Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=2[NH2:10])=[CH:4][CH:3]=1.[CH3:18][CH:19]=C(C)C.[CH3:23][C:24]([CH3:33])([CH2:29][C:30](O)=O)[CH2:25][C:26]([OH:28])=[O:27].Cl>C(Cl)(Cl)Cl.C(O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:8]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:9]=3[N:10]=[C:30]2[CH2:29][C:24]([CH3:23])([CH3:33])[CH2:25][C:26]([O:28][CH2:18][CH3:19])=[O:27])=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)O)CC(=O)O
Reactant: Nc1cc(F)ccc1NCc1ccc(Cl)cc1
Reactant: CC=C(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(C)(C)Cc1nc2cc(F)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of 2-(4-chlorobenzylamino)-5-fluoroaniline, prepared in Example 8, are dissolved in 100 ml of chloroform, stabilized with amylene, and 6 ml of triethylamine. A solution of 8.25 g of the acid chloride ethyl ester of 3,3-dimethylglutaric acid, prepared in Example 28, in 20 ml of chloroform, stabilized with amylene, is added dropwise. The mixture is stirred for two hours at room temperature, the crystals formed are filtered off and the solvents are evaporated off under vacuum. The residue obtained is dissolved in 200 ml of ethanol and 30 ml of concentrated hydrochloric acid and the mixture is refluxed for 10 hours. The solvents are evaporated off to dryness and the residue is taken up with water and then extracted with ethyl acetate. The organic phase is dried and evaporated under vacuum to give 14 g of ethyl 4-[1-(4-chlorobenzyl)-5-fluorobenzimidazol-2-yl]-3,3-dimethylbutanoate in the form of an oil, which is used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:35][C:36](OC)=O)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH:26]=[C:25]([O:24][CH3:23])[C:30]=1[O:31][CH3:32])[CH2:35][C:36]1[NH:22][C:20](=[O:21])[C:3]2[N:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1cc(OC)c(OC)c(OC)c1
Reactant: CC(O)C(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: COc1cc(Cc2nc3c(nnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc(OC)c1OC

Procedure:
Analogously to the procedure of Example XI, the title compound is prepared from 10 mg (0.024 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-[1,2,3]triazole-4-carboxamide and 20 mg (0.107 mmol) of methyl 3,4,5-trimethoxyphenylacetate.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH2:25][CH:26]1[CH2:29][CH2:28][CH2:27]1)[C:20]([N:22]([CH3:24])[CH3:23])=[O:21]>>[CH:26]1([CH2:25][CH:19]([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:20](=[O:21])[N:22]([CH3:23])[CH3:24])[CH2:27][CH2:28][CH2:29]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CN(C)C(=O)C(N)CC1CCC1
Product: CN(C)C(=O)C(CC1CCC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 2-amino-3-cyclobutyl-N,N-dimethyl-propionamide (54.48 mg, 0.32 mmol) as starting materials and isolated (20 mg, 24.3%) as white solid; LC-MS (UV peak area, ESI) 100%, 387.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([N:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]([CH3:23])[N:14]([CH3:24])[C:13]1=[O:25])(=[O:11])[CH:9]=[CH2:10].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][N:14]1[CH:15]([CH3:23])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]([C:8](=[O:11])/[CH:9]=[CH:10]/[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:25]
Reactant: Brc1cccnc1
Reactant: C=CC(=O)N1C(=O)N(C)C(C)C1c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1C(c2ccccc2)N(C(=O)/C=C/c2cccnc2)C(=O)N1C
Temperature: 110 °C

