Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)(O)[O-].[Na+].CP(OP(CC)(C)=O)(CC)=O>CN(C)C=O.O>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: COC(=O)CN
Agent: CCP(C)(=O)OP(C)(=O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the suspension of 3.35 g (0.01 mol) of Z-Trp-OH and 1.25 g (0.01 mol) of H-Gly-OCH3 in 15 ml of dimethyl formamide there were added portionwise altogether 7 ml of water and subsequently 5.1 g of a finely powdered sodium bicarbonate. The suspension was largely clarified by adding dropwise 4 ml of methylethyl phosphinic acid anhydride. A sample of the reaction solution diluted with water showed a neutral reaction. Upon heating to room temperature the solution was stirred overnight and the solvents were separated by distillation in a high vacuum at room temperature. The residue was taken up in a mixture of 25 ml of water and 70 ml of ethyl acetate, the ethyl acetate extract was separated and the aqueous phase was extracted twice using each time 10 ml of ethyl acetate. The combined ethyl acetate extracts were washed twice using each time 7 ml of water, a 5% potassium bisulfate solution (until an acid reaction took place) and a saturated sodium bicarbonate solution (until s slightly alkaline reaction took place). Upon drying over magnesium sulfate the ethyl acetate solution was largely separated by distillation in vacuo and the residue was digested with diisopropyl ether.
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[C:1]([NH:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH:25]=[CH2:24])=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C[C@@H](NC(C)=O)C(=O)OC)cc1
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a solution of 51 (989 mg, 4.17 mmol), and anhydrous K2CO3 (1.15 g, 8.34 mmol) in DMF (10 mL) was added allyl bromide (1.01 g, 8.34 mmol) and the resulting mixture was allowed to stir for 16 h under a nitrogen atmosphere. The reaction was quenched with water (30 mL), extracted with ethyl acetate (3×30 mL), and the combined organics were washed with water (5×20 mL) before drying. The solvent was evaporated to yield the title compound (985 mg, 3.56 mmol, 85%) as a pale yellow solid. [α]D25-24.2 (c. 0.1, EtOH). Mp 90° C. 1H NMR (CDCl3, 300 MHz): δ 6.97 (d, J=8.7 Hz, 2H, ArH2′ and ArH6′); 6.80 (d, J=8.7 Hz, 2H, ArH3′ and ArH5′); 6.09 (d, J=7.8 Hz, 1H, NH); 6.01 (m, 1H, H2″); 5.37 (dd, J=1.8, 17.4 Hz, 1H, H3a″); 5.25 (dd, J=1.8, 10.5 Hz, 1H, H3b″); 4.80 (m, 1H, H2); 4.47 (d, J=5.5 Hz, 2H, H1″); 3.68 (s, 3H, OCH3); 3.04 (m, 2H, H3); 1.99 (s, 311, NCOCH3). Mass Spectrum (CI, +ve) m/z 278 (100%) [MH+]. HRMS (EI) calcd for C15H19NO4 277.131408, found 277.130309.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](O)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:29]([N:28]([CH3:32])[CH3:27])=[O:30])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 140 °C
Yield: 6.3 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (39 mg, 0.15 mmol), potassium carbonate (32 mg, 0.30 mmol) and dimethylcarbamyl chloride (27 μL, 0.30 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 140° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 afforded 3 mg (29%) of 3-(2-pyridyl)-5-(3-cyano-5-(dimethylamino)carbonylphenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.85 (d, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 8.22 (d, 1H), 7.89 (m, 1H), 7.73 (s, 1H), 7.48 (dd, 1H), 3.14 (s, 3H), 3.06 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[CH:7]=[CH:6][N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1)#[CH:2].[OH:20][N:21]=[C:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC>C1COCC1>[C:23]1([C:22]2[C:1]([C:3]3[C:8](=[O:9])[CH:7]=[CH:6][N:5]([C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=4)[N:4]=3)=[CH:2][O:20][N:21]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1conc1-c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
To a solution of 3-ethynyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (104 mg, 0.391 mmol) and N-hydroxybenzenecarboximidoyl chloride (122 mg, 0.782 mmol) in THF (5 mL) was added Et3N (0.108 mL, 0.782 mmol) at 0° C. The suspension was stirred at room temperature for 14 h. The reaction was quenched with water. The mixture was extracted with AcOEt, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=50/50 to 0/100) and on basic silica gel (hexane/AcOEt=50/50 to 43/57) and crystallized with AcOEt/heptane to yield the title compound (82.4 mg, 55% yield) as a white solid: mp 217-219° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.87 (1H, d, J=8.0 Hz), 7.50-7.59 (3H, m), 7.86-7.92 (2H, m), 7.94-8.02 (3H, m), 8.15-8.26 (2H, m), 9.09 (1H, d, J=8.2 Hz). Anal. Calcd for C20H12F3N3O2: C, 62.67; H, 3.16; N, 10.96. Found: C, 62.60; H, 3.19; N, 10.95.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:30]1([C:35]2[CH:40]=[C:39]([CH2:41][NH2:42])[CH:38]=[C:37]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:42][CH2:41][C:39]3[CH:38]=[C:37]([C:43]4[CH:44]=[CH:45][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:47][CH:48]=4)[N:36]=[C:35]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)[CH:40]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cc(-c3ccc(C(F)(F)F)cc3)nc(N3CCCC3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A solution of acid 18 (0.24 g, 0.76 mmol) in THF (20 mL) was added with DEPC (0.15 mL, 1.3 mol eq) and the mixture was stirred at room temperature for several minutes. Then [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (0.27 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc and washed with water (1×50 mL) and brine. After drying over Na2SO4, the separated organic phase was evaporated under reduced pressure and the residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a pale yellow solid (0.18 g) after crystallization from a mixture of ethyl ether/petroleum ether. Yield=38%, 1HNMR (DMSO, 200 MHz) δ 0.86 (t, 3H), 1.21 (m, 4H), 1.91 (m, 4H), 3.42 (m, 6H), 4.21 (d, 2H, J=6.2), 6.26 (s, 1H), 6.45 (s, 1H), 7.27 (d, 1H, J=4), 7.58 (d, 1H, J=3.8), 7.82 (d, 2H, J=7.8), 8.21 (d, 2H, J=8.1), 8.41 (t, 1H); [M+1] 613.11 (C27H28ClF3N4O3S2 requires 612.12).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=S)[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH2:23][CH3:24])/[N:7]([CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:39]#[C:40][NH2:41]>C(#N)C.[Hg](OC(C)=O)OC(C)=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH2:23][CH3:24])=[N:41][C:40]#[N:39])/[N:7]([CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CN
Reactant: CCOc1ccc(C(F)(F)F)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1ccc(C(F)(F)F)cc1C(=NC#N)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Yield: 309.1 %

