Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=3)=[C:13]([CH3:25])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[NH4+].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([C:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[C:22]([C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)[N:21]=[CH:20][N:19]=3)=[C:13]([CH3:25])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-n2nc(C(C)(C)C)[nH]c2=O)ccc1Oc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-n2nc(C(C)(C)C)[nH]c2=O)ccc1Oc1cc(-c2cnn(C)c2)ncn1
Temperature: 85 °C
Reaction time: 16 h
Yield: 48.3 %

Procedure:
3-(tert-Butyl)-1-(5-((6-chloropyrimidin-4-yl)oxy)-6-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.10 g, 0.28 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.08 g, 0.36 mmol), and K2CO3 (0.10 g, 0.72 mmol) were suspended in a solution of dioxane (2.5 mL) and water (0.50 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.032 g, 0.028 mmol) was added and the reaction mixture was stirred at 85° C. for 16 h. The mixture was diluted with sat. NH4Cl (aq) 5 mL) and the resultant emulsion was extracted with EtOAc (4×10 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford a brown amorphous solid that was triturated with MeCN (1.5 mL). A white precipitate formed following sonication and was isolated by filtration and dried to afford 3-(tert-butyl)-1-(6-methyl-5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.055 g, 48.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.95 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.46 (d, J=1.1 Hz, 1H), 3.89 (s, 3H), 2.29 (s, 3H), 1.27 (s, 9H); MS (ESI) m/z: 420.3 (M+H+).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[S:12])[C:6]=2[CH:5]=[CH:4]1.CI.[C:15]([O-])(O)=O.[Na+].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[CH3:15][S:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][NH:3]2
Reactant: O=C([O-])O
Reactant: S=C1CCCc2[nH]ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1cccc2[nH]ccc12
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
NaH (637 mg, 15.87 mmol, 60% dispersion) was added in portions to a solution of 1,5,6,7-tetrahydro-indole-4-thione (2 g, 13.23 mmol) in THF (100 mL) at −20° C. under N2 and stirred for 20 min. MeI (1.3 mL, 19.84 mmol) was added in dry THF (10 mL), and the reaction mixture stirred at −20° C. for 1 h. The reaction mixture was then poured into NaHCO3 (sat'd aq), and the crude product extracted into benzene (˜250 mL). The organic layer was washed with brine, and dried over Na2SO4. To this was added DDQ (3 g, 13.23 mmol), and the mixture stirred at RT for 1 h. The solvent was removed under vacuum, the residue taken up in CHCl3, and the insoluble solid filtered off. The solvent was removed by evaporation to dryness and the solid immobilized on silica gel. The product was purified by column chromatography (0 to 25% EtOAc/hexane) to provide 4-methylsulfanyl-1H-indole (1.2568 g, 58.2% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH3:18].C(OC1C=CC([N+]([O-])=O)=CC=1C1N(C)N=CC=1)C.C1C(=O)N(Br)C(=O)C1.NC1C=CC=CC=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:19])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1ccc([N+](=O)[O-])cc1-c1c(Br)cnn1C
Agent: CCOc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Agent: O=C1CCC(=O)N1Br
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: CCOc1ccc(N)cc1-c1c(Br)cnn1C

Procedure:
4-Bromo-5-(2-ethoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole: The crude reaction mixture of 5-(2-ethoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole was treated with NBS in DMF, in a similar manner as described in Example 1.1, Step D, provided brominated compound 4-bromo-5-(2-ethoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole. It was reduced directly to the aniline as described in this example above. LCMS m/z (%)=326 (M+H79Br, 88), 328 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 8.38 (dd, J=2.7, 9.2 Hz, 1H), 8.22 (d, J=2.7 Hz, 1H), 7.59 (s, 1H), 7.11 (d, J=9.2 Hz, 1H), 4.14-4.32 (m, 2H), 3.76 (s, 3H), 1.43 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:21][S:22]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)=[O:23])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][C:12]1([CH2:18]CC)[O:17][CH2:16][CH2:15][CH2:14][O:13]1.CC1(CCO)OCCCO1>>[Na:1].[CH3:2][C:3]1[C:4]([CH2:21][S:22]([C:24]2[NH:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[N:28]=2)=[O:23])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][C:12]1([CH3:18])[O:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: CCCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCCO1
Agent: CC1(CCO)OCCCO1
Agent: [Na]
Product: Cc1c(OCCC2(C)OCCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 2.5 %

