Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([CH3:4])([CH3:3])[CH3:2].[Mg].[Sn:7]([Cl:11])(Cl)(Cl)[Cl:8].[Cl-].[Mg+2].[Cl-]>CCCCCCC.O1CCCC1>[C:1]([Sn:7]([Cl:11])([Cl:8])[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Cl
Reactant: Cl[Sn](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Sn](Cl)(Cl)C(C)(C)C

Procedure:
The Grignard reagent from t-butyl chloride (92.5 g., 1 mole), magnesium (24.3 g., 1 mole) and tetrahydrofuran (11.) was added dropwise to a solution of tin(iv) chloride (104 g., 0.4 mole) in heptane (11.). A vigorous reaction started at once and magnesium chloride precipitated. After completion of the addition, the mixture was refluxed for 4 hrs. Cooling and work-up gave a yellow oil. This was distilled to give the desired product as a clear oil which solidified readily (70.0 g., 58%), m.p. 42°-43° (lit., 142°); b.p. 66°/3 mm.; n.m.4. 81.45(s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].CC[O:12][C:13]([CH:15]([C:17]([C:19]([O:21]CC)=[O:20])=O)[CH3:16])=O.C(OCC)C>O>[C:19]([C@H:17]1[C@@H:15]([CH3:16])[C:13](=[O:12])[C:6]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:8][C:7]=2[CH3:9])[NH:5]1)([OH:21])=[O:20]
Reactant: Cc1cc(C)cc(N)c1
Reactant: CCOC(=O)C(=O)C(C)C(=O)OCC
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C)c2c(c1)N[C@@H](C(=O)O)[C@@H](C)C2=O

Procedure:
These compounds were prepared by the route outlined in Example 1 using 3,5-dimethyl aniline and diethyloxalpropionate as the starting materials in the first step. The cis and the trans isomers were distinguished by X-ray crystallography. Trans isomer (Example 3) [m.p. 156°-157° C. (diethyl ether)]; δ (360 MHz, CDCl3), 1.35 (3H, d, J=7.2 Hz, CH3CHBCHA), 2.23 (3H, s, CH3Ar), 2.54 (3H, s, CH3Ar), 2.97 (1H, m, CH3CHBCHA), 3.97 (1H, d, J=4.9 Hz, CH3CHACHB), 6.40 (2H, s, 6-H and 8-H); m/e 233 (M+), 188 (100%, -CO2H); Found: C, 66.73; H, 6.50; N, 5.95. C13H15NO3 requires C, 66.94; H, 6.48; N. 6.00%. Cis-isomer (Example 4) (oil); δ (250 MHz, CDCl3) 1.17 (3H, d, J=7.2 Hz, CH3CHBCHA). 2.24 (3H, s, CH3Ar), 2.57 (3H, s, CH3Ar), 2.95 (1H, dq, J=7.2 and 4.0 Hz, CH3CHBCHA), 4.43 (1H, d, J=4.0 Hz, CH3CHBCHA), 4.90 (1H, br, s, NH), 6.40 (1H, s, 6-H or 8-H), 6.42 (1H, s, 6-H or 8-H); m/e 233 (M+), 188 (100%, M-CO2H); Found: C, 64.97; H, 6.53; N, 5.72. C13H15NO3.0.4 H2O requires C, 64.93; H, 6.62; N, 5.82%.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:7])=[CH:4][CH:3]=1.[NH2:19][OH:20].Cl>C(N(CC)CC)C>[OH:20][NH:19][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: NO
Reactant: O=C(O)CCCCCCC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)c1ccc(Br)cc1)NO
Yield: 31 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 50d for 37 and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound was obtained as light yellow solid in 31% yield: 1H NMR (300 MHz, CD3OD/CDCl3=5/1) δ 7.82 (d, J=7.5 Hz, 2H), 7.62 (d, J=7.5 Hz, 2H), 2.95 (t, J=7.2 Hz, 2H), 2.11 (m, 2H), 1.55-1.79 (m, 4H), 1.38 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[CH:29][CH:30]=3)[CH2:25]2)[CH2:21][CH2:22][CH3:23])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl>C(Cl)Cl.C(OCC)C>[CH3:35][O:34][C:28]1[CH:27]=[C:26]2[C:31]([CH2:32][CH2:33][CH:24]([N:20]([CH2:21][CH2:22][CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16][N:11]3[C:12](=[O:15])[CH2:13][CH2:14][NH:8][CH2:9][CH2:10]3)[CH2:25]2)=[CH:30][CH:29]=1
Reactant: CCCN(CCCCN1CCN(C(=O)OC(C)(C)C)CCC1=O)C1CCc2ccc(OC)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCCCN1CCNCCC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115.2 %