Procedure:
The product of Example 36C (0.26 g, 0.55 mmol), triethylamine (0.21 mL, 1.5 mmol), cyanamide (50 mg, 1.1 mmol) and Hg(OAc)2 (0.23 g, 0.71 mmol) in acetonitrile (10 mL) were processed as described in Example 16E to provide the title compound (0.84 g, 1.7 mmol, 85% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.39 (s, 9H), 1.49 (t, J=6.8 Hz, 3H), 1.56-1.66 (m, 1H), 1.77-1.95 (m, 2H), 1.98-2.12 (m, 1H), 3.73-3.89 (m, 2H), 4.13-4.28 (m, 4H), 4.40-4.52 (m, 1H), 7.01 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 7.58-7.66 (m, 2H); MS (DCI/NH3) m/z 481 (M+H)+. Anal. calculated for C23H27F3N4O2S: C, 57.49; H, 5.66; N, 11.66. Found: C, 57.38; H, 5.59; N, 11.60.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine following a procedure analogous to that described for Intermediate 10. LC (method 4): tR=1.02 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.Cl.[NH2:10][OH:11].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[N:10][OH:11]
Reactant: NO
Reactant: O=Cc1sccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1sccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.3 %

Procedure:
3-Bromothiophene-2-carbaldehyde (28.7 g, 0.15 mol) in ethanol (50 mL) was added in one portion to a solution of hydroxylamine hydrochloride (13.8 g, 0.2 mol), sodium hydroxide (8 g, 0.2 mol) in water (30 mL) and ethanol (100 mL). The mixture was stirred at 0° C. for 2 hours and was kept at 0° C. overnight when a precipitate formed. The mixture was diluted with cold water (600 ml) and the solid was collected by filtration yielding 20.5 g, (67%). The aqueous solution was further extracted with ethyl acetate. The organic solution was washed with brine, dried with magnesium sulfate, filtered and evaporated yielding 6.9 g of additional product as a light yellow solid. The total yield was 27.4 g (89%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:13][O:14][CH:15]2[CH2:17][CH2:16]2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:3]=1.[C:18](Cl)([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)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:15]1([O:14][N:13]=[C:7]([C:4]2[N:3]=[C:2]([NH:1][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[S:6][N:5]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=NOC1CC1)c1nsc(N)n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)C(=NOC1CC1)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 4 h
Yield: 107.5 %

