Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[CH2:11][C:12]([NH:14][C:15]1[C:16]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[N:17][C:18]([CH3:27])=[CH:19][C:20]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:31][C:30]([F:33])([F:32])[CH2:29][O:28][C:16]1[C:15]([NH:14][C:12](=[O:13])[CH2:11][N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[C:20]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[C:18]([CH3:27])[N:17]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCO)CC2)c(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
1-(2-Hydroxyethyl)piperazine (1.95 g, 15.0 mmol) and 2-bromo-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (5.00 g, 12.5 mmol) were dissolved in acetonitrile (30 mL). Potassium carbonate (2.25 g, 16.3 mmol) was added to the solution, followed by stirring for 5 hours at room temperature. The reaction mixture was dilluted with water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, followed by drying over sodium sulfate anhydrate and concentration under reduced pressure. The obtained residue was purified through silica gel column chromatography (eluent: ammonia-saturated methanol/chloroform=1/20), to thereby yield 5.40 g of N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide as colorless crystals (yield 91%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]([CH:7]([C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:8])CO.[CH:14]([Cl:17])(Cl)[Cl:15]>C1S(=O)(=O)CCC1.S(Cl)(Cl)=O>[ClH:15].[ClH:1].[NH2:3][CH:4]([CH:7]([C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:8])[CH2:14][Cl:17]
Reactant: ClC(Cl)Cl
Reactant: CC(c1c[nH]cn1)C(N)CO
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: CC(c1c[nH]cn1)C(N)CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3 g (13.2 mmol) 2-amino-3-(1H-imidazol-4-yl)butanol dihydrochloride are solved in a mixture of 25 ml tetramethylenesulfone and 10 ml thionyl chloride and stirred 12 hours at room temperature. Dropwise addition of 200 ml chloroform affords 2-amino-1-chloro-3-(1H-imidazol-4-yl)butane dihydrochloride. Yield: 2.87 g (88.2%) of a hygroscopic precipitate.
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.[CH2:12]1N2CN3CN(C2)CN1C3.Cl.[C:23](O)(=[O:25])C>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C:10]=1[CH:23]=[O:25]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(=O)O
Reactant: Cc1noc2cc(O)ccc12
Agent: Cl
Product: COc1ccc2c(C)noc2c1C=O
Reaction time: 0.5 h

Procedure:
To a solution of commercially available 3-methylbenzo[d]isoxazol-6-ol (1.125 g; 7.54 mmol) in acetic acid (22.5 ml) was added hexamethylenetetramine (4.500 g; 32.09 mmol), and the resulting mixture was heated over a steam-bath for 6 h. The resulting hot mixture was then treated with 6 M aq. HCl (20 ml), and the heating was continued for 30 min. The solid obtained on dilution of the reaction mixture was filtered, and recrystallised from aq. MeOH to give the desired 6-hydroxy-3-methylbenzo[d]isoxazole-7-carbaldehyde as a yellow solid. LC-MS (conditions D): tR=0.79 min.; [M+H]+: 177.98 g/mol.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C@@H:29]([F:40])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:43])[CH3:42])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:46])[CH2:22][C:23]([CH3:45])([CH3:44])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C@H:29]([F:40])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:42])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:46])[CH2:22][C:23]([CH3:44])([CH3:45])[O:24]3)=[CH:15][CH:14]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@@H](F)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](F)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
110 μl (630 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 3.5 mg (20 μmol) of (1R,2S)-1-aminoindan-2-ol in 4 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 min. A solution of 77 mg (160 μmol) of 5-(4-fluorophenyl)-6-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 22A) in 4 ml of tetrahydrofuran are then slowly added dropwise, and the mixture is stirred at room temperature for 6.5 h. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1) gives the diasteromerically pure target compounds.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[CH3:21][C:22]1[CH:23]=[C:24]([NH2:37])[C:25]2[CH:26]=[N:27][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29]=2[CH:30]=1>>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][NH:37][C:24]1[CH:23]=[C:22]([CH3:21])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Cc1cc(N)c2cnn(-c3ccccc3)c2c1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F