Procedure:
The same procedure as in the steps (8c) to (8g) of Example 8, was repeated using 2-(2-methyl-1,3-dioxan-2-yl)ethanol obtained in the step (30a) to obtain the title compound (113 mg, total yield: 2.5%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.[Br:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25]Br>>[Br:22][C:23]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:24]=1[CH2:25][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(F)ccc1Br
Yield: 95 %

Procedure:
Compound 15.2 was prepared as described for example 6.2 by reacting compound 1.1 with 2-bromo-5-fluorobenzyl bromide. 4-[3-(2-Bromo-5-fluorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained in a yield of 95% (molecular weight 483.02 (C20H14BrF4N3O2); retention time Rt=2.10 min. [B]; MS (ESI): 484.26 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.O>CS(C)=O>[N:18]1([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][N:35]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NN2CCCCC2)s1
Solvent: O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NN2CCCCC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 87.4 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (29 mg, 0.1 mmol) in dimethyl sulfoxide (4.0 mL) was heated with 5-(hydrazinocarbonyl)thiophene-2-carboxylic acid piperidin-1-ylamide (27 mg, 0.1 mmol) prepared in Reference Synthetic Example 9 at 100° C. for 20 hours and allowed to cool to room temperature. 2 mL of water was added, and the precipitated solid was collected by filtration, washed with 1 mL of chloroform and dried to give 47 mg of the desired product (yield 87%).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[N:17]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[N:15][C:14]=3[C:33](O)=[O:34])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:36]([O:43][C:44](=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([NH2:51])[CH:46]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:43][C:44](=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([NH:51][C:33]([C:14]2[N:15]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:17]([CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C:13]=2[CH2:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:34])[CH:46]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: Cc1ccccc1-c1nc(C(=O)O)c(CCC23CC4CC(CC(C4)C2)C3)n1CC(=O)OC(C)(C)C
Product: Cc1ccccc1-c1nc(C(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)c(CCC23CC4CC(CC(C4)C2)C3)n1CC(=O)OC(C)(C)C
Yield: 60.7 %

Procedure:
The product of step b (324 mg, 0.68 mmol) was reacted with 3-amino-benzoic acid benzyl ester (154 mg, 0.68 mmol) according to the procedure of Example 20, step d to afford colourless foam (284 mg, 61%). 1H NMR (300 MHz, CDCl3) 9.21 (1H, s), 8.16 (2H, m), 7.80-7.77 (1H, m), 7.48-7.27 (10H, m), 5.36 (2H, s), 4.33 (2H, s), 3.02 (2H, m), 2.24 (3H, s), 2.01 (3H, br s), 1.77-1.37 (23H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:29])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=2)=[O:17])[CH:11]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10][CH:9]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[OH-].[K+]>CO.O>[C:33]([O:32][C:30]([CH:11]1[CH2:10][CH:9]([S:37]([C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)(=[O:38])=[O:39])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:12]1[C:13](=[O:29])[CH2:14][NH:15][C:16](=[O:17])[NH:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[C:25]([OH:27])=[O:26])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(S(=O)(=O)c3ccc(C)cc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)C2CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)O)c3)C2c2ccccc2F)cc1
Yield: 12.5 %

Procedure:
A The process is performed as described in Example 1A, but starting with 2.2 g of tert-butyl (2RS,4SR,5RS)-5-(2-fluorophenyl)-1-{2-[3-(3-methoxycarbonylphenyl)ureido]acetyl}-4-(4-methylphenyl)sulphonyl-2-pyrrolidinecarboxylate and 0.19 g of potassium hydroxide in a mixture of 60 cm3 of methanol and 20 cm3 of distilled water. After treatment, 0.27 g of (2RS,4SR,5RS)-3-(3-{2-[2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-(4-methylphenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid is obtained [Rf=0.5; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD at a temperature of 373 K, δ in ppm): 1.52 (s, 9H): C(CH3)3); from 2.35 to 2.55 and 2.79 (2 mts, 1H each: CH2 at 3); 2.45 (s, 3H: ArCH3); 3.66 and 3.96 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 4.05 (mt, 1H: H4); 4.62 (t, J=8 Hz, 1H: H2); 5.70 (d, J=3 Hz, 1H: H5); from 7.00 to 7.55 (mt, 8H: aromatic H); 7.80 (mt, 1H: H of the aromatic at 5 (H6)); 7.85 (d, J=8 Hz, 2H: H of the aromatic at 4 (ortho to the CH3)); 8.00 Ct, J=1.5 Hz, 1H: aromatic H CH2: ortho to the COOH))].
Reaction SMILES: [CH2:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][C@@H:6]([C:20](OC)=[O:21])[CH2:5]1)[CH2:2][CH3:3].[BH4-].[Na+]>CO.O>[CH2:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[CH:15][NH:14]4)[CH2:7][C@@H:6]([CH2:20][OH:21])[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1C[C@H](C(=O)OC)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCN1C[C@H](CO)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 82.4 %