Procedure:
A mixture of ethyl 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(5.26 g), trityl chloride (12.9 g) and 4-dimethylaminopyridine (224 mg) in pyridine (25 ml) was stirred at 50°-60° C. for 4 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to give a crystal. The crystal was washed with n-hexane and diisopropyl ether, heated in methanol (80 ml) under reflux, and finally cooled to give ethyl 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (11 g) as a crystal.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH3:17])[C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[C:18](=O)([O:20]CC)[NH2:19]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][CH:5]=[C:6]([CH3:17])[C:7]=2[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[N:19][C:18]1=[O:20]
Reactant: CNc1scc(C)c1C(=O)c1ccccc1Cl
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1csc2c1c(-c1ccccc1Cl)nc(=O)n2C
Temperature: 200 °C

Procedure:
A mixture of 16.0 g of 2-methylamino-3-(o-chlorobenzoyl)-4-methylthiophene, 16.1 g of ethyl carbamate and 1.22 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using chloroform as an eluent to give 1-methyl-4-(o-chlorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 267.5° - 268.5°C (after recrystallization from chloroformethanol).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.P(=O)(O)(O)O>C1COCC1.CCCCC>[CH3:11][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([B:17]([OH:22])[OH:18])[C:3]=2[CH:4]=[CH:5]1
Reactant: Cn1ccc2c(Br)cccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cn1ccc2c(B(O)O)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Intermediate 51 (4.90 g) in anhydrous THF (30 ml) was cooled to −78° C. under argon atmosphere, then added dropwise with 1.62 M solution of n-butyllithium in pentane (28.8 ml) over 30 minutes and stirred for 30 minutes. The mixture was added dropwise with (iPrO)3B (10.77 ml) over 10 minutes, stirred for 1 hour, then warmed to room temperature and further stirred for 2.5 hours. The reaction mixture was poured into 1.2 N aqueous phosphoric acid (250 ml) added with ice, and extracted with diethyl ether (200 ml×3). The organic layer was extracted with 0.4 N aqueous sodium hydroxide (150 ml×3), and the aqueous layer was acidified with 5 N aqueous hydrochloric acid under ice cooling and extracted with diethyl ether (200 ml×3) again. The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was washed with hexane to obtain the title compound (Intermediate 52, 3.17 g).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(O[Cl:17])(C)(C)C.CCOCC>CC(O)=O>[Cl:17][C:4]1[C:5]([OH:6])=[C:7]([O:8][CH3:9])[CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(C)(C)OCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(C=O)c(Cl)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
41.2 g (0.271 mol) of isovanillin was dissolved in 160 ml of 90% AcOH under heating. 29.41 g of t-BuOCl was added dropwise to the solution while it was kept at 35° to 40° C. The solution was stirred at room temperature for 3 hours and then 200 ml of ether was added thereto. The mixture was left to stand overnight and crystals thus formed were separated by filtration and washed with ether. 42.0 g of the crude crystals were recrystallized from acetonitrile to obtain 35 g of 2-chloro-3-hydroxy-4-methoxybenzaldehyde (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][C:14](O)=[O:15])[N:10]([CH2:17][CH3:18])[N:9]=2)=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([Cl:27])=[O:15])[N:10]([CH2:17][CH3:18])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCn1nc(-c2ccc(Cl)cc2)nc1CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1nc(-c2ccc(Cl)cc2)nc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 mmol (318 mg) of [3-(4-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-5-yl]acetic acid and 0.1 mmol (7 mg) of DMF are dissolved in 5 ml of anhydrous dichloromethane 1.3 mmol of oxalyl chloride (163 mg) in 3 ml of anhydrous dichloromethane are added dropwise. The solution is stirred at room temperature for 8 h and then concentrated under reduced pressure. The [3-(4-chlorophenyl)-1-ethyl-1H-1,2,4-triazol-5-yl]acetyl chloride obtained in this manner is processed further in crude form.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][CH2:22][CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][CH2:22][CH2:23][OH:24])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCCO
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
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: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NCCO)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with 2-aminoethanol (CAS 141-43-5) (36 mg, 0.6 mmol), HATU (141 mg, 0.36 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide 16. LC/MS (ESI+): m/z 309 (M+H). 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.64 (t, J=5.5 Hz, 1H), 8.60 (d, J=7.9 Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.17 (t, J=12.9 Hz, 1H), 8.07 (d, J=24.4 Hz, 2H), 7.98 (d, J=7.7 Hz, 1H), 7.68-7.56 (m, 1H), 4.76 (t, J=5.6 Hz, 1H), 3.57 (q, J=6.0 Hz, 2H), 3.41 (q, J=6.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>[Zn].C(O)(=O)C>[Cl:1][C:2](=[CH2:3])[CH2:4][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:13]
Reactant: O=Cc1ccccc1
Reactant: C=C(Cl)CCl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=C(Cl)CC(O)c1ccccc1
Yield: 95.2 %