Procedure:
To 4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl)-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (800 mg, 1.64 mmol) in methylene chloride (15 mL) was added trifluoroacetic acid (5 mL) in a single portion and the reaction was stirred at room temperature for 30 min. The mixture was concentrated to dryness in-vacuo, dissolved in water (40 mL) and treated with 15% aq. KOH (20 mL). The solution was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in-vacuo. The free base (636 mg, 1.64 mmol) was taken up in diethyl ether (30 mL) and treated with 1M HCl in ether (3.3 mL). The solid was collected and dried under vacuum to afford 732 mg of 4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one 5 as a dihydrochloride salt. MS: 374([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C([N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)C1C=CC=CC=1.[C:29]([C:31]1[CH:32]=[N:33][CH:34]=CC=1)#[N:30].C(N1C=CN=C1C1C=CC=CC=1)C1C=CC=CC=1>ClCCl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:34]2[N:30]=[CH:29][C:31]([C:22]3[NH:18][C:19]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[N:20][CH:21]=3)=[CH:32][N:33]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: c1ccc(Cn2ccnc2-c2cccnc2)cc1
Reactant: N#Cc1cccnc1
Agent: c1ccc(Cn2ccnc2-c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: Fc1cccc(-c2ncc(-c3cnc(-c4cccnc4)[nH]3)cn2)c1

Procedure:
The title compound was prepared by the method described in Example 1, except that (i) commercially available 3-flourobenzene boronic acid was used instead of benzeneboronic acid in Step A, and (ii) 3-(1-benzyl-1H-imidazol-2-yl)pyridine (prepared according to the method described in Example 8, Step A, except that commercially available 3-cyanopyridine was used instead of 3-fluorobenzonitrile) was used in place of the 1-benzyl-2-phenyl-1H-imidazole in Step C; Rf 0.35 with 95:5 v/v dichloromethane-methanol; melting point 309° C; 1H-NMR (400 MHz; DMSO-d6) δ 9.40 (s, 2H), 9.27 (d,1H), 8.64 (dd, 1H), 8.40 (dt, 1H), 8.31 (dd, 1H), 8.23 (bs, 1H), 8.18-8.13 (m, 1H), 7.66-7.55 (m, 3H), 7.42 (dt, 1H); MS (ESI+) m/z 318.0 (M+1); H-PGDS FPBA IC50: 0.156 μM; H-PGDS inhibitor EIA IC50: 0.041 μM.
Reaction SMILES: [OH2:1].[ClH:2].Cl.[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:8]=2[CH2:7]1.CN(C)C1CC[C:26]2[O:27][C:28]3C=CC(N)=C[C:29]=3[C:25]=2[CH2:24]1.Cl.Cl.[Cl-]>>[ClH:2].[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:24]([C:25]4[CH:29]=[CH:28][O:27][CH:26]=4)=[O:1])=[CH:13][C:12]=3[C:8]=2[CH2:7]1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Reactant: O
Agent: Cl
Agent: [Cl-]
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccoc4)cc3c2C1
Yield: 69.7 %

Procedure:
Beginning with 0.105 gm (0.35 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine dihydrochloride hemihydrate and 0.069 gm (0.53 mMol) furo-3-yl chloride, 0.088 gm (70%) of the title compound were recovered as an off-white solid by the procedure of Example 17.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:11]([Li])CCC.[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1(C)C=CC(C=O)=CC=1.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:18]2[CH:17]=[CH:16][C:21]([CH3:11])=[CH:20][CH:19]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: CCCCCC
Reactant: [Li]CCCC
Reactant: COC(=O)CC(C)=O
Agent: Cc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C2CC(O)=CC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 10 mL of methyl acetoacetate, 3.7 g of NaH 60% dispersion in oil, 58 mL of 1.6M n-butyl lithium in hexane, 10.9 mL of p-tolualdehyde and 250 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 138°-139° C.). 1H NMR (CDCl3) δ 2.39 (s, 3 H), 2.93 (dd, 2 H), 3.58 (dd, 2 H), 5.69 (dd, 1 H), 7.23-7.31 (m, 4 H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:12](ON1C(=O)CCC1=O)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C>O.CC(C)=O>[C:12]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 94.1 %