Procedure:
A solution of 3-bromopyridine (8.6 mL, 88.5 mmole), (4 R, 5 S)-1-acryloyl-3,4-dimethyl-5-phenylimidazolidin-2-one (14.4 g. 59 mmole), Pd(OAc)2 (662 mg, 2.95 mmole), P(o-tolyl)3 (1.80 g, 5.9 mmole), and (i-Pr)2NEt (22 mL, 124 mmole) in dry DMF (300 mL) was degassed (3×vacuum/N2 purge) then heated to 110° C. After 2 hr the mixture was cooled and poured into EtOAc. The resulting mixture was washed with H2O (3×), and the combined aqueous layers were back-extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered through a plug of silica gel, and concentrated. The residue was taken up in 1: EtOAc/hexanes and the solid was collected, washed with 1:1 EtOAc/hexanes, and dried in vacuo to afford a first crop of the title compound. The filtrate was concentrated and the crystallization process was repeated to afford a second crop. The total yield of the title compound was 17.53 g (92%): 1H NMR (400 MHz, CDCl3) δ 8.48-8.85 (m, 2H), 8.25 (d, J=15.9 Hz, 1 H), 7.89-7.97 (m, 1 H), 7.68 (d, J=15.9 Hz, 1 H), 7.15-7.38 (m, 6 H), 5.43 (d, J=8.5 Hz, 1 H), 3.90-4.02 (m, 1 H), 2.88 (s, 3H), 0.85 (d, J=6.6 Hz, 3 H); MS (ES) m/e 322 (M+H)+.
Reaction SMILES: C(O[C:6](=[O:13])[NH:7][C@H:8]([CH:11]=[O:12])[CH2:9][CH3:10])(C)(C)C.Br[C:15]([F:22])([F:21])C(OCC)=O.S([O-])(O)(=O)=O.[K+]>O1CCCC1.[Zn]>[CH2:9]([C@@H:8]1[NH:7][C:6](=[O:13])[C:15]([F:22])([F:21])[C@@H:11]1[OH:12])[CH3:10]
Reactant: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(F)(F)Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC[C@@H]1NC(=O)C(F)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
tert-Butyl[(1S)-1-formylpropyl]carbamate (24.00 g) and ethyl bromodifluoroacetate (77.0 g) were dissolved in tetrahydrofuran (220 mL), and to a suspension of a zinc powder (25.4 g) in tetrahydrofuran (50 mL) was added dropwise the solution at room temperature. After heating under reflux for 1 hr, the mixture was cooled to room temperature, 1 mol/L aqueous potassium hydrogen sulfate solution (400 mL) was added, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=10→40%), the obtained oil was dissolved in 4 mol/L hydrogen chloride/ethyl acetate solution (150 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (600 mL). Diisopropylethylamine (32.8 mL) was added, and the mixture was heated under reflux for 4 hr. The reaction solution was concentrated under reduced pressure, the residue was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate/hexane to give the title compound as a white powder (yield: 7.20 g, 54%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=3)[S:10][C:3]=12.[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[OH:32].C([O-])([O-])=O.[K+].[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1.ClCCl>[F:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[O:32][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=3)[S:10][C:3]=12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CCOC(=O)Cn1cnc(-c2cc3nccc(Cl)c3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)Cn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Temperature: 185 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A suspension of 373 (1.05 g, 3.26 mmol), 2-fluoro-4-nitrophenol (1.10 g, 7.00 mmol), and K2CO3 (2.0 g, 15 mmol) in diphenyl ether (10 mL) was heated with stirring to 185° C. for 3 h. The mixture was cooled, diluted with dichloromethane, filtered, and the filtrate was concentrated. Silica gel chromatography (75% ethyl acetate/hexanes) of the residue provided 374 (0.98 g, 68% yield). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.52 (d, J=5.3, 1H); 8.46 (dd, J=10.4, 2.5, 1H); 8.20-8.17 (m, 1H); 7.89 (d, J=1.2, 1H), 7.77-7.74 (m, 1H); 7.75 (s, 1H): 7.69 (t, J=8.2, 1H); 6.86 (d, J=5.3, 1H); 5.04 (s, 2H); 4.17 (q, J=7.2, 2H); 1.22 (t, J=7.2, 3H). LRMS (M+H): 442.9.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[CH3:15][C:16]1[CH:25]=[N:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>ClCCl.C(OCC)C>[CH3:8][C:3]1[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:14])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:24]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([CH3:15])[CH:25]=1
Reactant: COC(=O)c1ccncc1C
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cc[n+](N)cc1C
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
To an ice-cooled suspension (white) of O-(mesitylsulfonyl)hydroxylamine (1.75 g, 8.14 mmol) in dichloromethane (10 ml) is dropwise added a solution of methyl 3-methylisonicotinate (1.23 g, 8.14 mmol) in dichloromethane (3 ml). After the addition is completed, the resulting light yellow solution is stirred for 3 hours at 25° C. The solution is cooled to 0° C. and diluted with diethyl ether until a white solid precipitates. The suspension is stirred for 1 hour and the solid is collected by filtration, washed with ether and dried affording 1-amino-4-(methoxycarbonyl)-3-methylpyridinium 2,4,6-trimethylbenzenesulfonate (2.41 g, 80.8%) as a white solid. MS: m/z=167.2 (M+).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1.[CH2:19]([C:21]1[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24])[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([C:21]1[C:22]([CH:23]=[O:24])=[CH:25][CH:26]=[CH:27][C:28]=1[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1)[CH3:20]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 120 °C
Yield: 65.6 %

