CH2:55]C)C>CN(C=O)C>[CH3:52][N:54]([CH2:57][CH2:58][CH2:31][N:30]1[C:26]2[CH:7]=[CH:6][CH:1]=[CH:2][C:3]=2[CH2:4][CH2:10][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]1=2)[CH3:55]
Reactant: O=C(O)c1ccc(C(=O)O)c(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c1
Reactant: CCN(CC)CC
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CN(C)CCCN1c2ccccc2CCc2ccccc21
Reaction time: 17 h
Yield: 55 %

Procedure:
6-Carboxyfluorescein (1.00 g, 2.66 mmol) was dissolved in 8 mL DMF, 306 mg (2.66 mmol) of N-hydroxysuccinimide was added, 549 mg (2.66 mmol) of 1,3-dicyclohexylcarbo-diimide was added, and the reaction stirred for 17 hours, under N2, in the dark. The reaction mixture was vacuum filtered, filtrate combined with 7.84 mg (2.65 mmol) of 2-aminoimipramine (4c), 0.56 mL (4.0 mmol) of triethylamine, and 4.0 mL DMF, and reaction allowed to stir 4 days under N2, in the dark. Reaction solvents were removed in vacuo and residue purified on reverse phase C18 semi-preparative (1 mm) TLC plates, eluting with H2O/THF/HOAc (40/60/0.4) followed by preparative HPLC on a Waters mbondapak C18 column (19 mm×150 mm), eluting with H2O/THF/HOAc (35/65/0.4) at a flow rate of 7.0 mL/minute to yield 410 mg (24%) of the desired imipramine tracer (12) as an orange powder; mass spec (FAB) (M+H)+ 654.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][N:18]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C(=O)c1ccc2nonc2c1)C1CCN(S(C)(=O)=O)CC1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-Methyl-N-piperidin-4-yl-[2,1,3]-benzoxadiazole-5-carboxamide hydrochloride (0.38 g, 1.3 mmol) was suspended in chloroform (70 ml) and triethylamine (2 ml) was added. A solution of methane sulfonyl chloride (0.14 g, 1.26 mmol) in chloroform (10 ml) was added and the mixture was stirred at 20° C. for 2 h. The mixture was washed with water (50 ml) and H2SO4 (→pH 2) and NaHCO3 solution (50 ml) and the aqueous re-extracted with dichloromethane (2×50 ml). The combined organics were dried (MgSO4), concentrated under vacuum, and the crude product was purified on a silica gel column eluting with dichloromethane/THF (85:15) to give a white crystalline product, after crystallization from MTBE/hexane (204 mg). Mp=177-179° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=9.3 Hz, 1H); 7.85 (s, 1H); 7.42 (d, J=9.3 Hz, 1H); 4.75-4.46 and 4.10-3.90 and 3.10-2.40 (m, 5H); 2.92 (s, 3H), 2.83 (s, 3H) and 2.10-1.70 ppm (m, 4H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:24]([CH:26]=[CH2:27])=[O:25].O>O1CCCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:24]([OH:25])[CH:26]=[CH2:27])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Reactant: C=CC=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
10.3 g (40 mmol) of 1-(phenylsulfonyl)indole (synthesized analogous to T. Sakamoto; Y. Kondo; N. Takazawa; H. Yamanaka; J.Chem.Soc.Perkin Trans.1; 16; 1996; 1927-1934) in 110 ml tetrahydrofuran were cooled to −20° C. To the stirred solution 30 ml of 1.6 M n-butyllithium were added at −20° C. within 20 min. The resulting suspension was warmed to 10° C. and stirred at 10° C. for 4 hours. The mixture was again cooled to −20° C. and a solution of 3.4 g acrolein (61 mmol) in 20 ml THF was added dropwise within 20 min at −20° C. The solution was stirred at 20° C. for 16 hours. 150 ml water was added dropwise, the mixture was vigorously stirred for 10 min. The phases were separated, and the water phase was extracted with 3×100 ml of methyl-t-butyl-ether. The combined organic phases were washed with 100 ml of brine, dried on sodium sulfate and rotary evaporated (35° C., 20 mbar). The residue was purified by liquid chromatography (eluent toluene/ethyl acetate 6:1), the pure fractions were collected and rotary evaporated (40° C./15 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([B:16]1[O:20][C@@H]2C[C@@H]3C[C@H]([C@]2(C)[O:17]1)C3(C)C)[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[O:5].Cl.B([O-])OCC(C)C>CO.CCCCCC>[Br:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([B:16]([OH:20])[OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[O:5]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)c1ccccc1Br)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CC(C)COB[O-]
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Product: CC(C)C[C@H](NC(=O)CNC(=O)c1ccccc1Br)B(O)O
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a solution of 2-bromo-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (0.220 g, 0.44 mmol) in methanol/hexane (1:1) (2.2 mL) were added 1N HCl (1 mL, 1.0 mmol) and isobutyl boronate (0.078 g, 0.76 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was concentrated and purified by reverse phase HPLC to give [(1R)-1-({[(2-bromobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid (0.119 g, 73%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31]4[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([F:39])[CH:32]=4)=[N:25]3)[CH:18]=2)=[N:15][CH:16]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[CH2:23][N:24]2[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31]3[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([F:39])[CH:32]=3)=[N:25]2)=[N:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCc1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
49.3 70 mg (0.127 mmol) of tert-butyl[3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)propyl]carbamate are dissolved in 3 ml of dichloromethane, and 195 μl (2.54 mmol) of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 15 h and evaporated. The residue is digested with diethyl ether and dried in vacuo; yield: 74 mg of “A285”; HPLC: Rt=2.63 min (method C); LC-MS: 452 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>C(O)(=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:3][CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(O)cc1
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1c1ccc(O)cc1
Yield: 32.8 %

