Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=O)[CH2:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:30][NH:31][C:32]([NH:34][OH:35])=[NH:33].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=[N:30][NH:31][C:32](=[NH:33])[NH:34][OH:35])[CH2:9]1
Reactant: N=C(NN)NO
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)NO)CC(c1ccccc1Cl)C2
Temperature: 85 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazole (1.14 g), 1-amino-3-hydroxyguanidine p-toluenesulfonate (1.26 g) and concentrated hydrochloric acid (0.44 ml) in ethanol (12 ml) was stirred at 85° C. (bath temperature) for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (50 ml), tetrahydrofuran (20 ml) and an aqueous solution (20 ml) of anhydrous potassium carbonate (1.4 g). The mixture was shaken, and the separated upper layer was washed with an aqueous solution (10 ml) of anhydrous potassium carbonate (0.7 g) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (2.3 ml), and the mixture was concentrated under reduced pressure. To the residue was added a mixture of ether (30 ml) and ethanol (15 ml), and the mixture was stirred at room temperature for 15 hours to give solidified powder. The powder was stirred in ethanol (4 ml) at 90° C. (bath temperature) for 1 hours, and precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethanol (12 ml). The solution was stirred at 90° C. (bath temperature) for 14 hours. The reaction solution cooled, and crystals precipitated while stirring were filtered, washed with ethanol and dried to give 6-(2-chlorophenyl)-4-(1-hydroxyguanidin-3-yl)imino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 93) (604 mg) as pale yellow crystals.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].[CH3:9][C:10]([CH2:14]C)=[CH:11][CH2:12]O.C([O-])(=O)C.C([Sn+2]CCCCCCCC)CCCCCCC.C([O-])(=O)C>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH:9]=[C:10]([CH3:14])[CH2:11][CH3:12])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3]
Reactant: C/C=C(/C)C(=O)OC
Reactant: CCC(C)=CCO
Agent: CC(=O)[O-]
Agent: CCCCCCCC[Sn+2]CCCCCCCC
Solvent: Cc1ccccc1
Product: C/C=C(/C)C(=O)OCC=C(C)CC

Procedure:
A mixture of 22.8 g. of methyl angelate, 10 g. of 3-methyl-2-pentenol, 80 ml. of toluene and 1 g. of dioctyltin acetate was placed in a 300 ml. glass flask, which was equipped with a Soxhlet extractor filled on the top with molecular sieve 4A and a reflux cooler. The above mixture was heated under continuous reflux while returning the refluxed liquid through the molecular sieve 4A to the flask. The mixture resulted from the heating for a total of 17 hours was subjected to single distillation to give 14.2 g. of a distillate boiling at 115° C. (22 mmHg). The distillate was further subjected to rectification to give 9.70 g. of a distillate boiling at 115° C. (22 mmHg). Analysis of the compound by gaschromatography (Column: Silicone SE-52, 2%/chromosorb GHP) indicated a purity of 99.403% in terms of the area ratio. Refractive index (D ray, 20° C.) was 1.463. Infrared spectrum (liquid film) had absorptions at 2850-3020, 1720, 1670, 1650, 1455, 1385, 1350, 1255, 1225, 1155, 1080, 1040, 960, 845 and 760 cm-1.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:37])[CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[NH:27])[CH:23]=3)[C:18]2=[O:36])=[CH:11][CH:10]=1)C.CC(O)=O>CO>[C:32]([O:31][C:29]([NH:28][C:26](=[NH:27])[C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:36])[N:17]([CH2:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:38])=[O:5])=[CH:14][CH:13]=1)=[O:37])[CH2:25]2)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)COc1ccc(C(=O)CN2Cc3cc(C(=N)NC(=O)OC(C)(C)C)ccc3C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC(=N)c1ccc2c(c1)CN(CC(=O)c1ccc(OCC(=O)O)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aqueous 0.1N NaOH (11.4 ml; 1.14 mmol) was added to a solution of the compound of example 17a (0.375 g; 0.756 mmol) in MeOH (10 ml), The reaction mixture was stirred at room temperature for 30 min., acidified with AcOH and concentrated. The crude title compound obtained was filtered, washed with cold water and dried under vacuum. Yield, 140 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH2:23][CH3:24].C(O)(=O)/C=C/C(O)=O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH3:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCCI
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 8: 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.54 g, 2.7 mmol), acetonitrile (30 mL), sodium carbonate (0.38 g, 6.75 mmol), iodopropane (0.26 mL, 2.7 mmol). Yield: 0.22 g. The amine was converted to the fumaric acid salt: M.p. 136-137° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 8), 213 (13), 212 (bp), 182 (34), 84 (60).
Reaction SMILES: [OH-:1].[Na+].[C:3]([N:7]=[N:8][C:9](Cl)([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4]>C(O)(C)(C)C>[C:3]([N:7]=[N:8][C:9]([OH:1])([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)N=NC(C)(C)Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)N=NC(C)(C)O