Procedure:
The title compound was prepared similarly as shown in example 3 from L-lysine monohydrochloride (0.94 g, 5.1 mmol) and succinimidyl stearate (1.94 g, 5.1 mmol) in the presence of triethylamine (2.15 ml, 15.3 mmol) in 9.4 ml of water and 9.4 ml of acetone. The product was washed with cold water and ethanol and then dried yielding 1.98 g (92.7%) of the title compound. Infrared: 1580-1590 cm-1 (ionized carboxyl group), 1635 and 1520-1535 cm-1 (amide bands).
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.CO>[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2ccc3ccccc3n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
Lithium hydroxide monohydrate (108 mg) was added to a solution of methyl E-4phenyl-4-[4-(2-quinolinylmethoxy)benzyloxyimino]butyrate (585 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (2.6 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4-[4-(2-quinolinylmethoxy)benzyloxyimino]butyric acid (469 mg, yield 83%) as colorless crystals. m.p. 133-134° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27].[N:31]1C=CC=CC=1.[OH-].[NH4+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[C:7]2[C:14]([C:25](=[O:29])[C:26]([NH2:31])=[O:27])=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccncc1
Agent: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)ncnc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a solution of 831 mg (2.55 mmol) of [[6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 20 mL of chloroform was added 0.67 mL of oxalyl chloride followed by 0.30 mL of pyridine. The reaction was stirred for 18 hours at ambient temperature then poured into a solution prepared from 2.0 mL of concentrated ammonium hydroxide and 8.0 mL of water. The reaction was partitioned by the addition of 20 mL of methylene chloride and 10 mL of water. The organic phase was dried with sodium sulfate and concentrated. The residue was purified by flash chromatography (100 g of silica, ethyl acetate) to provide 420 mg (51%) of [[6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 455 mg (45%) of [[5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.13 (t, J=7.5 Hz, 3H), 2.95 (q, J=7.5 Hz, 2H), 3.77 (s, 3H), 5.06 (s, 2H), 5.53 (s, 2H), 6.28 (s, 1H), 6.70 (s, 1H), 7.13 (d, J=6.7 Hz, 2H), 7.27 (m, 3H), 8.46 (s, 1H)
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:29][C@@H:30]([CH2:49][CH3:50])[C@H:31]([N:35]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[C:36]1=[O:48])[C:32](O)=[O:33].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[CH2:6]([C@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:4][C@H:3]([OH:21])[C@@H:2]([NH:1][C:32](=[O:33])[C@@H:31]([N:35]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=2)[C:36]1=[O:48])[C@@H:30]([CH3:29])[CH2:49][CH3:50])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
A solution of the product from Example 6A (0.046 g, 0.119 mmol) in THF (0.9 mL) was treated with the product from Example 7B (0.050 g, 0.119 mmol), EDAC (0.035 g, 0.183 mmol), HOBT (0.025 g, 0.185 mmol), and NMM (0.040 mL, 0.364 mmol) at 0° C., stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid, dilute sodium bicarbonate solution, and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column, eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.080 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[CH:4][CH:3]=1.[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:18])[C:12]=2[C:13]2[N:14]=[CH:15][N:16]([C:25]3[CH:26]=[CH:27][C:22]([C:20](=[O:21])[CH3:19])=[CH:23][CH:24]=3)[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)cc1
Temperature: 120 °C
Yield: 47 %

Procedure:
A mixture of 4-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-[1,2,3]triazole (73 mg, 0.30 mmol), 4-fluoroacetophenone (37 μL, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) in DMF (1.5 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 16 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (51 mg, 47%) as an off white solid after recrystallisation from ethyl acetate. MS: m/e=362.2 [M+H]+.
Reaction SMILES: Br.CC1C=C(C)N2OC(=N)N=C2[N:4]=1.[N+]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[C:18]1([S:23]([NH2:4])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Cc1cc(C)n2oc(=N)nc2n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 1.6 g of 5,7-dimethyl-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-2-imine hydrobromide and 1.4 g of o-nitrobenzenesulfonyl chloride in 60 ml of anhydrous methylene chloride at 0° C. is added a solution of 1.0 g of triethylamine in 10 ml of anhydrous methylene chloride dropwise. After addition, the mixture is stirred at 0° C. for 0.5 hour and then at ambient temperature for 2.5 hours. The mixture is then filtered. The filtrate is concentrated under reduced pressure and then column chromatographied (silica gel) to yield 2-nitro-N-[5,7-dimethyl-2H-[1,2,4)oxadiazolo(2,3-a)pyrimidin-2-ylidene]]benzenesulfonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:21])[C:11]([O:13][C:14]2([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+]([C:25]1[CH:30]=CC(C(C)C(O)=O)=C[CH:26]=1)([O-])=O.C1C2CC3(O)CC(C2)CC1C3>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:21])[C:11]([O:13][C:14]23[CH2:20][CH:25]4[CH2:30][CH:18]([CH2:17][CH:16]([CH2:26]4)[CH2:15]2)[CH2:19]3)=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)OC1(C)CCCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: OC12CC3CC(CC(C3)C1)C2
Product: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc([N+](=O)[O-])cc1
Yield: 92 %