Procedure:
Prepared similarly to Example 14 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163) and 6-methyl-1-phenyl-1H-indazol-4-amine (Intermediate 10).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[S:28]([OH:31])(=O)=[O:29].C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[S:28]([Cl:35])(=[O:31])=[O:29]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(S(=O)(=O)O)c2cc(F)ccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(S(=O)(=O)Cl)c2cc(F)ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-fluoro-1-{[2-(3-fluorophenyl)-4-methylpyrimidine-5-carbonyl]amino}-1H-indole-3-sulfonic acid (1.06 g) in DCM (60 mL) at 0° C. is added dry DMF (10 drops). Oxalyl chloride (1.05 mL) is added drop wise and the mixture is stirred at 0° C. for 3 h. The mixture is filtered and the collected solid is washed with ether to afford 5-fluoro-1-{[2-(3-fluorophenyl)-4-methylpyrimidine-5-carbonyl]amino}-1H-indole-3-sulfonyl chloride (0.94 g). MS: 461 (M−H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][C:7]3[CH:11]=[CH:10][S:9][C:8]=3[C:2]1=2.[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[I-].[K+]>CS(C)=O>[CH2:12]([C:6]1([CH2:7][CH2:8][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:2]2[S:1][CH:5]=[CH:4][C:3]1=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCBr
Reactant: c1cc2c(s1)-c1sccc1C2
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCC1(CCCCCC)c2ccsc2-c2sccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4H-Cyclopenta[2,1-b:3,4-b′]dithiophene (CDT) (1.63 g, 9.14 mmol) in dimethyl sulfoxide (50 mL) was added hexyl bromide (3.1 g, 18.9 mmol) and a catalytic amount of potassium iodide (50 mg). The mixture was purged with argon for 10 minutes followed by the slow addition of solid potassium hydroxide (2 g). The now dark green mixture was stirred in the dark at room temperature for 72 hours. The mixture was then poured into de-ionized water (150 mL) and the organic phase extracted with diethyl ether (4×100 mL). The organic phases were collected and washed with brine (100 mL) and a saturated ammonium chloride solution (100 mL). The organic phase was dried over magnesium sulphate, filtered, and concentrated to give the crude product as yellow oil. Purification via flash chromatography with hexanes (monitored at 254 nm, collected at 320 nm) and drying under high vacuum for 48 hours gave pure product as colorless oil. Yield 2.8 g (88%). 1H NMR (500 MHz, CDCl3): δ=7.15 (d, 2H, 3JH-H=5 Hz), 6.94 (d, 2H, 3JH-H=5 Hz), 1.84 (m, 4H, C—CH2), 1.19 (m, 12H, alkyl-CH2), 0.95 (m, 4H, alkyl-CH2), 0.82 (m, 6H, alkyl-CH3).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH:20]1([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[ClH:19].[CH:20]1([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([NH:33][S:16]([C:14]3[S:15][C:11]([C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=4[CH3:10])=[CH:12][CH:13]=3)(=[O:18])=[O:17])[CH2:29][CH2:28]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: NC1CCN(CC2CCCCC2)CC1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NC3CCN(CC4CCCCC4)CC3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 73 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with (1-cyclohexylmethylpiperidin-4-yl)amine as described in Steps 5 and 6, Example 24 to give the title compound as a white solid (73% yield). LC/MS: RT 2.28 min; m/e 478; 1H NMR (δ, ppm): 11.85 (1H, br), 9.80 (1H, br), 8.18-8.37 (1H, m), 7.54-7.65 (1H, m), 7.34 (1H, s), 7.17 (1H, d), 2.70-3.75 (7H, m), 2.40 (2H, q), 2.32 (3H, s), 1.50-2.08 (10H, m), 0.80-1.35 (8H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[C:5](F)=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>C(O)CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:8]([CH3:9])=[N:14][NH:13][C:5]2=[CH:4][N:3]=1
Reactant: CC(=O)c1cc(Br)ncc1F
Reactant: NN
Solvent: O
Solvent: OCCO
Product: Cc1n[nH]c2cnc(Br)cc12
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
To a 250-mL round-bottomed flask equipped with a reflux condenser was added dry ethylene glycol (30 mL) and 325c (4.3 g, 20 mmol). Then hydrazine hydrate (5.0 mL, 4.8 g, 81.6 mmol) was added dropwise via a syringe. The mixture was heated at 165° C. for 3.5 h. The resulting orange-tan mixture was cooled to room temperature and the contents were poured onto a stirring mixture of 100 mL ice/water (1:1), whereupon precipitation occurred. After stirring for 10 min, the off-white precipitate was collected, which was dried in vacuo to afford 325d as an off-white solid (3.1 g, 74%). MS-ESI: [M+H]+ 211.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.C(N(CC)CC)C.[NH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]1>[Ni].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:16][CH:17]2[CH2:18][CH2:19][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:22]2)[CH:2]=1
Reactant: COC(=O)C1CCC(N)CC1
Reactant: O=Cc1cccnc1
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C1CCC(NCc2cccnc2)CC1
Temperature: 50 °C
Reaction time: 6.5 h

