Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=O)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].Cl.[NH2:30][OH:31].N1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([C:19](=[N:30][OH:31])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: NO
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=NO)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 68.2 %

Procedure:
Compound 1 (0.300 g, 0.812 mmol) was dissolved in ethanol (10 mL), and hydroxylamine monohydrochloride (0.113 g, 1.63 mmol) and pyridine (0.145 mL, 1.79 mmol) was added to the solution, followed by stirring at 60° C. for 3.5 hours. The reaction mixture was diluted with chloroform, and sequentially washed with water, 0.5 mol/L hydrochloric acid, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude crystals were recrystallized from ethanol to obtain Compound 3 (0.213 g, yield 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCN(CC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)S(=O)(=O)c1ccc(N)cc1
Reaction time: 2 h
Yield: 106.5 %

Procedure:
A 250 mL Parr shaker bottle was charged with 4-nitro-N,N-diethyl-benzenesulfonamide (617 mg, 2.39 mmol), ethyl acetate (50 mL), and 10% palladium on activated carbon (100 mg). The bottle was place on a Parr shaker apparatus and charged with hydrogen to a pressure of 52 psi. The reaction mixure was shaken for two hours, filtered through celite, and concentrated to provide 4-Amino-N,N-diethyl-benzenesulfonamide as a green solid (581 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=O)[NH:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.C([O-])(O)=O.[Na+].CCOC(C)=O>Cl.CO.[Zn]>[O:9]=[S:8]1(=[O:10])[C:4]2[CH:3]=[C:2]([NH2:1])[CH:13]=[CH:12][C:5]=2[CH2:6][NH:7]1
Reactant: Nc1ccc2c(c1)S(=O)(=O)NC2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)S(=O)(=O)NC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
To a solution of 6-amino-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (7.0 g, 35 mmol, Preparation #1) in concentrated HCl (80 mL) was added zinc dust (19.0 g, 292 mmol), in portions over about 30 min while maintaining the temperature below about 70° C. The mixture was stirred at rt for about 3 h. The mixture was basified with a solution of saturated aqueous NaHCO3 (50 mL), then with solid NaHCO3 (pH=7). The mixture was added to EtOAc (100 mL), filtered and the filtrate was extracted with EtOAc (3×150 mL). The organic phases were combined, washed with brine (3×150 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give a solid. The residue from filtration was triturated with EtOAc (2×200 mL) and filtered. The organic phases were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give a solid. All the solids were dissolved in MeOH, combined and then concentrated to give 1,1-dioxo-2,3-dihydro-1H-1lambda*6*-benzo[d]isothiazol-6-ylamine (5.7 g, 88%): 1H NMR (DMSO-d6) δ 7.54 (s, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.83 (dd, J=2.5, 2.0 Hz, 1H), 6.79 (d, J=1.5 Hz, 1H), 5.81 (s, 2H), 4.18 (s, 2H).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1.O>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (6 g, 250 mmol, 60 wt % in mineral oil) was added to mixture of 4-iodo-1H-pyrazole (10 g, 50 mmol) in THF (200 mL) at room temperature under N2. The mixture was stirred at room temperature for 1 hour. Ethyl 4-chloro-3-oxobutanoate (11.6 g, 75 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: EtOAc) to afford ethyl 4-(4-iodo-1H-pyrazol-1-yl)-3-oxobutanoate. MS ESI calc'd. for C9H12IN2O3 [M+H]+ 323. found 323. 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.48 (s, 1H), 5.05 (s, 2H), 4.19-4.15 (m, 2H), 3.40 (s, 2H), 1.28-1.24 (m, 3H).
Reaction SMILES: C1COCC1.Cl[C:7]1[NH:11][C:10]2[CH:12]=[C:13]([NH:27][C:28]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:37])=[O:29])[CH:14]=[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[CH3:26])=[O:17])[C:9]=2[N:8]=1.[CH:38]([O:41][CH2:42][CH2:43][NH2:44])([CH3:40])[CH3:39]>C(OCC)(=O)C>[Cl:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[C:28]([NH:27][C:13]1[CH:14]=[C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[CH3:26])=[O:17])[C:9]2[N:8]=[C:7]([NH:44][CH2:43][CH2:42][O:41][CH:38]([CH3:40])[CH3:39])[NH:11][C:10]=2[CH:12]=1)=[O:29]
Reactant: CC(C)OCCN
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2c(F)cccc2Cl)cc2[nH]c(Cl)nc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2c(F)cccc2Cl)cc2[nH]c(NCCOC(C)C)nc12
Yield: 72.2 %

