Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1([S:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:23][B-:24]([F:27])([F:26])[F:25].[H+]>C(OCC)C.C1C=CC=CC=1>[F:23][B-:24]([F:27])([F:26])[F:25].[C:3]1([S+:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccccc1
Reactant: O=S(c1ccccc1)c1ccccc1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of magnesium turning (12 g) in ethyl ether (500 ml), bromobenzene (83.5 g, 0.54 mole) was added dropwise under reflux with stirring and continued to stir for 1 hour under reflux. to this Grignard reagent, benzene (500 ml) was added and concentrated until 500 ml. To this resultant mixture, a solution of diphenylsulfoxide (30 g, 0.15 mole) in benzene (200 ml) was added and reacted with stirring for 40 hours under reflux. After the reaction mixture was cooled to 0° C., 40% tetrafluoroboric acid (50 ml) was added dropwise at 0°-5° C. and reacted with stirring for 5 hours at the same temperature. After standing at room temperature overnight, the aqueous layer separated was extracted with methylene chloride (100 ml×3), the organic layer was washed with H2O, dried over anhydrous sodium sulfate and dried. The residual crude solid was recrystallized from chloroform/ethyl ether to give 28 g of triphenylsulfonium tetrafluoroborate as white crystals. m.p. 291°-292° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4].CCN(C(C)C)C(C)C.[CH:21]1([CH2:26][C:27]2[N:31]([CH:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:30]3[CH:37]=[CH:38][C:39]([C:41](Cl)=[O:42])=[CH:40][C:29]=3[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[CH:6]1([CH2:5][C@H:2]([NH:1][C:41]([C:39]2[CH:38]=[CH:37][C:30]3[N:31]([CH:32]([CH2:33][CH3:34])[CH2:35][CH3:36])[C:27]([CH2:26][CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:28][C:29]=3[CH:40]=2)=[O:42])[CH2:3][OH:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: N[C@H](CO)CC1CCCCC1
Reactant: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)Cl)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)N[C@H](CO)CC3CCCCC3)ccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 26.3 %

Procedure:
47 mg of (S)-2-amino-3-cyclohexyl-propan-1-ol and 0.14 ml DIPEA were dissolved in 2 ml dry THF. The mixture was cooled to −10° C. and 67 mg of 2-cyclopentylmethyl-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carbonyl chloride in 1 ml of dry THF were added. The mixture was stirred under exclusion of moisture for 15 min at −10° C. and then at RT over night. It was then filtered, the filter was washed with 10 ml ethyl acetate. The filtrate was evaporated, the residue was taken up in 20 ml ethyl acetate and extracted with 20 ml 5% NaHCO3. The organic phase was dried and evaporated and the residue was purified by HPLC to yield 24 mg (27%) of 2-cyclopentylmethyl-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carboxylic acid ((S)-1-cyclohexylmethyl-2-hydroxy-ethyl)-amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1.[CH2:28](O)[CH3:29].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:28][CH3:29])=[O:24])=[CH:26][CH:27]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccccn3)[nH]2)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccccn3)[nH]2)cc1

Procedure:
Material from Example 3 was heated at reflux in a solution of ethanol/sulfuric acid for 18 h. The solution was concentrated to removed the ethanol and the resulting aqueous solution was extracted with chloroform to yield the title compound. ESMS (M+H)+=388.2.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A165) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:10])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@](C)(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@](C)(C(=O)N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
630 mg (2.374 mmol) of N-(tert-butoxycarbonyl)-2-phenyl-D-alanine were dissolved in 20 mL of dry DMF and O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoborate (TBTU, 1.37 g, 4.27 mmol), morpholine (0.412 mL, 4.73 mmol) and diisopropylethylamine (1.63 mL, 9.5 mol) were added. The mixture was stirred at room temperature for 1 hour, then the solvent was removed and the residue dissolved with dichloromethane. The solution was washed with saturated NaHCO3, brine, water and dried over Na2SO4. 700 mg of the title compound were recovered (88% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([C:22]([F:25])([F:24])[F:23])[C:14]=1Cl)([O-:12])=[O:11]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14]2[C:15]([C:22]([F:24])([F:25])[F:23])=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=2[N+:10]([O-:12])=[O:11])=[N:3][CH:4]=1
Reactant: COc1ccc(N)nc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Product: COc1ccc(Nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)nc1