Procedure:
6.13 g of pyridine-3-aldehyde, 5.77 g of triethylamine and 9 g of methyl 4-amino-cyclohexanecarboxylate are mixed into 250 ml of methanol. 3 g of Raney nickel are added thereto in order to hydrogenate the mixture, with stirring, for about 6.5 hours at 50° C. and 3 bar. After the catalyst has been eliminated by suction filtering the filtrate is evaporated down. The crude product is purified through silica gel with methylene chloride/methanol.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=C.C(=O)([O-])[O-].[K+].[K+].[C:37]1([CH2:43][CH2:44][CH2:45]Cl)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[CH:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([CH2:45][CH2:44][CH2:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:29][CH2:30]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: ClCCCc1ccccc1
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCc2ccccc2)CC1
Temperature: 60 °C

Procedure:
In a 50 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole (898 mg, 2.12 mmol), potassium carbonate (1.46 g, 10.58 mmol), 3-(phenyl)propyl chloride (0.2 ml, 506 mg, 2.54 mmol) and N,N-dimethylformamide (7 ml). The resulting mixture was heated to 60° C. and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography. The reaction was quenched by the addition of water. The aqueous fraction was extracted wtih ethyl acetate. The organic fractions were combined, washed thrice with saturated sodium bicarbonate solution, and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[C:13]3[N:16]=[CH:17][S:18][C:12]=3[N:11]=[C:10]2S)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C:14](=[O:15])[C:13]2[N:16]=[CH:17][S:18][C:12]=2[N:11]=1
Reactant: O=c1c2ncsc2nc(S)n1-c1ccc(F)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=c1c2ncsc2nc(Cl)n1-c1ccc(F)cc1
Temperature: 135 °C

Procedure:
6-(4-Fluorophenyl)-5-mercapto[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one hydrochloride (0.2 g, 0.633 mmol) is added to POCl3 (10 mL), and the resulting solution is refluxed at 135° C. for 41 h. Most of the volatiles are removed under reduced pressure and the residual solvent is co-evaporated with toluene (50 mL×3). The dark solid obtained is dissolved in CH2Cl2 (200 mL) and washed with saturated NaHCO3 solution (100 mL×5), brine (50 mL×2), and dried over MgSO4. After removing solvent, silica gel column chromatography (EtOAc:hexanes=50:50) yields the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) 8.88 (1H, s), 7.26 (4H, m).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C@H:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[CH:5][CH:4]=1)=[O:2].[C:17]([C@@H:21]([C@H:23]([C:25]([O:27][CH3:28])=[O:26])[OH:24])O)([O:19][CH3:20])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:14]([C@H:12]1[CH2:11][O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]3[O:24][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[C@H:21]([C:17]([O:19][CH3:20])=[O:18])[O:2]3)=[CH:8][CH:7]=2)=[N:13]1)([CH3:16])[CH3:15]
Reactant: CC(C)[C@H]1COC(c2ccc(C=O)cc2)=N1
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@@H]1OC(c2ccc(C3=N[C@@H](C(C)C)CO3)cc2)O[C@H]1C(=O)OC
Reaction time: 2.5 h