Procedure:
THF (1 mL) was added to 2-chloro-6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-1H-benzimidazole-4-carboxamide (50 mg) and 2-aminoethyl isopropyl ether (32 mg). The mixture was stirred at 150° C. in a sealed pressure-proof stainless steel container for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with brine and concentrated under reduced pressure. The residue was purified on column chromatography to obtain 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide (41 mg) as pale yellow powder. This was dissolved in MeOH (1 mL), 2N hydrogen chloride/EtOH solution (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (35 mg) as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:11][O:10]2)=[CH:4][CH:3]=1.[OH2:12]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:12])[CH2:11][OH:10])=[CH:6][CH:7]=1
Reactant: Brc1ccc(CC2CO2)cc1
Reactant: O
Solvent: C1COCCO1
Product: OCC(O)Cc1ccc(Br)cc1

Procedure:
A mixture of 90 parts of 2-(4-bromophenylmethyl)oxirane, 8 parts of ethanedoic acid, 100 parts of water and 300 parts of 1,4-dioxane is stirred and refluxed overnight. The reaction mixture is evaporated. The residue is dissolved in trichloromethane. The solution is washed with 110 parts of a sodium hydroxide solution 10%, dried, filtered and evaporated. The residue is distilled (bp. 165° C. at 0.6 mm. pressure). The distillate is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 25 parts of 3-(4-bromophenyl)-1,2-propanediol; mp. 60.6° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)CC
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Temperature: 120 °C
Yield: 63 %

Procedure:
A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester (prepared as described in Preparation E, 3.4343 g, 10.74 mmol) and 1-ethyl-propyl-amine (10 ml) in 10 ml of DMSO was heated at 120° C. for 15 hr. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid. The yellow solid was recrystallized with hexane to give 2.519 g (63%) of the title compound of Preparation F as white crystals, mp 106-107.5° C. Anal. for C22H30N2O3 (C,H,N). 1H NMR (CDCl3) δ 8.04(d,1H), 6.85(s,2H), 6.06(s,1H), 3.85(s,3H), 3.32(m,1H), 2.28(s,3H), 2.10(s,3H), 2.07(s,3H), 1.62(m,4H), 0.95(t,6H) ppm.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[N:26][CH:27]=1>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:21][C:22]3[CH:27]=[N:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:20]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(CNc2cccn3nc(Cl)nc23)c1
Reactant: COc1ccc(N)cn1
Product: COc1cccc(CNc2cccn3nc(Nc4ccc(OC)nc4)nc23)c1

Procedure:
N(8)-(3-Methoxy-benzyl)-N(2)-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) and 5-amino-2-methoxypyridine (48.11 mg, 0.3875 mmol) in a manner analogous to Example 2d. Product was isolated as a red foam (41.48 mg, 32%). 1H NMR (400 MHz, CD3OD, δ, ppm): 8.42 (s, 1H), 8.04 (d, J=9 Hz, 1H), 7.83 (d, J=6.5 Hz, 1H), 7.24 (m, 1H), 6.98 (s, 2H), 6.83-6.71 (m, 3H), 6.40 (d, J=7.4 Hz, 1H), 4.48 (s, 2H), 3.88 (s, 3H), 3.76 (s, 3H). MS=377 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20]C(C)(C)C)=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:25][C@@H:26]([CH:30]([CH3:32])[CH3:31])C(O)=O>>[NH2:25][C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:11]1[NH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][N:10]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)[C@H](N)C(=O)O
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
The title compound was prepared from (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate and (S)-2-amino-3-methylbutanoic acid by the procedures detailed in Examples 1 and 2. 1HNMR (300 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.68 (d, J=5.9 Hz, 1H), 7.65 (d, J=5.9 Hz, 1H), 7.46-7.58 (m, 3H), 5.14, 5.05 (dd, J=7.0, 3.0 Hz, 1H, rotamers, 1:1 ratio), 3.66 (app t, J=6.5 Hz, 1H), 3.53-3.61 and 3.38-3.47 (m, 1H, rotamers, 1:1 ratio), 3.28 (s, 2H), 1.70-2.21 (m, 6H), 0.75-0.88 (m, 6H). LCMS: Anal. Calcd. for C18H23BrN4O: 390, 392. found: 391, 393 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([Cl:22])[C:11]=1[C:12]([OH:14])=[O:13].CN(C)C1C=CC=CC=1>CCOCC>[Cl:22][C:15]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Reaction time: 2.67 h

