Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38]Br)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>CN(C=O)C.O>[CH2:20]([O:22][CH:23]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][N:7]2[C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[O:3][C:2]2([CH3:13])[CH3:1])=[CH:34][CH:35]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]
Reactant: CC1(C)NC(=O)c2ccccc2O1
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCN2C(=O)c3ccccc3OC2(C)C)cc1)OCC
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazine (0.3 g, 1.69 mmol) in DMF (3 mL) was added potassium carbonate (0.47 g, 3.39 mmol) and stirred for 30 min. To this reaction mixture was added a solution of ethyl 2-ethoxy-3-[4-(2-bromoethoxy) phenyl]propanoate (0.70 g, 2.03 mmol) (disclosed in U.S. patent application Ser. No. 09/012, 585) in DMF (1mL) and stirred for 24 h at 60-70° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel using a gradient of 5-15% of ethyl acetate in pet ether as eluent to afford the title compound (0.34 g, 45%) as a liquid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([NH:7][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a rt solution of 550 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine (prepared in accordance with the procedure set forth in UK 2 185 255, Example 2A) in 8.5 mL pyridine was added 370 μL of benzoyl chloride. The reaction was stirred for 1 h and then concentrated under reduced pressure. The residue was dissolved in chloroform and washed with 0.5 N hydrochloric acid and then saturated aqueous sodium carbonate. The organic portion was dried with sodium sulfate and concentrated under reduced pressure and purified by means of MPLC (12 g SiO2, 40% ethyl acetate:heptane) to give the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[CH2:12][C:13]1[CH:14]=[C:15]([CH2:21][CH:22]([O:26][CH:27]([CH3:29])[CH3:28])[C:23]([O-:25])=[O:24])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH2:12][C:13]1[CH:14]=[C:15]([CH2:21][CH:22]([O:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: OCc1ccc(Cl)cc1Cl
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COCc1ccc(Cl)cc1Cl

Procedure:
Using 2,4-dichlorobenzyl alcohol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2,4-dichlorobenzyl)oxy]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:16])[O:9][C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[N:11][C:6]=2[CH:5]=[C:4]([O:17]CC2C=CC=CC=2)[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[C:7]2[C:8](=[O:16])[O:9][C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[N:11][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(OCc2ccccc2)cc2nc(OC(C)C)oc(=O)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc2nc(OC(C)C)oc(=O)c12
Yield: 63.6 %

Procedure:
A solution of 5-methyl-7-benzyloxy-2-isopropoxy-4H-3,1-benzoxazin-4-one (50 mg) in ethyl acetate (80 ml) was hydrogenated over 10% palladium on charcoal at 50 psi hydrogen on a Parr hydrogenator for 5 hours. The catalyst was removed by suction filtration through Celite. The filtrate was evaporated to give a white solid which was further purified by thick layer chromatography (30% ethyl acetate: pet. ether 30-60) to give 5-methyl-7-hydroxy-2-isopropoxy-4H-3,1-benzoxazin-4-one as a white solid (23 mg), m.p. 258°-260° C. (decomp.), IR (KBr): 3100-3400, 1715, 1650, 1600 cm-1. H--NMR (CDCl3): 1.40 (d, 6H, CH3CHCH3), 2.40 (s, 3H, CH3), 5.3 (p, 1H, CH), 6.7 (m, 2H, ArH).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16](=[O:32])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.OC1C=CC(NC([C@@H]2CCCN2)=O)=CC=1.Cl>C(O)(C)C>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:32])=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(Nc1ccc(O)cc1)[C@@H]1CCCN1
Solvent: CC(C)O
Product: O=C(Nc1ccc(O)cc1)[C@H]1CCCN1

Procedure:
This compound was prepared from (R)-2-(4-benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester, using the same method used to prepare (S)-pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide. The free base was dissolved in hot isopropanol (20 mL) and treated with a saturated solution of hydrogen chloride in isopropanol (3 mL). The product crystallized as the hydrochloride salt, 2.43 g (59% for 2 steps). MS m/z 207 (MH+). 1H NMR(DMSO-d6) δ 1.93 (m, 3H), 2.39 (m, 1H), 3.26 (m, 2H), 4.35 (t, 1H), 6.76 (d, 2H), 7.43 (d, 2H), 9.43 (br s, 1H) and 10.70 (s, 1H). Anal. calcd for C11H14N2O2: C, 54.44; H, 6.23; N, 11.54. Found: C, 54.33; H, 6.26; N, 11.57.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[CH:15]=1)=[O:13].[NH2:23][C:24]1[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:28][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:8])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[CH:15]=1)=[O:13]
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1cc2nccnc2s1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cc2nccnc2s1
Yield: 52 %

