Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:5]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.C1C(=O)N([Cl:49])C(=O)C1>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:5]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:9][C:10]2[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)=[N:6][C:7]=1[Cl:49]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Solvent: CC#N
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)c(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Temperature: 60 °C

Procedure:
A solution of 49A (300 mg, 0.49 mmol) in 5 mL of acetonitrile was cooled to 0° C. and treated with NCS (0.49 mmol). The reaction was heated to 60° C. overnight. The reaction mixture was partitioned with EtOAc and aqueous saturated NaHCO3, then washed with brine. The organic layer were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography to provide the title compound. MS (m/z) 641 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>C(O)C.O>[CH3:11][C:9]([CH3:12])([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:7])[CH3:10]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a suspension of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester (8.8 mmol, 3.79 g) in ethanol (20 mL) was added aqueous 1.0 N sodium hydroxide (17.57 mL) at room temperature. The mixture was stirred for 2 h at room temperature. Then, the mixture was diluted with water (50 ml) and the ethanol was removed under reduced pressure. The aqueous solution was washed with diethyl ether (100 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (200 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 3.44 g (94% yield) of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine as a light brown foam solid. ES-HRMS m/e calcd for C21H27N3O6 (M+Na) 440.1792, found 440.1792.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=2)=[C:7]([C:20]([OH:22])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[NH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1>CN(C)C=O>[CH2:1]([C:5]1[S:9][C:8]2[N:10]=[C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)=[O:19])=[CH:15][N:16]3[C:20](=[O:22])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)O)c(Nc2ccc(C(=O)O)cn2)s1
Reactant: Nc1nnn[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1

Procedure:
A mixture of 6-[(5-butyl-3-carboxy-2-thienyl)amino]-3-pyridinecarboxylic acid (Example 39), 3.2 g (0.01 mol) and 9.93 g (0.06 mol) of 1,11 -carbonyldiimidazole (Aldrich Chemical Company) in 100 ml of dimethylformamide is heated in a wax bath under a nitrogen atmosphere with stirring at 100° to 108° C. for seventy minutes, cooled and stirred at room temperature for one hour. To the previous mixture is added 5-aminotetrazole monohydrate (Aldrich Chemical Company), 2.06 g (0.02 mol) and the mixture is heated at 100°-108° C. for ninety minutes. The solvent is evaporated and the residue dissolved in dimethylformamide, filtered, cooled and the precipitate collected and washed with methanol to give 1.2 g of 2-butyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 293° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[NH:7][C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[Cl:17][O-].[Na+].Cl>>[Cl:17][C:9]1[C:10](=[O:11])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:16])[NH:7][C:8]=1[C:12]([F:15])([F:13])[F:14]
Reactant: [O-]Cl
Reactant: CCCCn1c(=O)cc(C(F)(F)F)[nH]c1=O
Agent: Cl
Agent: [Na+]
Product: CCCCn1c(=O)[nH]c(C(F)(F)F)c(Cl)c1=O
Reaction time: 1 h

Procedure:
3-n-butyl-6-(trifluoromethyl)uracil (1.0 g.) was dissolved in 15 ml. of 5.25% sodium hypochlorite solution and allowed to stand at room temperature for 1 hour. The suspension which was present was acidified to pH 1 with hydrochloric acid and the solid removed by filtration. After purification by chromatography and recrystallization from cyclohexane, the product had a melting point of 138°-139°C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([NH:14][C:15]2[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31](=[O:32])[NH:21][C:16]1[C:15]([NH:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:34])([CH3:23])([CH3:24])[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ncccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ncccc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 119.4 %

Procedure:
Triethylamine (1.5 mL, 11.0 mmol) was added to a mixture of N3-phenylpyridine-2,3-diamine (510 mg, 2.75 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.94 g, 4.96 mmol), HOAt (670 mg, 4.96 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.95 g, 4.96 mmol) in anhydrous DCM (30 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min then slowly warmed to RT. Stirring at RT was continued for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a light brown foam (1.17 g, quantitative). LCMS (Method C): RT 3.04 min [M+H]+ 357.3.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1>N1C=CC=CC=1.CCOCC>[C:7]1([CH3:8])[CH:9]=[CH:10][C:4]([S:1]([O:19][CH2:18][CH:16]2[CH2:15][O:14][C:13]([CH3:20])([CH3:12])[O:17]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 8 h