Procedure:
2-t-butylazo-2-hydroxypropane was prepared by reacting aqueous sodium hydroxide and 2-t-butylazo-2-chloropropane in t-butyl alcohol. The 2-t-butylazo-2-hydroxypropane was isolated by diluting the alcohol solution with water and extracting with pentane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccn1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccccn1
Yield: 55.4 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (680 mg, 2 mmol) and 2-aminopyridine (200 mg, 2 mmol) to give 460 mg of the title compound (55%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.08 (bs, 1H), 10.58 (s, 1H), 8.31 (d, 1H, J=4.6 Hz), 8.07 (t, 2H, J=8.1 Hz), 7.79 t, 1H, J=8.1 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.10 (dd, 1H, J=4.6, 8.1 Hz), 5.17~5.27 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.81 (dm, 1H, J=17.1 Hz), 2.76 (dd, 1H, J=13.5, 7.2 Hz), 2.57 (dd, 1H, J=13.5, 5.4 Hz), 2.07 (dm, 1H, J=13.5 Hz), 1.80~1.94 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([C:25]([F:28])([F:27])[F:26])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Fc1ccc2c(c1)CCNC2C(F)(F)F
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2cc(F)ccc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: CO.[OH-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17]1)=[N:11][N:10]=[C:9]2[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([Cl:37])[CH:30]=1>O1CCCC1>[C:22]([CH:19]1[CH2:20][CH2:21][N:16]([C:12]2[C:13]3[C:8](=[CH:7][C:6]([Cl:5])=[CH:15][CH:14]=3)[C:9]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([Cl:37])[CH:30]=3)=[N:10][N:11]=2)[CH2:17][CH2:18]1)([OH:24])=[O:23]
Reactant: CCOC(=O)C1CCN(c2nnc(NCc3ccc(OC)c(Cl)c3)c3cc(Cl)ccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNc2nnc(N3CCC(C(=O)O)CC3)c3ccc(Cl)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Methanol (50 ml), tetrahydrofuran (50 ml) and 1N aqueous solution (10 ml) of sodium hydroxide were added to 3.00 g of the compound prepared in Example 42. The obtained mixture was stirred at room temperature overnight and freed from the solvent by vacuum distillation. The residue was dissolved in 100 ml of water, followed by the addition of 10 ml of 1N hydrochloric acid. The crystals thus precipitated were recovered by filtration to give 2.76 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]([C:13]([OH:15])=O)[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH2:8][O:7][C:6]=2[C:5]([CH3:20])=[CH:4][CH:3]=1.[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:25]=1[NH2:26])([CH3:23])[CH3:22]>>[CH:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:24]([CH:21]([CH3:23])[CH3:22])[C:25]=1[NH:26][C:13]([CH:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH2:8][O:7][C:6]2[C:5]([CH3:20])=[CH:4][CH:3]=[C:2]([CH3:1])[C:12]1=2)=[O:15])([CH3:33])[CH3:32]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Cc1ccc(C)c2c1OCc1ccccc1C2C(=O)O
Product: Cc1ccc(C)c2c1OCc1ccccc1C2C(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 55.7 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.34 g of 6,11-dihydro-1,4-dimethyldibenz[b,e]oxepin-11-carboxylic acid obtained in Example 64 (Compound AC) in place of Compound A and 1.18 g of 2,6-diisopropylaniline in place of aniline to obtain 1.19 g of Compound 49.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])=O)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:11][C@@H:12]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH2:16]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@@H](N)Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
A solution of (2S)-2-(benzyloxycarbonyl)amino-1-{4-(tert-butoxycarbonyl)piperazin-1-yl}-3-phenyl-1-propanone (4.2 g, Reference compound No. 25-1) in ethanol (30 ml) is saturated with a nitrogen gas. Then, 5% palladium hydroxide/carbon (2.1 g) is added to the solution, and the whole is stirred overnight under a hydrogen atmosphere (4.2 kgf/cm−1). The reaction mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure, ethyl acetate is added to the resulting residue, and the whole is extracted with a 10% aqueous citric acid solution. Sodium hydrogencarbonate is added to the extract to basify the system, and the whole is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled reference compound (1.32 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][C:6]#[N:7].[Na].[CH3:11][OH:12]>>[F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][C:6](=[NH:7])[O:12][CH3:11]
Reactant: CO
Reactant: N#CCOCC(F)(F)F
Agent: [Na]
Product: COC(=N)COCC(F)(F)F