Procedure:
A solution of 0.8 g of (S)-2-(4-formylphenyl)-4-isopropyl-2-oxazoline and 1 g of dimethyl L(+)-tartrate in 50 ml of toluene is treated with 0.1 g of toluene-4-sulphonic acid. The mixture is heated to boiling for 2.5 hours and the water formed is distilled off simultaneously. Then, 4 drops of triethylamine are added to the reaction mixture. After cooling the mixture is washed with 20 ml of 1N sodium hydrogen carbonate solution and twice with 20 ml of water each time, dried over sodium sulphate and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 1:1) and recrystallization from ethanol gives pure dimethyl (4R,5R)-2-(4-[(S)-4-isopropyl-2-oxazolinyl]phenyl)-1,3-dioxolane-4,5-dicarboxylate
Reaction SMILES: [OH-].[Na+].CC(C1C=C(C(C)(C)C2C=CC=CC=2)C=CC=1O)(C)C1C=CC=CC=1.[N+:28]([C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33])([O-:30])=[O:29].[ClH:38].[N:39]([O-])=O.[Na+]>CO.O.C(O)(=O)C>[Cl-:38].[N+:28]([C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[N+:33]#[N:39])([O-:30])=[O:29]
Reactant: O=N[O-]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Cl
Agent: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: N#[N+]c1ccccc1[N+](=O)[O-]
Product: [Cl-]
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Using the general procedure of Example 4, 13.6 grams (0.34 mole) of sodium hydroxide pellets were dissolved in 145 ml of methanol followed by the addition of 16.5 grams (0.05 mole) of 2,4-di-(α,α-dimethylbenzyl)phenol and an additional 20 ml of methanol. The resulting solution was cooled to 2° C. Meanwhile a solution of o-nitrobenzenediazonium chloride was prepared by diazotizing a mixture of 8.3 grams (0.06 mole) of o-nitroaniline and 17.3 grams of concentrated hydrochloric acid and 6 ml of water with a solution of 4.3 grams of sodium nitrite in 8 ml of water. The diazonium solution was added gradually to the alkaline solution over a two-hour period at 2° C. The resulting deep purple reaction mixture was stirred for 30 minutes at 2° C., and then acidified with 20 ml of glacial acetic acid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]3[S:21][C:20]([CH2:22][CH3:23])=[CH:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[OH:30].[Na+].[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[C:43](Cl)=[O:44]>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:6]([C:7]2[S:21][C:20]([CH2:22][CH3:23])=[CH:19][C:8]=2[C:9](=[O:30])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]([CH2:11][NH:10][C:43]([C:35]2[NH:34][C:42]3[C:37]([CH:36]=2)=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:44])=[N:4][N:3]=1
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: CCc1cc2c(s1)-n1c(Br)nnc1CN=C2c1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(Br)nnc2CNC(=O)c2cc3ccccc3[nH]2)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
9-Bromo-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (1.0 g) was added to 2M sulfuric acid (26.5 ml), and the mixture was stirred at 80° C. overnight. Sodium hydrogencarbonate was added to the reaction mixture to make the mixture alkaline. Chloroform and indole-2-carbonyl chloride were added, and the mixture was stirred at room temperature for 1.5 hours. The obtained crystals were filtered and washed with ethyl acetate to give 0.196 g of N-(3-bromo-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-5-ylmethyl)indole-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:32])=[CH:4][C:5]2[C:6]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][C:7]=3[N:8]([CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]=2[CH:10]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([Cl:32])=[CH:4][C:5]2[C:6]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:7]=3[N:8]([CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCCc3ccccc3)c3cc(Cl)c(Cl)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: Clc1cc2c3c(n(CCCc4ccccc4)c2cc1Cl)CCNCC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 115 %