Procedure:
57.2 g (300 mmol) of tosyl chloride are added to a solution of 39.6 g (300 mmol) of (2,2-dimethyl[1,3]dioxolan-4-yl)methanol in 170 ml of pyridine at 0° C. The mixture is stirred overnight, diluted with ether, washed with a 1N hydrochloric acid solution until the aqueous phase is at acid pH, and then washed with a saturated sodium hydrogen carbonate solution.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[OH:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].ClCCl.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=1.[O-]Cl.[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:26][C:25]([C:23]3[CH:22]=[C:21]([C:31]([F:32])([F:33])[F:34])[CH:20]=[C:19]([Cl:18])[CH:24]=3)([C:27]([F:30])([F:29])[F:28])[O:10][N:9]=2)=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: O/N=C/c1ccc(Br)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1cc(Cl)cc(C2(C(F)(F)F)CC(c3ccc(Br)c(C(F)(F)F)c3)=NO2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed (E)-N-[[4-bromo-3-(trifluoromethyl)phenyl]methylidene]hydroxylamine (1.5 g, 5.60 mmol, 1.00 equiv), dichloromethane (20 mL), 1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.6 g, 5.83 mmol, 1.10 equiv), NaOCl (10 mL). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 30 mL of H2O. The resulting solution was extracted with 3×50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3×50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 1.7 g (56%) of 3-[4-bromo-3-(trifluoromethyl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:17])=O>ClCCl>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:17])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)c(C(=O)O)cc1Cl
Solvent: ClCCl
Product: COc1cc(OC)c(C(=O)Cl)cc1Cl

Procedure:
A solution of 5-chloro-2,4-dimethoxybenzoic acid (6.4 g) in dichloromethane (250 ml) was treated with thionyl chloride (30 ml) and the mixture heated at reflux for 18h. Removal of volatile material in vacuo afforded the title compound as a white solid (6.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[F:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)[C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C.CCOC(C)=O>[F:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][N:49]1[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)c1ccc(OCC2CCCN2)c(F)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (324.5 mg, 0.676 mmol), methyl 3-fluoro4-(2-pyrrolidinyl)methoxybenzoate (171.1 mg, 0.676 mmol), Et3 N (113 ul, 0.811 mmol) in DMF (5 mL) was stirred for 2 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:2, v/v) as eluent to afford methyl 3-fluoro-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoate (365.1 mg, 0.664 mmol) as an oil. To a stirred solution of this compound in THF (4.4 mL) and H2O (1.1 mL) was added LiOH (46.3 mg, 1.932 mmol), and the reaction mixture was stirred at room temp overnight. The mixture was diluted with CHCl3 and acidified by the addition of 1 N HCl. The separated organic layer was washed with brine and dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-EtOAc—CHCl3 to afford 102 mg (30%) 38 as a white crystalline powder. mp 123–126; IR (KBr) 1616, 1537, 1282, 756 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.87–2.09 (m, 4H), 2.25 (s, 3H), 3.48–3.57 (m, 2H), 3.60 (s, 2H), 3.83 (s, 3H), 4.11–4.16 (m, 1H), 4.24 (dd, J=2.9, 9.8 Hz, 1H), 4.28–4.34 (br s, 1H), 6.74 (dd, J=1.5, 8.3 Hz, 1H), 6.87 (s, 1H), 6.94 (t, J=7.3 Hz, l), 7.12 (d, J=7.8 Hz, 1H), 7.15 (t, J=8.3 Hz, 1H), 7.34 (t, J=8.8 Hz, 1H), 7.66 (dd, J=2.0, 12.2 Hz, 1H), 7.73 (d, J=9.3 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.46 (s, 1H), 8.55 (s, 1H); MS (FAB) m/z 536 (M++1); Anal. Calcd for C29H30N3O6.0.5H2O: C, 63.96; H. 5.74; N, 7.72; F; 3.49. Found: C, 64.11; H, 5.80; N, 7.39; F, 3.54.
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:45]1[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[N:50]2.O>CN(C=O)C.[C-]#N.[C-]#N.[Zn+2]>[N+:55]([C:52]1[C:51]2[N:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:45]([C:2]#[N:3])=[CH:54][CH:53]=1)([O-:57])=[O:56]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(Br)c2cccnc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc([N+](=O)[O-])c2ncccc12
Temperature: 100 °C
Yield: 73.1 %

Procedure:
Zn(CN)2 (739 mg, 6.3 mmol), DIPEA (0.41 ml, 2.37 mmol), X-phos (225 mg, 0.47 mmol) and Pd2 (dba)2 (90 mg, 0.16 mmol) were added to a degassed (with argon) solution of 5-bromo-8-nitroquinoline 470 (400 mg, 1.58 mmol) in DMF (4 ml) and the mixture was heated at 100° C. in microwave for 20 min. After cooling, the mixture was poured into water and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (96:4) as the eluent to give the title compound (230 mg, 63%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([O:56]C)=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[OH-].[K+].Cl>CO>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([NH:32][C@H:33]([C:41]([CH:43]1[C:50]2([NH2:52])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:53][C:44]1([C:54]([OH:56])=[O:55])[CH2:45]3)[CH2:49]2)=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)C1C2(N)CC3CC(C2)CC1(C(=O)O)C3
Reaction time: 2.5 h

Procedure:
To a solution of 1.1 g of methyl Boc-L-tyrosylmethionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate in 10 ml of methanol is added 10 ml of water. The pH is adjusted to 13.0 with a 4 M solution of potassium hydroxide and held at pH 13-13.5 for 2.5 hours. The pH is adjusted to 11.0 with 12 N hydrochloric acid, and the methanol is removed under vacuum. The residual aqueous solution is adjusted to pH 2.0 by the slow addition of hydrochloric acid causing the product to crystallize. The product is collected by filtration and washed with water then dried for two hours at 50° C. and 0.1 mm of pressure. The residue is dissolved in a 6 N solution of ammonia. The excess ammonia is removed under vacuum and the remaining aqueous solution is adjusted to pH 4.0 with 1 N acetic acid. The product crystallizes and is collected by filtration, washed with water and dried for 16 hours at 50° C. and 0.1 mm pressure to give Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylic acid which is represented by the following formula ##STR26##
Reaction SMILES: N1C=CC=CC=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1>O1CCOCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:11][CH:10]=1)=[O:8]
Reactant: c1cn[nH]c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.9 %