Procedure:
A solution of 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)benzoic acid 50 (25 mg, 0.080 mmol), 3-aminobenzotrifluoride (9.87 μl, 12.86 mg, 0.080 mmol), TBTU (38.4 mg, 0.120 mmol) and DIPEA (0.039 mL, 0.239 mmol) in DMF (1 mL) under a nitrogen atmosphere was stirred overnight at 40° C. The reaction mixture was poured into 3% citric acid solution. The resulting precipitation was collected and washed with water to give the title compound N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 51 (19 mg, 53%). NMR (400 MHz, DMSO-d6) 2.38 (s, 3H), 7.46 (d, J=7.4 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.90 (dd, J=7.8 and 1.6 Hz, 1H), 8.04 (d, J=1.6 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.25 (s, 1H), 8.57 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.90 (d, J=2.3 Hz, 1H), 10.55 (s, 1H), 10.66 (s, 1H). (m/z)=457 (M+H)+.
Reaction SMILES: C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:51]([CH3:52])=[CH:50][CH:49]=[CH:48][C:47]=2[CH3:53])=[CH:42][C:41]=1[CH2:54][OH:55])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O[C:57]1[CH:64]=[CH:63][C:60]([CH:61]=[O:62])=[CH:59][CH:58]=1>C1COCC1>[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:51]([CH3:52])=[CH:50][CH:49]=[CH:48][C:47]=2[CH3:53])=[CH:42][C:41]=1[CH2:54][O:55][C:59]1[CH:58]=[CH:57][CH:64]=[CH:63][C:60]=1[CH:61]=[O:62])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: Cc1cccc(C)c1-c1ccc(O[Si](C)(C)C(C)(C)C)c(CO)c1
Reactant: O=Cc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1ccc(O[Si](C)(C)C(C)(C)C)c(COc2ccccc2C=O)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine were added to a THF solution of (4-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methanol and 4-hydroxybenzaldehyde, followed by stirring at room temperature for 14 hours to obtain 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}-2′,6′-dimethylbiphenyl-3-yl)methoxybenzaldehyde.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[Sn](Cl)(Cl)Cl.[CH2:21]=[O:22]>C1(C)C=CC=CC=1>[OH:22][C:21]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: C=O
Reactant: Cc1ccccc1O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc(C=O)c1O

Procedure:
To a stirred solution of o-cresol (4.0 g, 37 mmol) in triethylamine (3.8 ml, 26.6 mmol) and toluene (100 ml) is added dropwise SnCl4 (0.95 g, 36.5 mmol) under an atmosphere of nitrogen. After the addition of paraformaldehyde the mixture is heated at reflux for 18 h. The reaction mixture is quenched by pouring onto crushed ice and the pH is adjusted to 2 by addition of aqueous HCl. The product is extracted with ether and the resulting organic phase is washed with brine and dried over sodium sulfate. Evaporation of the solvent and purification by chromatography yields the title compound. (CDCl3, 400 MHz): 11.26 (s, 1H); 9.86 (s, 1H); 7.37 (m, 2H); 6.91 (t, 1H); 2.23 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@:13]1([CH3:37])[S:19][C@H:18]2[N:15]([C:16](=[O:20])[CH2:17]2)[C@H:14]1[C:21]([O:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(N(CC)CC)C>ClCCl>[CH:12]([C@:13]1([CH3:37])[S:19][C@H:18]2[N:15]([C:16](=[O:20])[CH2:17]2)[C@H:14]1[C:21]([O:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[O:11]
Reactant: C[C@@]1(CO)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: -60 °C
Reaction time: 3 h