Procedure:
Obtained using the procedure described in section a of Example 2, starting with 19.6 g (0.141 mole) of (2,2,2-trifluoroethoxy)acetonitrile and 0.3 g (0.013 gram-atom) of sodium in 95 ml of methanol. Reaction time: 24 hours. Yld: 15.6 g (65%), b.p.15 44°-47° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reaction time: 14 h
Yield: 39.4 %

Procedure:
Under a nitrogen atmosphere, to a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (100 mg), ethyl 3-cyclopropyl-3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (94 mg) and triphenylphosphine (182 mg) in THF (3.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (315 μL) at room temperature, and the mixture was stirred for 14 hr. Triphenylphosphine (182 mg) and a 40% solution of diethyl azodicarboxylate in toluene (315 μL) were added to the reaction mixture, and the mixture was further stirred at room temperature for 14 hr. The solvent of the reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (71 mg) as a pink oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1.Cl.O1CCOCC1>CCOC(C)=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(Cl)ncnc2c1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2c1

Procedure:
To 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (137 mg, 0.5 mmol) was added 4-chloro-7-methoxyquinazoline (97 mg, 0.5 mmol) according to the procedure described in Example 1B. The resulting compound was dissolved in EtOAc (5 mL) and 4N HCl in dioxane (0.2 mL, 0.8 mmol) was added. The mixture was sonicated, stirred and concentrated in vacuo to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxyquinazolin-4-yloxy)phenyl)urea as the mono-hydrochloride (103 mg, 0.22 mmol, 44%). 1H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.15 (s, 1H), 8.69 (s, 1H), 8.28 (d, 1H), 7.58 (s, 1H), 7.45-7.35 (m, 3H), 7.27 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 3.98 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 434 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:18]C)(=[O:17])[CH:14]([CH3:16])[CH3:15].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[NH4+].[Cl-]>C1COCC1.CN1C(=O)N(C)CCC1>[CH3:15][C:14]([CH3:16])([CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[C:13]([OH:18])=[O:17]
Reactant: COC(=O)C(C)C
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1oc(-c2ccccc2)nc1CC(C)(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6M in hexane, 5.05 ml) was added dropwise to a solution of diisopropylamine (1.16 ml) in THF (30 ml) at 0° C. under argon. The resulting mixture was stirred for another 15 minutes before it was cooled to −78° C. and a solution of methyl isobutyrate (0.84 ml) in THF (3 ml) was added dropwise. After the addition was completed, the reaction mixture was allowed to warm to 0° C. and than again cooled to −78° C. At this temperature a solution of 4-chloromethyl-5-methyl-2-phenyl-oxazole [CAS 103788-61-0, commercially available] (1.17 g) in THF (6 ml) and DMPU (7.7 ml) was added. Stirring was continued for another 30 minutes before a saturated NH4Cl solution (1 ml) was added. Then the THF was removed in vacuo and water was added to the remaining residue. This mixture was extracted with ether and the combined organic extracts were washed with water and brine and dried (MgSO4). After evaporation of the solvent the crude alkylation product (1.46 g) was dissolved in THF (20 ml) and LiOH solution (1M, 14.5 ml) was added. The reaction mixture was stirred overnight, concentrated and washed with ether. Then the pH was adjusted to 1 by addition of 3N HCl and the resulting suspension was extracted with ether. Finally the combined extracts were washed with water and brine, dried (MgSO4) and the solvent was removed in vacuo. The product was obtained as a white solid (1.33 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.[F:19]C1C=CC(F)=CC=1B(O)O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:19])=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2cc(F)ccc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2,5-difluorophenyl)boronic acid gave the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:3].CCN(C(C)C)C(C)C.[Br:20][C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:38][C:39]([C:41]3[S:42][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:44][CH:45]=3)=[O:40])[C:35](O)=[O:36])=[CH:29][CH:28]=2)=[N:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:20][C:21]1[CH:26]=[N:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][C@H:34]([NH:38][C:39]([C:41]3[S:42][C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:44][CH:45]=3)=[O:40])[C:35]([NH:1][C@@H:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:3])=[O:36])=[CH:31][CH:32]=2)=[N:23][CH:22]=1
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)s1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)s1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring solution of tert-butyl D-alaninate (5.60 g, 30.80 mmol) in DMF (50 mL) were added DIEA (8.29 g, 64.18 mmol) and (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid (12.5 g, 25.67 mmol). The solution was cooled to 0° C. at ice bath and then HATU (9.06 g, 38.50 mmol) in 15 mL DMF solution was slowly added. The reaction was stirred 1 hour at 0° C. and then warmed to RT with stirring for 2 hours. The reaction solution was extracted with DCM (3×50 mL) and aqueous NaHCO3 (3×30 mL). The combined organics were dried over MgSO4 and evaporated. The final compound was purified by column chromatography (40% DCM in hexane) to afford 14.7 g (94%) of tert-butyl ((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)-D-alaninateas solid powder. LCMS-ESI (m/z) calculated for C29H35BRN4O4S: 614.2. found 615.3 [M+H]+, tR=3.914 min. (Method 16). 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=3.6 Hz, 2H), 8.36 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.34 (d, J=3.8 Hz, 1H), 6.81 (d, J=3.8 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.34 (d, J=7.2 Hz, 1H), 4.88 (d, J=5.9 Hz, 1H), 4.41 (t, J=7.2 Hz, 1H), 3.31 (dd, J=13.6, 5.8 Hz, 1H), 3.20 (dd, J=13.6, 7.8 Hz, 1H), 1.51-1.32 (m, 18H), 1.27 (d, J=7.1 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 172.02, 171.31, 162.28, 162.13, 161.42, 158.55, 142.27, 136.34, 134.66, 130.20, 128.82, 127.92, 123.07, 118.63, 80.90, 54.45, 48.86, 39.59, 39.38, 32.39, 28.04, 17.68.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17](C)C)[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.COC(=O)[C@H](C)N>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Agent: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)N1Cc2ccc(Br)cc2C1=O