Procedure:
Copper acetate (91 mg, 0.5 mmol), pyridine (53 mg, 0.67 mmol) and active Molecular Sieve 4A (250 mg) were added to a solution of 4-formylphenylboronic acid (100 mg, 0.67 mmol) and pyrazole (16 mg, 0.33 mmol) in 1,4-dioxane (4 ml), and they were stirred at room temperature for 72 hours. The reaction mixture was filtered through Celite, and the obtained filtrate was concentrated and then purified by the silica gel TLC chromatography to obtain 1-(4-formylphenyl)pyrazole (yield: 38 mg, 66%) in the form of a white powder.
Reaction SMILES: C(OC(=O)N[N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[C:20]([Cl:35])[C:19]3=[O:36])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C>CS(C)=O.O>[Cl:35][C:20]1[C:19](=[O:36])[N:18]([CH2:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][CH:9]=[CH:10]3)[C:23]([CH3:24])=[CH:22][C:21]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(ccn2NC(=O)OC(C)(C)C)c1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2[nH]ccc2c1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]indole-1-carbamic acid tert-butyl ester (1.08 g, 2.1 mmol) dissolved in 40 mL of DMSO was stirred at 120° C. for 20 hours. The reaction was cooled to room temperature, diluted with water, and washed 5 times with ethyl acetate. The combined organics were washed 1 time with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 11.1 (br s, 1H), 7.67 (d, J=6.7 Hz, 1H), 7.36-7.32 (m, 2H), 7.23 (s, 1H), 7.18 (d, J=2.3 Hz, 1H), 6.93 (dd, J=8.4, 1.2 Hz, 1H), 6.57 (s, 1H), 6.38 (s, 1H), 5.37 (s, 2H), 5.29 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][NH2:2].CO.[O:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[C:7](OCC)=[O:8]>CO>[CH3:1][NH:2][C:7](=[O:8])[C:6](=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1
Reactant: CCOC(=O)C(=O)c1ccccc1COC1CCCCO1
Reactant: CN
Solvent: CO
Product: CNC(=O)C(=O)c1ccccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A 40% methylamine-methanol solution (2.65 g, 0.0341 mol) was added to a mixed solution of ethyl 2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetate (2.00 g, 0.0068 mol) and methanol (20 ml). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (1.30 g, Yield: 69.0%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:18])=[O:17].[N+:25]([O-])([OH:27])=[O:26]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([N+:25]([O-:27])=[O:26])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:17])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1[nH]c2ccc(Br)c([N+](=O)[O-])c2c1S(=O)(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl 5-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (56 mg, 0.13 mmol, 1.0 equiv) was dissolved in 3 mL of sulfuric acid and cooled to 0° C. A 1 mL aqueous solution of nitric acid (10 mg, 0.15 mmol, 1.15 equiv) was added dropwise and the reaction was stirred for 10 minutes at 0° C., after which an additional 1 mL aqueous solution of nitric acid (5 mg, 0.06 mmol, 0.5 equiv) was added dropwise. After stirring for 30 minutes, the reaction mixture was partitioned between ethyl acetate and water, which was extracted three times with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 15% ethyl acetate/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound ESI+MS: 462.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[N:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]=O.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:12]=[N:11][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: COC(=O)CN=C=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.40 g (8.00 mmol) of 4-chlorobenzoyl chloride, 1.00 g (10.09 mmol) of methyl isocyanatoacetate and 5.9 ml (42.39 mmol) of triethylamine are dissolved in 15 ml of dry THF and stirred at RT for 48 h. The solvent is then removed on a rotary evaporator. The residue is taken up in 20 ml of ethyl acetate and washed once with 5 ml of water. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is suspended in 10 ml of cyclohexane and filtered off. It is then recrystallized from about 10 ml of methanol. This gives needle-shaped crystals which are dried in a drying cabinet at 50° C. A further product fraction is obtained by reprecipitation after recrystallization.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:33](=O)[CH3:34]>>[CH2:33]([N:4]1[CH2:5][CH2:6][C@@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[C@H:2]([F:1])[CH2:3]1)[CH3:34]
Reactant: CC=O
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CCNC[C@H]5F)c4n3)cnc2c1
Product: CCN1CC[C@@H](Oc2cccc3ccc(-c4cnc5cc(OCCOC)ccn45)nc23)[C@H](F)C1

Procedure:
Prepared from 8-((trans)-3-fluoropiperidin-4-yloxy)-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinoline according to the procedure for Example 29, using acetaldehyde in place of formaldehyde. MS APCI (+) m/z 465.1 (M+1) detected.