Procedure:
A mixture of 10.7 g of p-toluidine, 11.8 g of 2,6-dichloro-3-nitrobenzoic acid and 25 ml of N,N-dimethylaniline was stirred at 135° for 160 minutes. The mixture was diluted with ether and extracted with lN aqueous sodium hydroxide. Acidification of the aqueous solution, extraction with chloroform, and evaporation of the extract provided 6-chloro-2-[(4-methylphenyl)amino]-3-nitrobenzoic acid as orange prisms, mp 192°-197° C.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:28][CH:29](Br)[CH3:30]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:30][CH2:29][Br:28])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Br)Br
Reactant: Oc1cccc2c1c1ccccc1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: BrCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 9-benzyl-9H-Carbazol-4-ol (2.46 g, 9.00 mmol), potassium carbonate (5.11 g, 27.0 mmol), and DMF (10 mL) is added dibromoethane (3.90 mL, 45.0 mmol). The mixture is stirred at 80° C. for 4.5 h and then allowed to cool and stir the remainder of the night. The mixture is then stirred at 85° C.; after about 2 h an additional 1.0 mL of dibromoethane is added. After 5.5 h the mixture is cooled and the solvent and excess dibromoethane are removed in vacuo. The residue is partitioned between Et2O, water, and brine. The organic layers are dried over MgSO4 and taken to dryness. Chromatography on silica gel (250 mL) using EtOAc-heptane (10/90 to 20/80) to give 1.80 g (53%) after crystallization from CH2Cl2-hexane; IR (drift) 1583, 1458, 1446, 1342, 1333, 1281, 1270, 1245, 1154, 1147, 1114, 783, 753, 734, 719 cm−1; 1H NMR (CDCl3) δ3.87, 4.58, 5.51, 6.66, 7.02, 7.12, 7.2-7.4, 8.43. Anal. Calcd for C21H18BrNO: C, 66.33; H, 4.77; N, 3.68; Br, 21.01. Found: C, 66.30; H, 4.76; N, 3.62.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33][SH:34])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][CH2:33][S:34][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: CC(C)(C)OC(=O)NCCS
Product: Cc1ccc(NC(=O)Nc2ncc(SCCNC(=O)OC(C)(C)C)s2)c(C(=O)C2CCCC2)c1
Yield: 40 %

Procedure:
(2-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-ethyl)-carbamic acid tert-butyl ester (202 mg, 40%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and (2-mercapto-ethyl)-carbamic acid tert-butyl ester (354 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[CH3:50][C:51]([CH3:68])([CH2:65][CH:66]=[CH2:67])[CH2:52][O:53][C:54]([NH:56][C@@H:57]([C:61]([CH3:64])([CH3:63])[CH3:62])[C:58](O)=[O:59])=[O:55].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:50][C:51]([CH3:68])([CH2:65][CH:66]=[CH2:67])[CH2:52][O:53][C:54]([NH:56][C@@H:57]([C:61]([CH3:63])([CH3:62])[CH3:64])[C:58]([N:30]1[CH2:31][C@:27]([O:26][CH3:25])([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:59])=[O:55]
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Reactant: C=CCC(C)(C)COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC(C)(C)COC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Yield: 67.1 %