Procedure:
The suspension that consists of 5.0 g (45.8 mmol) of 4-aminophenol, 4.49 g of maleic acid anhydride and 40 ml of acetic acid is refluxed for 3 hours. It is concentrated by evaporation, residual acetic acid is removed azeotropically by repeated distillation with acetic acid, and the residue is purified by chromatography on fine silica gel. 2.83 g (15.0 mmol, 33%) of the title compound is isolated.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21](OC1C=CC=CC=1)=[O:22].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:21]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:22])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: C1CCNCC1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)N3CCCCC3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and piperidine, the title compound was prepared as light yellow powder. MS: m/e=392(M+H+).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:6])[CH2:4][CH3:5].[OH-].[K+].[CH:9](=O)CC.[C:13]([OH:18])(=O)[C:14](O)=O>CO>[CH3:1][CH2:2][C@@H:3]([OH:6])[C@@H:4]([C:13]([CH2:14][CH3:9])=[O:18])[CH3:5]
Reactant: CCC=O
Reactant: CCC(=O)CC
Reactant: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)[C@@H](C)[C@H](O)CC
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A 1-liter, 2-necked flask equipped with a dropping funnel, thermometer, and magnetic stirrer was charged with 344.0 g. (4 moles) of freshly distilled 3-pentanone. After cooling the apparatus to 15° C., an addition was made of 30.6 ml. of 16.8% (w/w) potassium hydroxide in methanol. This was followed by dropwise addition over 4 hrs. of 58.0 g. (1 mole) of freshly distilled propionaldehyde mixed with another 172.0-g. lot of 3-pentanone. Stirring was continued for an additional 30 min. after which the base (KOH) was neutralized with 3.5 g. of anhydrous oxalic acid. The solution was filtered and then distilled under vacuum to remove unreacted 3-pentanone and methanol. The aldol distilled at 70° C. (0.45 mm.) and yielded 66.7 g. (46% based on propionaldehyde). The distribution of R*S* and R*R* diastereomers was approximately 1:1.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([OH:25])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].Cl.[CH2:27](O)[CH3:28]>O>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([OH:25])[C:22]([O:24][CH2:27][CH3:28])=[O:23])=[CH:18][CH:19]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(CC(O)C(=O)O)cc1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)C(O)Cc1ccc(OCCn2c(CC)nc(C)cc2=O)cc1
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of 3-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl]-2-hydroxypropionic acid (346 mg, 1.0 mmol) (obtained from preparation 28) in ethanol (3 ml) containing concentrated hydrochloric acid (0.1 ml) was refluxed for 10 h. The solution was cooled to room temperature, diluted with water and extracted with EtOAc (2×10 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the title compound (97 mg, 26%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:21]2[O:25][CH:24]=[N:23][C:22]=2[C:26](Cl)=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:22]1[N:23]=[CH:24][O:25][C:21]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:27]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ncoc1-c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ncoc1-c1ccccc1
Yield: 39.9 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0452 g, 0.192 mmol), 5-phenyl-1,3-oxazole-4-carbonyl chloride (0.041 g; 0.192 mmol), and triethylamine (0.0672 mL; 0.479 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.028 g (40%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-phenyloxazole-4-carboxamide as a solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:45]([O:25][C@@H:15]1[C@@H:14]([CH2:26][O:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:16]1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OC(=O)c2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methyl 2,3-di-O-benzyl-6-O-p-toluenesulfonyl-α-D-glucopyranoside (J. Org. Chem., 2001, 66, 5965-5975) (163.9 g, 310 mmol) was dissolved in methylene chloride (1.5 L) and 4-dimethylaminopyridine (43.5 g, 352 mmol) and triethylamine (49.0 mL, 352 mmol) were added thereto. Benzoyl chloride (43.2 mL, 372 mmol) was dropwise thereto and the mixture was stirred at 0° C. for 1 hour. After diluted hydrochloric acid (2N, 500 mL) was added to the reaction mixture and the mixture was extracted with methylene chloride (1 L), the organic layer was washed with saturated aqueous sodium hydrogencarbonate (1 L) and saturated brine (1 L) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 1:1, V/V) to obtain the desired title compound (196 g, yield 99%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH2:31]([NH:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([N:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:39])=[O:29]
Reactant: COc1ccc(C[C@@H]2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: CNCc1ccccc1
Reactant: O=C(Br)CBr
Product: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCN2CC(=O)N(C)Cc2ccccc2)cc1OC