Procedure:
125.40 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 60.00 g of benzaldehyde, 180 g of toluene, 240 g of 5% acetic acid and 73.88 g of zinc powder at 45° C., and then the mixture was allowed to react at the same temperature for 3 hours. After the reaction was completed zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution and dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 98.23 g of 2-chloroallylphenylcarbinol. The results were as follows.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[C:11]2[C:16]([C:17]([CH2:24][OH:25])=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O.CN(C)C>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[C:11]2[C:16]([C:17]([CH:24]=[O:25])=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1c2ccccc2c(CO)c2ccccc12)C(=O)OC(C)(C)C
Agent: CN(C)C
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CN(Cc1c2ccccc2c(C=O)c2ccccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
Compound 3 (2.30 g, 6.55 mmol) was dissolved in the mixture of dry DMSO (20 mL) and trimethylamine (20 mL). To the solution thus prepared was added the solution of pyridine sulfur trioxide (7.30 g, 45.9 mmol) dissolved in dry DMSO (20 mL) over a period of 30 min. The reaction mixture was stirred at room temperature under nitrogen for 30 min, and then poured into ice-water (300 mL), extracted with ethyl acetate (3×100 mL), dried over MgSO4. Solvent evaporation gave a yellow solid (2.30 g, 100%), without further purification. 1H NMR (CDCl3) δ 11.51 (s, 1H), 8.90 (d, J=8.5 Hz, 2H), 8.51 (d, J=8.5 Hz, 2H), 7.70-7.61 (m, 4H), 5.56 (s, 2H), 2.48 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 65 h
Yield: 25.9 %

Procedure:
8.56 g (42.99 mmol) of 2-methyl-5-fluoro-3-nitrobenzoic acid is added in 76 ml of N,N-dimethylformamide and mixed with 9.15 g (64.48 mmol) of methyl iodide and 8.91 g (64.48 mmol) of potassium carbonate. After 65 hours of stirring at room temperature, the reaction mixture is added to ice water and extracted several times with ethyl acetate. The combined organic extracts are washed with water and brine. After drying (sodium sulfate), desiccant is suctioned out, and the solvent is spun off. Repeated chromatography on silica gel (mobile solvent:ethyl acetate/hexane) yields the desired compound, specifically in a yield of 25.9% (2.37 g).
Reaction SMILES: C(OC(N[C@:7]([CH2:35][CH2:36]CC)([C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C@H:18]1[C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])=O)CC1C=CC=CC=1)=O)C.Cl.[CH2:40]([O:42][C:43]([NH:45][C@:46](CCCC)([C:54](N1CCC[C@H]1C(OCC1C=CC=CC=1)=O)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH3:41]>>[CH2:40]([O:42][C:43]([NH:45][C@H:46]([C:54]([C@@:18]1([C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])[CH2:32][CH2:33][CH2:34][N:17]1[CH2:15][CH2:7][CH2:35][CH3:36])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH3:41]
Reactant: CCCC[C@@](Cc1ccccc1)(NC(=O)OCC)C(=O)N1CCC[C@H]1C(=O)N[C@H](C=O)CCCNC(=N)N
Reactant: CCCC[C@@](Cc1ccccc1)(NC(=O)OCC)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Product: CCCCN1CCC[C@]1(C(=O)N[C@H](C=O)CCCNC(=N)N)C(=O)[C@H](Cc1ccccc1)NC(=O)OCC

Procedure:
By methods substantially equivalent to those described in Example 17, 1.47 g of EtOCO-Phe(αn-Bu)-Pro-Arg-H·HCl was prepared from EtOCO-Phe(αn-Bu)-Pro-OBzl (TLC Rf =0.74, 50% ethyl acetate:hexanes). EtOCO-Phe(αn-Bu)-Pro-Arg-H·HCl was purified by RPHPLC (98/2 (A/B), 60 min; to 85/15 (A/B), 300 min).