Procedure:
The compound of example 335 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and L-alanine methyl ester hydrochloride.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O-:3])=[O:2].[CH:12](=[O:15])[CH2:13][CH3:14].CC(O)C>CCCCCC>[CH:6]1([C@H:5]([CH2:4][N+:1]([O-:3])=[O:2])[C@H:13]([CH3:14])[CH:12]=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=[N+]([O-])/C=C/C1CCCCC1
Reactant: CCC=O
Solvent: CCCCCC
Solvent: CC(C)O
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])C1CCCCC1

Procedure:
The title compound was prepared from (E)-(2-nitrovinyl)cyclohexane and propionaldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 210 nm (2-propanol:hexane=1:99), 1 mL/min, tmajor=17.0 min, tminor=19.1 min, the diastereomeric ratio was determined by
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:7]([CH3:21])[CH:6]=1)=[O:4].[OH-].[Na+].C(O)=O>CO.O>[CH3:21][N:7]1[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:19])([F:20])[F:18])=[C:9]([CH3:10])[C:5]([C:3]([OH:4])=[O:2])=[CH:6]1
Reactant: COC(=O)c1cn(C)c(-c2ccccc2C(F)(F)F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=CO
Product: Cc1c(C(=O)O)cn(C)c1-c1ccccc1C(F)(F)F
Yield: 90.4 %

Procedure:
To a solution of 1,4-dimethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.5 g, 8.4 mmol) in MeOH (20 mL) was added 4N NaOH (10 mL) and the mixture was heated to reflux overnight. Evaporation of solvent gave a solid, which was re-dissolved in water. The solution was acidified with formic acid. The resulting solids were collected by filtration, washed with water and then dried under high vacuum to afford the title compound as an off-white solid (2.15 g, 90%). MS (ES): 284 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3](O)[CH2:4][CH2:5][CH:6]=1.C[O:9][C:10](OC)([N:12]([CH3:14])[CH3:13])[CH3:11]>C1(C)C=CC=C(C)C=1>[Br:1][C:2]1[CH:3]([CH2:11][C:10]([N:12]([CH3:14])[CH3:13])=[O:9])[CH2:4][CH2:5][CH:6]=1
Reactant: OC1CCC=C1Br
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1cccc(C)c1
Product: CN(C)C(=O)CC1CCC=C1Br
Yield: 62.7 %

Procedure:
2-Bromo-cyclopent-2-enol (Intermediate D3) (2.18 g, 13.4 mmol) and N,N-dimethylacetamide dimethyl acetal (3.5 mL, 21.5 mmol) in m-xylene (˜20 mL) were heated to 140° C. for 14 h. The mixture was freed of solvent and the residue was purified on a column of silica gel with 30% to 50% EtOAc:hexanes to give 2-(2-bromo-cyclopent-2-enyl)-N,N-dimethyl-acetamide (Intermediate FOUR1) 1.95 g (63%) as a brown oil.