Procedure:
In accordance with the process of Preparation 8 except using 1.2 g. of 2-amino-5-methoxypyridine and 2.8 g. of 2,4-dinitro-6-trifluoromethylchlorobenzene, the reaction was carried out for 5 hours. The reaction mixture was treated as the process of Preparation 6 to obtain 1.2 g. of the object compound having the melting point of 102° to 105° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:26](=[O:27])[CH2:25][C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:13]=2)[CH2:8]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)Cc3ccccc3)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and phenacetyl chloride.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][NH:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]=[CH2:17])=[C:10]([Cl:18])[CH:9]=1.[OH-].[Na+].Cl>CC(C)=O>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]([NH:5][CH2:4][C:3]([OH:20])=[O:2])=[O:19])=[CH:9][C:10]=1[Cl:18])[CH:16]=[CH2:17]
Reactant: C=CCOc1ccc(CC(=O)NCC(=O)OC)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCOc1ccc(CC(=O)NCC(=O)O)cc1Cl
Temperature: 40 °C
Yield: 79.5 %

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-glycine methyl ester (0.594 g) was suspended in acetone (8.0 ml) to which was added aqueous sodium hydroxide solution (1M, 4.0 ml) and the whole was warmed to 40° C. for 30 min. After the solution had been cooled to 0° C., the pH was adjusted to 2-3 using dilute hydrochloric acid (3M) and quickly extracted with ethyl acetate (20 ml). The extract was dried (anhydrous sodium sulphate). The solvent was evaporated at reduced pressure to leave a solid residue (450 mg), m.p. 115°-119° C. After recrystallisation from ethyl acetate/light petroleum (b.p. 60°-80° C.) the above-named product, m.p. 117°-119° C., was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.[CH3:14][CH:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:14]([CH:9]1[CH2:8][C:7](=[O:13])[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10]1)[CH:15]=[CH:16][CH3:17]
Reactant: COc1ccc2c(c1)OCCC2=O
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1CC(=O)c2ccc(OC)cc2O1
Yield: 41 %

Procedure:
A solution 11.9 g of 7-methoxy-4-chromanone, 13.8 ml of 3-buten-2-ol and 120 mg of p-toluenesulfonic acid in 14 ml of 2,2-dimethoxypropane and 120 ml of anhydrous toluene was boiled under reflux for 24 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 6.3 g (41%) of (RS)-2-(2-buten-1-yl)-7-methoxy-4-chromanone were obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15]([CH2:17]Cl)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:13][CH2:14][C:15]1[N:12]=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[O:11][CH:17]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccc(/C=C/C(N)=O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(/C=C/c2nc(CCl)co2)cc1
Yield: 72.2 %

Procedure:
A mixture of (E)-3-(4-methylphenyl)-2-propenamide (8.06 g) and 1,3-dichloroacetone (6.98 g) in toluene (50 ml) were refluxed for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saline, and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane 1:4) to yield the titled compound (8.44 g) as a white crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C@H:25]([CH2:28][CH3:29])[CH2:26][OH:27]>>[OH:27][CH2:26][C@H:25]([NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH2:28][CH3:29]
Reactant: CC[C@@H](N)CO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: CC[C@H](CO)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 85 %