Procedure:
100 ml of dichloromethane were treated with 0.84 ml (9.6 mmol) of oxalyl chloride under argon and cooled to -60° C. Thereto there were added dropwise 0.73 ml (10.25 mmol) of DMSO, followed by 2.5 g (6.52 mmol) of benzhydryl (2S,3R,5R)-3-hydroxymethyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate dissolved in 100 ml of dichloromethane. The mixture was stirred at the same temperature for 3 hours and then 3.2 ml (23.0 mmol) of triethylamine were added. The cooling bath was removed and the mixture was left to warm to room temperature. The orange solution was poured into 1000 ml of 0.2N hydrochloric acid and the aqueous phase was extracted twice with dichloromethane. The organic phases were washed with water and saturated, aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The thus-obtained product (2.50 g, 100%) can be processed without further purification or can be recrystallized from diethyl ether. Yield: 2.00 g (80%) of white crystal powder; m.p. 111.8°-112.8° C. IR(KBr): 2720, 1788, 1743, 1718 cm-1MS: (M--CH2CO) 339 1H-NMR (250 MHz, CDCl3): δ[ppm]=1.26(s,3H), 3.06(dd,1H,J=16.2Hz, 2Hz, 6-H), 3.54(dd,1H,J=16.2Hz, 4Hz,6-H), 5.34(s,1H,2-H), 5.42(dd,1H,J=2Hz, 4Hz,5-H), 6.95(s,1H,CHPh2), 7.30-7.38 (m,10H,Ph), 9.20(s,1H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1>C(O)(C(F)(F)F)=O>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(c1)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
Sodium borohydride (2.0 g, 53 mmol) (Aldrich) was added in small portions to a mixture of 6-Chloro-1H-indole (1.0 g, 6.6 mmol) (Aldrich) in TFA (10 mL), which was cooled in ice-water bath, at such a rate that gas evolution was not too vigorous. When the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo and the residue was dissolved in DCM. The organic layer was washed with Na2CO3 solution, dried with Na2SO4, and concentrated to give 0.6 g crude 6-Chloro-2,3-dihydro-1H-indole. MS: [M+H]+=154
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[N:9]1[C:21](=[O:42])[CH2:22][NH:23][C:24](=[O:41])[NH:25][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][CH:40]=1)[C:29]([O:31]CC[Si](C)(C)C)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH-].[Na+]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[N:9]1[C:21](=[O:42])[CH2:22][NH:23][C:24](=[O:41])[NH:25][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][CH:40]=1)[C:29]([OH:31])=[O:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2c(F)cccc2Cl)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2c(F)cccc2Cl)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 10.4 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 41, but starting from 1.37 g of 2-trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-chloro-6-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoate and 4.3 cm3 of a 1M solution of tetrabutylammonium fluoride. The crude product is dissolved in 10 cm3 of a 0.5N aqueous sodium hydroxide solution and washed with 2 times 20 cm3 of ethyl acetate. The aqueous phase is brought to a pH of 2 by addition of a 1N aqueous sulphuric acid solution. The product precipitated is separated by filtration, washed with 2 times 5 cm3 of distilled water and dried in air. 0.12 g of (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(2-chloro-6-fluorophenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoic acid, melting at 148° C., is thus obtained ([α]D20 =+3.1°±0.8° (C=0.518%; DMF), [proton NMR (250 MHz, DMSO D6 d in ppm, J in Hz), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 1.5 (s, 9H, --C(CH3)3); 3.48 (dd, J=12.5 and 6.5. 1H, of S--CH2); 3.62 (dd, J=12.5 and 5, 1H, the other H of S--CH2 --); 3.96 (dd, J=17.5 and 5, 1H, of N--COCH2 --N); 4.18 (dd, J=17.5 and 5.5, 1H, the other H of N--COCH2 --N); 5.11 (dd, J=6.5 and 5, N--CH--COO); 6.24 (broad, 1H, --NHCO--); 6.01 (s, 1H, S--CH--N); 7.05 to 7.65 (m, 6H, aromatic); 7.98 (bs, 1H, in position 2 on CO--NH--Ph--); 8.66 (broad, 1H, ArNHCO--)], [infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2980, 2930, 2700 to 2250 (broad band), 1715, 1695, 1655, 1605, 1590, 1560, 1490, 1460, 1370, 1150, 785, 760, 680].
Reaction SMILES: COCCOCCOCC(O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.NCCC([C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([O:55][CH2:56][CH:57]2[CH2:62][CH2:61][CH2:60][CH2:59]C2)[CH:50]=1)O>CN(C=O)C.C(OCC)(=O)C>[C:56]1([O:55][C:51]2[CH:50]=[CH:49][CH:54]=[CH:53][CH:52]=2)[CH:57]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: NCCC(O)c1cccc(OCC2CCCCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COCCOCCOCC(=O)O
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (0.6 g, 3.34 mmol), TBTU (1.2 g, 4.0 mmol) and DIPEA (1.3 ml, 4.0 mmol) in DMF (20 ml) was added 3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol (1.0 g, 3.34 mmol). The resulting mixture was stirred for 18 hr at room temperature. The reaction mixture was then diluted with ethyl acetate (100 ml), washed with water (2×100 ml), brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave Example 77 as a colorless oil. Yield (0.7 g, 50%): 1H NMR (400 MHz, DMSO-d6) δ 7.65 (t, J=5.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 6.82-6.85 (m, 2H), 6.72-6.75 (m, 1H), 5.22 (d, J=4.8 Hz, 1H), 4.48-4.52 (m, 1H), 3.82 (s, 2H), 3.72 (d, J=6.4 Hz, 2H), 3.42-3.52 (m, 2H), 3.39-3.41 (m, 2H), 3.30 (s, 3H), 3.12-3.17 (m, 2H), 2.86 (s, 2H), 2.66 (s, 2H), 1.61-1.79 (m, 8H), 1.08-1.28 (m, 3H), 0.98-1.06 (m, 2H).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:23][CH3:24])[C@@H:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)[OH:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:9]([CH2:23][CH3:24])[C@@H:10]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]=1)[OH:11]
Reactant: CCC(NC(=O)OC(C)(C)C)[C@H](O)c1nc(-c2ccccc2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Reaction time: 1 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) was combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), and N-hydroxy-benzamidine (292 mg, 2.14 mmol). Dichloromethane (10 mL) was added and then 4-methylmorpholine (1 mL). The reaction mixture was stirred at ambient temperature for 16 h. After dilution with ethyl acetate (200 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in pyridine (10 mL) and heated at 80° C. for 15 h. The pyridine was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (eluent: ethyl acetate) to yield (290 mg, 0.83 mmol) of (S)-2-tert-butoxycarbonylamino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol. (S)-2-tert-Butoxycarbonylamino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol (145 mg, 0.41 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (4 mL) was added. After stirring for 1 h, the reaction mixture was evaporated to dryness to yield (S)-2-amino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(O)c2cc1OCCCS(C)(=O)=O
Product: COc1cc2ncnc(Cl)c2cc1OCCCS(C)(=O)=O
Yield: 65 %