Procedure:
10 grams of 6-n-propyl-8β-methoxycarbonylergoline were added to a mixture of 10 g of sodium borohydride in 125 ml of methanol. The reaction mixture was refluxed for about 2 hrs; then a second 5 g batch of sodium borohydride was added. The reaction mixture was cooled after 5 hrs, diluted with water, and the precipitate was filtered to give 7.5 g of 6-n-propyl-8β-hydroxymethylergoline melting at about 166°-168° C. A solution of 15 g of 4-toluenesulfonyl chloride in 100 ml of pyridine was added slowly to a cooled solution of 7.5 g of 6-n-propyl-8β-hydroxymethylergoline in 300 ml of pyridine. The mixture was stirred for 7 hrs whereafter it was poured over iced water and the precipitate was filtered to give 9 g of 6-n-propyl-8β-toxyloxymethylergoline melting at 147°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[CH2:12]=[C:13]1[O:16][C:15](=[O:17])[CH2:14]1.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:15](=[O:17])[CH2:14][C:13](=[O:16])[CH3:12]
Reactant: COC(=O)c1ccccc1N
Reactant: C=C1CC(=O)O1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1NC(=O)CC(C)=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
A solution of 2-amino-benzoic acid methyl ester (1.51 g, 10 mmol) and triethylamine (97.2 mmol/ml, 0.0194 mL, 0.14 mmol, 0.014 eq) in toluene (4 mL) was heated to 60° C. and then a solution of 4-methylene-oxetan-2-one (0.84 g, 10 mmol) in toluene (2 ml) was added to the solution over 15 minutes. The reaction was heated at 80° C. for 6 hours and then at 50° C. for 16 hours. Progress of the reaction was monitored by TLC (silica gel, hexane-ethyl acetate (7:3 v/v)), analytical HPLC and LCMS and upon its completion the mixture was partitioned between ethyl acetate and aqueous hydrochloric acid (1 N). The organic layer was washed with water, saturated sodium bicarbonate, water and then brine, dried over Na2SO4 and concentrated to give an orange solid. The solid was crystalized from methylene chloride/ethyl acetate and hexane to provide 2-(3-oxo-butanoylamino)-benzoic acid methyl ester (1.83 g, 78%) as large colorless prisms, mp 81-83° C. (lit., mp 79-80° C.). LCMS MH+ 235.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1F
Temperature: 70 °C
Reaction time: 20 h
Yield: 50.6 %

Procedure:
2,4-Difluoronitrobenzene (8.0 g) was dissolved in N,N-dimethylformamide (110 ml) and the solution was admixed with 1H-1,2,4-triazole (3.47 g) and potassium carbonate (6.95 g) and the mixture was stirred under a nitrogen atmosphere at 70° C. for 20 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the ethyl acetate layers were combined and washed 5 times with water and then with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:1.3). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield 1-(3-fluoro-4-nitrophenyl)-1H-1,2,4-triazole (5.29 g) as yellow powdery crystals.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:33][OH:34])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:30])[F:31])[CH:23]=1)[CH2:33][O:34][C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (3-fluoro-4-(4-fluoro-3-(trifluoromethyl)phenoxy)phenyl)methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]2[O:19][CH2:18]2)=[CH:11][C:10]=1[N:20](C(OC(C)(C)C)=O)[S:21]([CH3:24])(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([NH:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([C:46]2[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(O)C>[CH2:32]([N:39]([CH2:18][C@H:17]([OH:19])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:11]=1)[C@H:40]1[CH2:41][CH2:42][C@H:43]([C:46]2[CH:47]=[CH:48][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:55][CH:56]=2)[CH2:44][CH2:45]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 50 °C