Procedure:
As described for example 208, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using (R)-(+)-2-amino-1-butanol instead of (S)-(+)-2-amino-1-butanol, to the title compound (210 mg, 85%) which was obtained as a white solid. MS: m/e=380.2 [M−H]−.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH2:12]([C:18]([NH:20][NH2:21])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16]C>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:18](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCCCCCC(=O)NN
Product: CCCCCCN1C(=O)/C(=N\NC(=O)CCCCC)c2ccccc21
Yield: 32 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and hexanecarbohydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 32%. 1H NMR (DMSO-d6): δ 0.82-0.91 (m, 6H), 1.27-1.33 (m, 10H), 1.62 (m, 4H), 2.71 (br s, 1H), 3.74 (t, J=7.2 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 12.44 (br s, 1 H). 13C NMR (DMSO-d6): δ 14.25 (CH3), 14.29 (CH3), 22.30 (CH2), 22.42 (CH2), 26.33 (CH2), 27.36 (CH2), 31.26 (CH2), 31.28 (CH2), 39.59 (CH2), 110.46 (CH), 119.72 (C), 120.62 (CH), 123.41 (CH), 131.73 (CH), 143.22 (C═N), 161.01 (C═O). HRMS (ES+) calcd for C20H30N3O2 (M+H+), m/e, 344.2335; found, 344.2333.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH2:3].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13]>N1C=CC=CC=1>[CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH:3][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([F:8])[CH:10]=1
Reactant: CNC(=S)N(C)N
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: CNC(=S)N(C)NC(=O)c1cccc(F)c1
Reaction time: 8 h

Procedure:
To a stirred, room temperature, solution of 2,4-dimethylthiosemicarbazide (5.96 g, 50.0 mmol) and dry pyridine (100 mL) was added dropwise 3-fluorobenzoyl chloride (7.93 g, 50.0 mmol). After stirring overnight, the reaction mixture was evaporated at reduced pressure. The concentrate was slurried with water and that which did not dissolve was collected by filtration. Crystallization of this material from ethanol afforded the desired product as colorless needles, mp 202°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([NH2:27])[CH2:23][CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:27][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: CC(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(NCCC(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 81.2 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and isopentylamine (0.18 mL, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 40% methylene chloride in hexane to give light yellow solid (0.49 g, 82%): GCMS m/z 393.00 (M+). 1H NMR (CDCl3/400 MHz) 7.58 (s, 1H), 7.09 (s, 1H), 6.31 (s, 1H), 5.64 (q, 1H, J=7.0 Hz), 4.27 (m, 2H), 3.19 (m, 2H), 1.71 (m, 1H), 1.57 (m, 2H), 1.31 (m, 3H), 0.96 (m, 6H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=O)[CH3:9])(C)(C)C.Cl>C(Cl)(Cl)Cl>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:27])[CH:8]([CH3:9])[N:7]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:13]=2[CH:14]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)cc1C(=O)c1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1N=C(c2ccccn2)c2cc(Br)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
To a stirred solution of ester 124 (16 g, 35.69 mmol) in CHCl3 (300 mL) at rt, hydrogen chloride gas was added in slowly. After 20 min, the addition was stopped and the solution was allowed to stir overnight at rt. The reaction mixture was washed with a saturated solution of sodium bicarbonate (2×50 mL) and water (2×50 mL). The organic layer was concentrated under reduced pressure. The residual oil was dissolved in methanol-water (3:1, 300 mL) and the pH was adjusted to 8.5 by the addition of aq sodium hydroxide (1 N). The reaction mixture was stirred for 10 h at rt. The solution was concentrated under reduced pressure and water (80 mL) was added. The solution was extracted with CH2Cl2 (3×70 mL) and concentrated under reduced pressure. The crude solid 125 was purified by recrystallization from methanol/water to provide pure 125 (9.42 g, 80%). mp 227-229° C.; IR (KBr, cm−1) 2928, 1684, 1611, 1476; 1H NMR (CDCl3) δ 9.47 (bs, 1H), 8.62 (d, J=4.7 Hz, 1H), 8.0 (d, J=7.90 Hz, 1H), 7.81 (td, J=7.7, 1.6 Hz, 1H), 7.56 (dd, J=8.6, 2.2 Hz 1H), 7.50 (dd, J=2.1 Hz, 1H), 7.36 (dd, J=7.4 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 3.85 (q, J=6.5 Hz, 1H), 1.76 (d, J=6.5 Hz, 3H); MS (EI) m/e (relative intensity) 330 (M+, 50), 329 (50), 314 (52), 288 (100), 250 (30), 208 (32), 179(50), 88(72); [α]26D=403.2 (c 0.50, EtOAc).
Reaction SMILES: CO[CH:3]([NH:7][C:8]([NH2:10])=[O:9])[C:4]([OH:6])=O.[C:11]1([C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14])[OH:12].NC(N)=O>Cl>[OH:12][C:11]1[CH:18]=[C:17]([CH:3]2[NH:7][C:8](=[O:9])[NH:10][C:4]2=[O:6])[CH:16]=[CH:15][C:13]=1[OH:14]
Reactant: COC(NC(N)=O)C(=O)O
Reactant: Oc1ccccc1O
Agent: Cl
Agent: NC(N)=O
Product: O=C1NC(=O)C(c2ccc(O)c(O)c2)N1
Reaction time: 18 h
Yield: 44 %