Procedure:
The intermediate 4-hydroxy-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline (700 mg, 2.24 mmol) from the previous step was reacted with POCl3 in the manner described in Example 4A Step 2 to give 4-chloro-7-methoxy-6-(3-(methylsulfonyl)propoxy)quinazoline (480 mg, 1.45 mmol, 65%). LC-MS (ESI) m/z 331 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([OH:15])=O.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([CH:8]2[C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[O:11][CH2:10][CH2:9]2)=[O:15])=[CH:22][CH:23]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: COc1cccc2c1OCCC2C(=O)O
Product: COc1cccc2c1OCCC2C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1
Yield: 48.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 8-methoxychroman-4-carboxylic acid, (0.64 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.83 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-8-methoxychroman-4-carboxamide (0.69 g) was obtained.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([C@@:15]1([CH2:29][CH2:30][OH:31])[CH2:19][C:18](=[O:20])[N:17]([C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:8]([O:12][C:13]([C@@:15]1([CH2:29][CH2:30][O:31][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:19][C:18](=[O:20])[N:17]([C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCO)(C(=O)OC(C)(C)C)CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@@](CCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
Triethylamine (3.0 mL, 21.8 mmol) was added to a solution of (3S)-3-(2-hydroxyethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.42 g, 7.25 mmol) in dichloromethane (70 mL), and the mixture was cooled to 0° C. tert-Butyldimethylsilyl trifluoromethanesulfonate (2.50 mL, 10.9 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. After addition of an ice piece and stirring, the reaction solution was poured into a mixture of ethyl acetate (50 mL) and saturated sodium bicarbonate (50 mL), followed by extraction with ethyl acetate (200 mL, 100 mL). The organic layers were combined and washed with brine (50 mL). After drying over anhydrous sodium sulfate and filtration, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1→2:1) to give 2.84 g (88%) of the title compound as a white solid.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][C:23]1([CH3:48])[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[C:29]2[CH:28]=[C:27]([O:35][C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][CH:45]=3)[C:42]([CH2:46][OH:47])=[CH:41][CH:40]=[CH:39]4)[CH:26]=[CH:25][C:24]1=2>ClCCl>[CH3:22][C:23]1([CH3:48])[CH2:32][CH2:31][C:30]([CH3:33])([CH3:34])[C:29]2[CH:28]=[C:27]([O:35][C:36]3[CH:37]=[C:38]4[C:43](=[CH:44][CH:45]=3)[C:42]([CH:46]=[O:47])=[CH:41][CH:40]=[CH:39]4)[CH:26]=[CH:25][C:24]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(CO)cccc4c3)ccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc4c(C=O)cccc4c3)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
100 ml of dichloromethane and 1.7 g (4.5 mmol) of pyridinium dichromate were introduced into a round-bottomed flask. The mixture was cooled to 0° C. and a solution of 1.2 g (3.3 mmol) of 6-(5,6,7,8-tetra-hydro-5,5,8,8-tetramethyl-2-naphthyloxy)naphthalene methanol in 20 ml of dichloromethane was added dropwise. The mixture was stirred at room temperature for one hour, the reaction medium was filtered over silica, the filtrate was evaporated to dryness and the solid was triturated in heptane and filtered off. 1.07 g (90%) of the expected aldehyde was recovered, having a melting point of 123°-4° C.