Procedure:
To a solution of 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D44) (550 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (463 mg) and tripotassium phosphate (1080 mg) in N,N-dimethylformamide (DMF) (4 mL) and water (1.000 mL) stirred under nitrogen was added Pd(Ph3P)4 (196 mg). The reaction was sealed and heated under microwave at 120° C. for 15 min. After cooling, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (2*8 mL), dried over sodium sulphate, concentrated and purified by column chromatography to afford 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D46) (420 mg) as a solid. MS (ES): C21H19N3O2S requires 377. found 378.0 (M+H+).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].O>C(Cl)Cl>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)c1ccc(OCOC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Ethyl 2-(4-(methoxymethoxy)phenyl)propanoate (485 mg, 2.04 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (5 mL) at 0° C. The mixture was stirred for 40 minutes at 0° C. and then slowly added solid sodium bicarbonate (7.14 g) and water (100 mL) at 0° C. The mixture was extracted with methylene chloride. The organic layer was dried with MgSO4. The organic layer was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=4/1.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH2:50]([N:52]([CH:56]1[CH2:60][CH2:59][NH:58][CH2:57]1)[C:53](=[O:55])[CH3:54])[CH3:51]>>[C:28]([C:32]1[N:33]=[C:34]([N:58]2[CH2:59][CH2:60][CH:56]([N:52]([CH2:50][CH3:51])[C:53](=[O:55])[CH3:54])[CH2:57]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CCN(C(C)=O)C1CCNC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CCN(C(C)=O)C1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and N-ethyl-N-(pyrrolidin-3-yl)acetamide. MS (m/e): 456.5 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9](=[O:49])[CH2:10][C:11]1[CH:48]=[CH:47][CH:46]=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1>C(Cl)Cl.C1CCCCC1>[NH:35]1[CH2:36][CH2:37][CH:32]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:45]=[CH:46][CH:47]=[CH:48][C:11]=4[CH2:10][C:9]([NH2:8])=[O:49])[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=3)=[CH:31][CH:30]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 23 h
Yield: 83.5 %

Procedure:
Trifluoroacetic acid (0.595 mL, 7.78 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I49) (90.8 mg, 0.156 mmol) in dry DCM (5 mL) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 23 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (30 mL) and 2M NaOH (30 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a white solid which was suspended in DCM (2 mL) and cyclohexane (10 mL). The resulting precipitate was filtered to afford title compound (11) (63 mg, 84%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.67-7.64 (m, 2H), 7.44 (s, 1H), 7.27-7.12 (m, 6H), 6.93 (s, 1H), 3.50 (s, 2H), 3.14-3.06 (m, 2H), 3.02-2.99 (m, 4H), 2.62-2.46 (m, peaks obscured by DMSO), 1.67 (d, J=11.4 Hz, 2H), 1.49 (qd, J=12.5, 3.9 Hz, 2H). LCMS Method C: rt 4.84 min; m/z 484 [M+H]+.
Reaction SMILES: [N:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[N:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[OH:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(c1ccccn1)C(c1ccccc1)N1CCOCC1
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccn1)C(c1ccccc1)N1CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
2-Morpholin-4-yl-2-phenyl-1-pyridin-2-yl-ethanone (15 mg, 0.053 mmol) was dissolved in 3 mL of dry THF and cooled to −78° C. Phenylmagnesium bromide (159 μL, 1.0 M solution in TBH, 0.159 mmol) was added dropwise and the mixture was allowed to stir for 15 minutes. The reaction was quenched with 1 mL of aqueous NaHCO3(sat) and warmed to ambient temperature. The mixture was poured into NaHCO3 (sat) and extracted 2× with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC. The appropriate fractions were poured into NaHCO3(sat) and extracted 2× with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo to provide the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=C(C=CC=3)C(O)=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.FC1C=C(N)C(N)=CC=1F.[Br:46]C1C=C(Cl)C=CC=1C(O)=O>>[Br:46][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[NH:12][C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=1
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Reactant: O=C(O)c1ccc(Cl)cc1Br
Agent: Nc1cc(F)c(F)cc1N
Product: Fc1cc2nc(-c3ccc(Cl)cc3Br)[nH]c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and 2-bromo-4-chloro-benzoic acid (CAS Reg. No. 936-08-3). Colorless solid (54%). MS (Turbo Spray): m/z=344.1 (M+H).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH2:8]([OH:30])[CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][S:16][CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][OH:29].[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[S:37]([O:30][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][S:16][CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][S:37]([C:7]1[CH:6]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38])([C:34]1[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: OCCOCCOCCSCCCSCCOCCOCCO
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCSCCCSCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 20 ml of methylene chloride and 5.1 g of triethylamine was added 5.6 g of 9,13-dithia-3,6,16,19-tetraoxaheneicosane 1,21-diol. Then 6.1 g of p-toluenesulfonyl chloride at 0° to 5° C. in 20 ml of methylene chloride was added dropwise. The mixture was stirred overnight at room temperature and then was washed with 50 ml of water. The organic layer was dried over MgSO4. After filtration, the solvent from the filtrate was evaporated and the residue was purified using silica gel column chromatography (CH2Cl2/CH3COCH3) (50:1 v/v). About 8 g (78%) of 9,13-dithia-3,6,16,19-tetraoxaheneicosane-1,21-diol ditosylate was collected. The process step for obtaining this composition is shown schematically below:
Reaction SMILES: [CH:1]1([C:4](OC)=O)C[CH2:2]1.[N:8]1[O:9][N:10]=[C:11]2[C:16]([CH:17]=O)=[CH:15][CH:14]=[CH:13][C:12]=12.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>>[N:8]1[O:9][N:10]=[C:11]2[C:16]([CH:17]3[C:11]([C:12]#[N:8])=[C:16]([CH:4]4[CH2:1][CH2:2]4)[NH:19][C:20]4=[N:21][NH:22][CH:23]=[C:24]34)=[CH:15][CH:14]=[CH:13][C:12]=12
Reactant: O=Cc1cccc2nonc12
Reactant: COC(=O)C1CC1
Reactant: Nc1cc[nH]n1
Product: N#CC1=C(C2CC2)Nc2n[nH]cc2C1c1cccc2nonc12