Procedure:
HATU (248 mg, 0.652 mmol) was added to a solution of, (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (200 mg, 0.593 mmol), (S)-2-((2,2-dimethylpent-4-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (201 mg, 0.741 mmol) and DIEA (0.311 mL, 1.778 mmol) in DCM (8 mL) and stirred at r.t. 60 hours. The reaction was evaporated and purified on the Biotage (10-40% EtOAc:Hex) to give (2S,4R)-methyl 1-((S)-2-((2,2-dimethylpent-4-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (235 mg, 0.398 mmol, 67% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.83-0.94 (m, 6H) 0.97-1.02 (m, 1H) 1.06-1.10 (m, 1H) 1.12-1.19 (m, 7H) 1.95-2.07 (m, 2H) 2.46-2.59 (m, 1H) 2.88 (d, J=12.80 Hz, 1H) 2.92-3.03 (m, 3H) 3.65-3.74 (m, 1H) 3.74-3.79 (m, 3H) 3.79-3.86 (m, 1H) 4.00-4.09 (m, 1H) 4.14-4.21 (m, 1H) 4.31-4.42 (m, 1H) 4.85-4.92 (m, 1H) 4.95-5.09 (m, 2H) 5.17-5.26 (m, 1H) 5.38-5.49 (m, 1H) 5.67-5.84 (m, 2H) 6.60-6.75 (m, 1H) 7.25-7.30 (m, 1H) 7.30-7.42 (m, 6H) 7.61-7.68 (m, 1H). LCMS: r.t.=2.25 min., [M+H]+=591 Phenomenex Luna S10 (3×50 mm); Solvent A=95% water 5% methanol—10 mM ammonium acetate, Solvent B=5% water—95% methanol—10 mM ammonium acetate; gradient=0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 ml/min; inj. vol.=10 ul; wavelength=220 nm.
Reaction SMILES: [C:1]1([CH:7]([CH2:20][CH2:21][CH3:22])[CH2:8][NH:9][C:10]2[N:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[C:12](C)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:23](=[O:27])([OH:26])([OH:25])[OH:24].[CH:28](O)(C)C>>[P:23]([OH:27])([OH:26])([OH:25])=[O:24].[C:1]1([CH:7]([CH2:20][CH2:21][CH3:22])[CH2:8][NH:9][C:10]2[N:11]=[CH:12][C:13]([CH3:28])([O:17][CH3:18])[CH:14]([CH3:16])[N:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(CNc1nc(C)c(OC)c(C)n1)c1ccccc1
Reactant: CC(C)O
Agent: O=P(O)(O)O
Product: CCCC(CNC1=NC(C)C(C)(OC)C=N1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.09 g of 2-phenylpentylamino-4,6-dimethyl-5-methoxypyrimidine was dissolved in 15 ml isopropylalcohol and cooled to 0° C. Phosphoric acid (85%, 9 g) was added and the mixture stirred at 0° C. for 30 minutes. White solid precipitated and was collected after removal of the isopropylalcohol, washing with pentane and drying in vacuo at 45° C. M.p.: 107°-8° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:15]=[C:16]([C:20]([NH:22][C:23]3[CH:35]=[C:34]([C:36]4[CH:40]=[CH:39][S:38][CH:37]=4)[CH:33]=[CH:32][C:24]=3[C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH:17]=[N:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]2[CH:15]=[C:16]([C:20]([NH:22][C:23]3[CH:35]=[C:34]([C:36]4[CH:40]=[CH:39][S:38][CH:37]=4)[CH:33]=[CH:32][C:24]=3[C:25]([OH:27])=[O:26])=[O:21])[CH:17]=[N:18][CH:19]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccsc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccsc2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (4.0 mL) was added to the obtained tert-butyl 2-(5-phenylpyridine-3-carboxamido)-4-(thiophen-3-yl)benzoate, followed by stirring at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 47 mg of 2-(5-phenylpyridine-3-carboxamido)-4-(thiophen-3-yl)benzoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:14][C@H:13]([OH:15])[CH2:12][C@H:11]2[C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[Si:25]([O:15][C@H:13]1[CH2:14][N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]#[N:9])=[CH:5][N:4]=2)[C@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1c1ncc(C#N)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1c1ncc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a