Procedure:
A mixture of 818 mg (1.82 mmol) of 4-benzyloxy-3-(N-tert-butoxycarbonyl-N-methylsulfonylamino)-1-((2S)-2,3-epoxypropoxy)benzene and 450 mg (1.82 mmol) of ethyl trans-4-[4-(benzylamino)cyclohexyl]benzoate in the form of a base is heated under reflux in 15 ml of absolute ethanol for 16 hours. The mixture is cooled, 3 ml of an ethanol solution saturated with hydrochloric acid are added thereto and the medium is heated at 50° C. for 6 hours. The solvent is evaporated and the medium is taken up in a mixture of 50 ml of a saturated sodium bicarbonate solution and 50 ml of ethyl acetate. The organic phase is washed with a saturated aqueous NaCl solution. The organic phase is dried, filtered and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on a silica gel column, eluting with a methylene chloride/methanol/NH4OH (95/5/0.5) mixture. The title compound is obtained in the form of a white solid. [M+H+]=687.
Reaction SMILES: [N:1](=[C:3]1[CH:8]([CH3:9])[N:7]([CH3:10])[C:6](=[O:11])[CH2:5][S:4]1)[OH:2].[CH3:12][N:13]=[C:14]=[O:15]>C(N(CC)CC)C>[CH3:12][NH:13][C:14]([O:2][N:1]=[C:3]1[CH:8]([CH3:9])[N:7]([CH3:10])[C:6](=[O:11])[CH2:5][S:4]1)=[O:15]
Reactant: CC1C(=NO)SCC(=O)N1C
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C1SCC(=O)N(C)C1C

Procedure:
Utilizing the procedure of Example V, 2-oximino-3,4-dimethyltetrahydro-1,4-thiazin-5-one was reacted with methyl isocyanate in the presence of triethylamine to yield 3 g of 2-[O-(methylcarbamoyl)oximino]-3,4-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 161°-163° C.
Reaction SMILES: [N:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH3:18])[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-]>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[NH:1]2)[CH3:18]
Reactant: CCOc1ccccc1C=C(N=[N+]=[N-])C(=O)OC
Solvent: Cc1ccccc1
Product: CCOc1cccc2[nH]c(C(=O)OC)cc12
Temperature: 25 °C

Procedure:
Methyl 2-azido-3-(2-ethoxyphenyl)propenoate (2.061 g, 10 mmol) was suspended in toluene (500 ml) and the mixture was refluxed for three hours and then maintained at room temperature overnight. The solids were collected by filtration in order to give the desired product in the form of a yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].P(Br)(Br)[Br:21]>C(COC)OC.CCOCC>[Br:21][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:18][CH3:19])=[C:7]([CH:17]=1)[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: COc1ccc(CO)cc1CNC(=O)OC(C)(C)C
Reactant: BrP(Br)Br
Solvent: COCCOC
Solvent: CCOCC
Product: COc1ccc(CBr)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.65 g of t-butyl N-[5-(hydroxymethyl)-2-methoxybenzyl]carbamate was dissolved in 20 ml of dimethoxyethane, 0.53 ml of phosphorus tribromide was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ether and washed with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 1.76 g of the title compound from the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[Na+].O>O1CCCC1.O.CO>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH:12]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][N:6]=2)=[O:26])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.5 %

Procedure:
A solution of 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (prepared as in Example 31(B)(c), 62.6 mg, 0.16 mmol) in tetrahydrofuran/water/methanol (0.40 mL, 3:1:1) was treated with a 2N aqueous sodium hydroxide solution (0.16 mL, 0.32 mmol). The reaction was stirred at 25° C. for 24 h. The reaction mixture was then poured into water and extracted with chloroform (2×30 mL). The aqueous layer was then acidified to pH=1 with a 1N aqueous hydrochloric acid solution. The product was extracted into chloroform/methanol (9:1, 3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate w/acetic acid) afforded 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid (17.0 mg, 31.5%) as a white solid: mp 206-208° C.; EI-HRMS m/e calcd for C20H21ClN2O2 (M+) 372.1240, found 372.1244.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:31][C:32]1[CH:33]=[C:34]2[C:38](=[N:39][CH:40]=1)[NH:37][CH:36]=[CH:35]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[NH:37]1[C:38]2[C:34](=[CH:33][C:32]([O:31][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:40][N:39]=2)[CH:35]=[CH:36]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Yield: 84.6 %

Procedure:
tert-Butyl 4-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}piperazine-1-carboxylate (2.0 g, 4.42 mmol) was dissolved in N,N-dimethylacetamide (60 ml) and 5-hydroxy-7-azaindole (651 mg, 4.86 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (671 mg, 4.86 mmol) added. The reaction mixture was heated at 85° C. for 3 hours. The mixture was cooled, filtered and concentrated under reduced pressure. Column chromatography of the residue (8-10% methanol/dichloromethane) gave 4-(7-azaindol-5-yloxy)-7-{3-[4-(tert-butoxycarbonyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (2.0 g, 85%) as a white solid.