Procedure:
Using a method similar to that used in the preparation of 1-methylcyclohexyl 2-(p-nitrophenyl)propionate, 14.6 g of 2-(p-nitrophenyl)propionic acid, but using 1-adamantol instead of 1-methylcyclohexanol, were reacted to obtain 22.74 g (92% yield) of 1-adamantyl 2-(p-nitrophenyl)propionate as a light yellow viscous liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:31]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:36])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:31]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:36])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CS(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4S(C)(=O)=O)n3)cc21

Procedure:
Title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product isolated as a white solid (32 mg, 22%). MP=217-218, LCMS: 534.09 (M+H), 1H-NMR (CDCl3, 400 MHz) 6 (8.18 (s, 1H), 7.97 (s, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.55-7.46 (m, 4H), 7.21 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 3.75-3.73 (m, 2H), 2.99 (s, 3H), 2.29-2.26 (m, 2H), 2.10-1.99 (m, 2H), 1.33 (s, 6H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([C:45](Cl)=[O:46])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].O>O1CCCC1>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([C:45]([C:2]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=2[O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[O:46])=[CH:43][CH:44]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccc(C(C)(C)C)cc3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 25 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.35 ml) was added to the cooled solution, and the mixture was stirred at −78° C. for 20 min. 4-Tert-butylphenylcarbonyl chloride (0.15 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 min. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (31 mg, yield 25%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[Cl:24].[OH-].[Na+].C(Cl)Cl>CO>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[C:5]([Cl:24])[CH:6]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)c(Cl)c2)CC1
Yield: 90 %

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-chlorobenzoic acid methyl ester was saponified to the carboxylic acid with aqueous NaOH in MeOH using the procedure of Step 3 in Example 11. 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-chlorobenzoic acid was obtained as a foam by evaporation of a DCM solution under reduced pressure (90% yield).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22](O)=[O:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].B>C1COCC1>[OH:23][CH2:22][C:17]12[CH2:18][CH2:19][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:21][CH2:20]1)[CH2:15][CH2:16]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Agent: B
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 17 h

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid, IX, Example 85b, 0.82 kg) and tetrahydrofuran (9.02.1) are mixed under nitrogen and borane.tetrahydrofuran complex (1 M) in THF (4.18 l) is added at such a rate as to maintain the internal temperature between 10 to 20°. The reaction mixture is stirred at 10 to 200 for 17 hours until all of the starting material is consumed (TLC; dichloromethane/methanol, 9/1; visualization UV then potassium permanganate). Methanol (3.44 l) is added to the reaction mixture, and the mixture is heated to reflux for 1 hr. The reaction is cooled to between 15 and 40° and the solvent removed by reduced pressure at 40 to 45°. The residue is partitioned between ethyl acetate (13.61 l) and hydrochloric acid (1 M, 2.23 l) and the aqueous layer is removed with any undissolved solid material. The mixture is clarified and the residual organic phase from the filtration of the aqueous layer/solid mixture is combined with the bulk organic layer. Saturated sodium hydrogen carbonate (2.23 l) is added and the layers separated, retaining any solids with the aqueous phase. The aqueous phase/solid mixture is filtered and the residual organic phase from these mother liquors are combined with the bulk organic layer. The combined organic layers are washed with saturated saline (2.23 l), the layers are separated and residual solids are retained with the aqueous phase. The aqueous layer/solid mixture is filtered and organics in the mother liquors from the filtration are combined with the bulk organic layer, dried with magnesium sulfate (0.41 kg), filtered, washed with ethyl acetate (0.82 l) and the solvent removed under reduced pressure at 40 to 45°to give the title compound.