solution of methyl (2S,4R)-1-(3-chloro-5-cyanopyridin-2-yl)-4-hydroxypyrrolidine-2-carboxylate (0.270 g; 0.96 mmol) and imidazole (0.098 g; 1.44 mmol) in DMF (3 mL) was added tert-butyl dimethylsilylchloride (0.159 g; 1.05 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. Further imidazole (0.049 g; 0.72 mmol) and tert-butyldimethylsilyl chloride (0.080 g; 0.53 mmol) was added and the reaction stirred at ambient temperature for 3 hours. The reaction mixture was diluted with EtOAc and washed sequentially with water and brine. The organic phase was poured through a hydrophobic frit and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (6:1) to afford the title product (0.311 g, 82%). 1H NMR (CDCl3, 400 MHz) δ 8.16 (1H, d, J=2 Hz), 7.57 (1H, d, J=2 Hz), 4.79 (1H, t, J=8 Hz), 4.46-4.44 (1H, m), 4.17-4.13 (1H, dd, J=11.2, 4.8 Hz), 3.77-3.74 (1H, m), 3.63 (3H, s), 2.15 (1H, m), 1.96 (1H, m), 0.79 (9H, s), 0.14-0.02 (6H, m).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]>>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH:28][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)=[CH:21][CH:20]=1)([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(CCCN)cc1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1ccc(CCCNCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared as in Example 1a from 3-trifluoromethylphenylglyoxal (1.99 g) and 3-(4-carbomethoxyphenyl) propylamine (1.9 g) and crystallised from hexane m.p. 86°-96°. τ(CDCl3) 7.9-8.35 (2H,m), 7.55 (2H, broad, replaceable by D2O), 7.0-7.5 (6H,m), 6.15 (3H,s), 5.3 (1H,m), 2.85 (2H,d,J=8 Hz), 2.3-2.6 (4H,m), 2.05 (2H,d,J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C:5]2([N:30]=1)[C:14]1([CH2:17][O:16][CH2:15]1)[C:13]([CH3:19])([CH3:18])[O:12][C:11]1[C:6]2=[CH:7][C:8]([NH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)=[O:22])=[CH:9][CH:10]=1.C(=O)=O>>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:30]=1)[C:14]1([CH2:15][O:16][CH2:17]1)[C:13]([CH3:18])([CH3:19])[O:12][C:11]1[C:6]2=[CH:7][C:8]([NH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)=[O:22])=[CH:9][CH:10]=1
Reactant: CC1(C)Oc2ccc(NC(=O)c3ccc(Cl)cn3)cc2C2(COC(N)=N2)C12COC2
Agent: O=C=O
Product: CC1(C)Oc2ccc(NC(=O)c3ccc(Cl)cn3)cc2[C@]2(COC(N)=N2)C12COC2
Yield: 43.5 %

Procedure:
N-(2-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-6′-yl)-5-chloro pyridine-2-carboxamide (352 mg, 0.821 mmol) was subjected to chromatography using supercritical CO2 (supercritical CO2/[EtOH with 0.1% diethylamine]=60:40) on Chiralcel OD-H column (10×250 mm) eluting at a flow rate 10 mL/minute (40° C. column temperature). After concentration of collected fractions of the first peak (retention time=5.23 minutes) at reduced pressure, recrystallization of the residue with EtOH/water (1:1) provided a hydrate of N-[(4R)-2-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-6′-yl]-5-chloropyridine-2-carboxamide (153 mg, 44%) as a crystal. After concentration of collected fractions of the second peak (retention time=8.16 minutes) at reduced pressure, recrystallization of the residue with EtOH/water (1:1) provided a hydrate of N-[(4S)-2-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-6′-yl]-5-chloropyridine-2-carboxamide (152 mg) as a crystal.