Procedure:
To a solution of tert-butyl 8,9-dichloro-6-(3-phenylpropyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.42 mmol) in CH2Cl2 (5 mL), TFA (0.65 mL, 8.4 mmol) was added while stirring at rt. After 4 h, the reaction was made basic with 10% aqueous NaOH, then extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to 0.12 g of crude material. After the hydrochloride salt was prepared, it was further purified by recrystallization from MeOH/EtOAc to give 99 mg (57%) of a white solid: mp 148.0-150.5° C.; 1H NMR (300 MHz, DMSO) δ 9.26 (br s, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.28 (m, 2H), 7.20 (m, 3H), 4.19 (m, 2H), 3.19 (m, 2H), 3.08 (m, 2H), 2.61 (m, 2H), 1.89 (pentet, J=7.5 Hz, 2H); 13C NMR (400 MHz, DMSO) δ 141.0, 138.4, 134.0, 128.2, 128.1, 126.5, 125.8, 123.0, 121.4, 118.7, 111.3, 110.2, 45.8, 44.0, 42.3, 31.9, 31.5, 22.5, 20.2; IR (diffuse reflectance) 3021, 2997, 2970, 2953, 2888, 2850, 2825, 2812, 2760, 2709, 2632, 1473, 1421, 1106, 700 cm−1; MS (EI) m/z 374, 372 (M+), 332, 331, 330, 228, 226, 91, 86, 84.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:22]#[C:23][CH3:24])[CH2:18][C:19](O)=[O:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.C1COCC1.[NH2:42][C:43]1[S:44][CH:45]=[CH:46][N:47]=1>O>[S:44]1[CH:45]=[CH:46][N:47]=[C:43]1[NH:42][C:19](=[O:20])[CH2:18][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)[C:22]#[C:23][CH3:24]
Reactant: Nc1nccs1
Reactant: CC#CC(CC(=O)O)c1ccc(OCc2ccc(OC)cc2)cc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: O
Product: CC#CC(CC(=O)Nc1nccs1)c1ccc(OCc2ccc(OC)cc2)cc1
Yield: 1.6 %

Procedure:
A pear-shaped flask was charged with a stir bar, compound 12 (50 mg, 0.154 mmol), carbonyl diimidazole (25 mg, 0.154 mmol) and THF (4 mL). The mixture was refluxed for 1 hour, and 2-amino thiazole (16 mg, 0.154 mmol) was then added. The reaction was refluxed for 48 hours, poured into water and extracted with ethyl acetate. The organic layer was concentrated and the resulting residue was purified via HPLC to yield 1.0 mg (2%) of 3-[4-(4-Methoxy-benzyloxy)-phenyl]-hex-4-ynoic acid thiazol-2-ylamide (24) as a film. 1H NMR (400 MHz) (acetone-d6) δ 7.39 (4H, m), 7.11 (1H, s), 6.95 (3H, m), 5.03 (2H, s), 3.82 (3H, s), 2.95 (2H, m), 1.79 (3H, s).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][C:10]([NH2:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH:7]=[CH2:8])[CH2:3][NH:21][C:10]([CH3:20])([CH3:9])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: C=CCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: C=CCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 26.9 %

Procedure:
Using the method of Example 15, supra, allyl glycidyl ether (119 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 79 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 294 (M+1, 0.1), 278 (0.9), 222 (1.5), 172 (100), 163 (11), 121 (20); 1H-NMR (CDCl3) δ7.04 2H, di J=8.6), 6.79 (2H, d, J=8.6), 5.85 (1H, ddd, J=22.2, 10.5 and 5.7), 5.23 (1H, dd, J=17.3 and 1.5), 5.14 (1H, dd, J=10.3 and 1.5), 3.96 (2H, d, J=5.7), 3.74 (4H, m), 3.43 (2H, d, J=5.7), 2.83 (1H, broad s), 2.77 (1H, dd, J=11.7 and 4.1), 2.62 (5H, m), 1.02 (3H, s), 1.01 (3H, s); 13C-NMR (CDCl3) δ158.0, 134.5, 131.3, 129.9, 117.0, 113.3, 72.8, 72.2, 69.0, 55.0, 53.3, 46.3, 44.5, 26.6, 26.4.