Procedure:
One mole (148.12 g) of α-methoxyhydantoic acid, 1.25 moles (137.64 g) of catechol, 1 mole (60.06 g) of urea and 300 ml of concentrated HCl (36 percent volume) were placed into the 2-liter flask of Preparation 1, and are stirred at 60° C. to 65° C. for 18 hours. The heterogeneous solution is filtered and is recrystallized from ethanol to give the title compound, with a melting point of 212° C.-214° C., in a yield of 44 percent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J28) (271 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (346 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].C(Cl)Cl>ClCCCl>[NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24]
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Yield: 62.8 %

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (1.1 g, 2.7 mmol) was dissolved in 50 ml of anhydrous 1,2-dichloroethane and 3.4 g (10.8 mmol) of borontribromide-dimethylsulfide complex was added to the solution. The solution was refluxed for 16 hr and, methylene chloride (100 ml) was added. Washing with water followed by drying (anhydrous sodium sulfate) and removal of the solvent afforded a residue which was triturated with ether to afford the title compound (0.6 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([SH:14])[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].Cl.CCOCC>O.[OH-].[Na+]>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[NH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1nc(SCc2ccccc2)n[nH]1
Reactant: CC(Br)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(Sc1nc(SCc2ccccc2)n[nH]1)C(=O)O
Reaction time: 8 h
Yield: 48.7 %

Procedure:
3-Benzylthio-5-mercapto-1,2,4-triazole (56 g) was added with stirring and cooling to a solution of sodium hydroxide (10.1 g) in water (150 ml). A cold solution of 2-bromopropionic acid (38.4 g) in aqueous sodium hydroxide (10 g in 50 ml water) was added dropwise with stirring. The mixture was stirred for a further 6 hours at room temperature and allowed to stand overnight. After acidification with concentrated hydrochloric acid (30 ml), the precipitated white sticky solid was taken into ether. The ether solution was washed with water, dried, and the volume reduced to about 200 ml. The product crystallised, and was isolated by filtration to give 36.1 g of desired product, mp 123°-124° C. Successive reductions of the mother liquors gave further product, giving a total yield of 60 g.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Cl[C:17]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=[C:19]([Cl:27])[N:18]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:27][C:19]1[N:18]=[C:17]([NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[C:26]2[C:21](=[N:22][CH:23]=[CH:24][N:25]=2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Reactant: Clc1cc2nccnc2c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CNc2nc(Cl)cc3nccnc23)C1

Procedure:
A solution of (S)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (100 mg, 0.5 mmol), 5,7-dichloropyrido[4,3-b]pyrazine (100 mg, 0.5 mmol) and DIPEA (77 mg, 0.6 mmol) in THF (5 mL) was stirred at room temperature for 4 hours. The volatiles were removed under reduced pressure, and the residue was treated with ethyl acetate, with brine, and concentrated to give the crude title compound.
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[C:6]([CH2:20][CH:21]=[CH2:22])[CH:5]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:26])=O>CN(C)C=O.C(Cl)Cl>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:26])=[O:15])=[C:6]([CH2:20][CH:21]=[CH2:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCCC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCc1cc(C(C)=O)c(O)cc1OCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3.06 g of 6-(4-acetyl-5-hydroxy-2-allylphenoxy)hexanoic acid, 1.74 ml of oxalyl chloride, 100 ml of methylene chloride, and ten drops of dimethylformamide was mixed at 0° C. and allowed to warm to room temperature. After stirring for 4 hours, the solvents were removed by evaporation to provide the desired title product. NMR.