Procedure:
prepared by reaction of (1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with N-benzyl-N-methylamine
Reaction SMILES: S1C=CC=C1.C(O)C.[Cl:9][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[CH3:23])=[O:12].[H][H]>[Pt].CO>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[CH2:10][Cl:9])=[C:15]([CH3:23])[CH:16]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)CCl
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Solvent: CCO
Product: Cc1cc(N)ccc1NC(=O)CCl
Yield: 92 %

Procedure:
To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol were added 15 parts of 2-chloro-N-(2-methyl-4-nitrophenyl)acetamide and 400 parts of methanol. The whole was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The solid residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 12 parts (92%)of N-(4-amino-2-methylphenyl)-2-chloroacetamide (intermediate 70).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:18][CH2:19][CH:20](O)[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH2:21]([CH:20]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:18][CH2:19]1)[CH2:22][CH3:23]
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCCC(O)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCC1CN=C2C=CC(c3cccc(C(F)(F)F)c3)=NN21
Temperature: 130 °C

Procedure:
A mixture of 3.0 g of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine and 5.0 g of 1-amino-2-pentanol is heated at 130° C. for 18 hours, cooled, diluted with water and extracted with dichloromethane. As for Example 3, the obtained product is reacted with thionyl chloride and the ring is closed with potassium carbonate in ethanol to give 2,3-dihydro-3-propyl-6-[3-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazine which is dehydrogenated with lead tetraacetate to give the product of the Example.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:29][C:30]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CCOCC>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([O:20][C:30]3[CH:29]=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:26][C:25]=3[Br:24])[CH:19]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(O)cc(F)c2)cc1C
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)CCc1ccc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 77.6 %

Procedure:
A mixture of 3-[4-(3-fluoro-5-hydroxy-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester (0.557 g, 1.75 mmol), 3-bromo-4-fluorobenzotrifluoride (0.425 g, 1.75 mmol) and 325 mesh potassium carbonate (0.29 g, 2.10 mmol) in dry DMSO (10 mL) is heated to 100° C. and stirred 2.5 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 5/1 hexanes/ethyl acetate to afford 0.735 g (78%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C2H21O4F4Br 540, found 558 and 560 (M+NH4, 100%).