Procedure:
The title compound was prepared from methyl cyclopropanecarboxylate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
Reaction SMILES: [CH2:1]([N:4]1C[CH2:8][CH2:7][CH2:6][C:5]1=O)[CH2:2][CH3:3].[OH-].[Na+].Cl.[C:14](=[O:17])([O-])[O-:15].[Na+].[Na+].[Br:20][C:21]1[CH:22]=[CH:23][C:24](F)=[C:25]([CH:28]=1)[CH:26]=[O:27]>O.CS(C)=O>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:4]([CH2:5][CH2:6][CH2:7][CH2:8][C:14]([OH:15])=[O:17])[CH2:1][CH2:2][CH3:3])=[C:25]([CH:26]=[O:27])[CH:28]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: O=C([O-])[O-]
Reactant: CCCN1CCCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCCCC(=O)O)c1ccc(Br)cc1C=O
Temperature: 0 °C
Yield: 96.7 %

Procedure:
A mixture of 1-propyl-2-piperidone (7.5 g) and 4N sodium hydroxide (26.6 ml) was refluxed for 4 hours. The mixture was cooled to 0° C. and conc. hydrochloric acid (8.85 ml) was added thereto. To the mixture were added sodium carbonate (11.3 g), 5-bromo-2-fluorobenzaldehyde (5.4 g) and DMSO (70 ml), and the resulting mixture was heated at 135° C. for 6 hours. The mixture was allowed to cool. Water was added and the mixture was extracted with THF-ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain brown oil of 5-(4-bromo-2-formyl-N-propylanilino)pentanoic acid (8.8 g)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:26])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24]O)[CH:18]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[H][H]>C(O)C.C(Cl)(Cl)Cl.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:26])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=2)[CH3:13])=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(O)c(C)c2)cc1

Procedure:
N-(2-[4-Carbomethoxyphenyl]-1-methylethyl)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine (3.0 g) was hydrogenated in a mixture of ethanol (200 ml) and chloroform (20 ml) at 1 atmosphere and room temperature in the presence of 5% palladium on charcoal (150 mg) until hydrogen uptake was complete. The catalyst was removed and the product was recrystallised as the hydrochloride from ethyl acetate as a 32.5:67.5 mixture of diastereoisomers, mp 103°-107° (2.0 g). τ(d6DMSO) 8.88 (3H, d, J=6 Hz), 7.90 (3H, s), 6.10-7.20 (7H, m), 6.20 (3H, s), 5.02 (1H, m), 2.70-3.30 (3H, m), 2.62 (2H, d, J=8 Hz), 2.10 (2H, d, J=8 Hz), 0.62 (1H, br).