Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:21]O>>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([O:6][CH3:21])=[O:5]
Reactant: CO
Reactant: NC(CC(=O)O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Yield: 62 %

Procedure:
A solution of 79.5 g (0.378 mol) D, 3-amino-3-(3-nitrophenyl)propionic acid, in 21 of methanol is admixed with 200 ml of sulphuric acid (conc.). The solution is heated at boiling point for 1 h. Most of the methanol is removed under reduced pressure and the residue is poured into ice-water. Using sodium carbonate, the pH is adjusted to 8. The aqueous phase is extracted with dichloromethane. Drying of the organic phase and removal of the solvent under reduced pressure gives the ester E, methyl 3-amino-3-(3-nitrophenyl)propionate, (52.8 g, 62%) as a white solid. 10 g (44.6 mmol) of E are dissolved in 20 ml of DMF. The solution is admixed with 12.3 g (88.2 mmol) of potassium carbonate, and 15.2 g (88.2 mmol) of benzyl chloroformate are added dropwise. The mixture is stirred at 23° C. for 2 h. The mixture is diluted with 200 ml of toluene and washed three times with water, and the organic phase is dried using sodium sulphate and concentrated under reduced pressure to give the colourless oil of methyl 3-benzyloxycarbonylamino-3-(3-nitrophenyl)propionate (12.6 g, 79%). MS (DCI/NH3): 376 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([NH2:28])[CH3:27]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:28][CH2:26][CH3:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in TI-IF).
Reaction SMILES: C([BH3-])#N.[Na+].[O:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Cl.[C:13]([C:17]1[O:21][N:20]=[C:19]([NH:22][C:23]([C@@H:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][NH:26]2)=[O:24])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CCOC(C)=O>[C:13]([C:17]1[O:21][N:20]=[C:19]([NH:22][C:23]([C@@H:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:26]2[CH:8]2[CH2:9][CH2:10][O:5][CH2:6][CH2:7]2)=[O:24])[CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2C2CCOCC2)no1
Reaction time: 4 h

Procedure:
Sodium cyanoborohydride (71 mg, 1.13 mmol) and tetrahydro-pyran-4-one (75 mg, 0.75 mmol) are added to a solution of (S)-perhydro-azepine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide hydrochloride (prepared according to Method T, step 6) (0.2 g, 0.75 mmol) in DCM (8.0 mL). After stirring for four hours, the reaction mixture is diluted with EtOAc and washed twice with water. The organic phase is dried over anhydrous Na2SO4 and after removal of the solvent under reduced pressure, the crude is purified by prep TLC to afford the title compound; m/z 350 [M+H].
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].[CH3:17]I>CN(C=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:10]([OH:16])=[N:11][C:12]([S:15][CH3:17])=[N:13][CH:14]=1)(=[O:7])=[O:8])([CH3:1])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)NS(=O)(=O)c1c[nH]c(=S)[nH]c1=O
Solvent: CN(C)C=O
Product: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
N-(1,1-Dimethylethyl)-1,2,3,4-tetrahydro-4-oxo-2-thioxo-5-pyrimidinesulfonamide (30.69 g, 116.7 mmol) was dissolved in DMF (300 mL) and methyliodide was added (8.72 mL, 140 mmoles) and the mixture was stirred at ambient temperature for 24 hours. An additional quantity of methyliodide (2.5 mL) was added and the reaction stirred an additional 24 hours. A final addition of methyliodide (2.0 mL) was made followed by another 24 hours of stirring to complete the reaction. The DMF was removed under reduced pressure, the residue was suspended in water (300 mL), sodium carbonate was added until the solution was neutralized, then the pH was adjusted to 8 with sodium hydroxide pellets. The aqueous solution was filtered, extracted with three 150 mL portions of ethyl acetate. The pH of the aqueous portions was adjusted to 3 with 37% HCl, the white solid that precipitated out was filtered, washed with water, and dried in a vacuum oven to yield 20.16 gm (72.78 mmol, 62%) of product which was used as is in the next step. An analytical sample crystallized from ethanol/water, had a m.p. 225.5° C.
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of the compound from Example 8, step 2 (100 mg 0.3 mmol) in CH2Cl2 was added acetic anhydride (0.1 mL) and triethylamine (0.4 mL) sequentially at rt. The reaction mixture was stirred at it for 1 h and poured onto water (100 mL). The precipitate was collected by filtration and washed with water to give the title compound (58 mg, 64%) as an off-white solid: MS (ESI) m/z 297 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H), 3.12 (m, 4H), 3.63 (t, J=5.2 Hz, 2H), 3.78 (t, J=5.2 Hz, 2H), 6.91-6.99 (m, 6H), 7.05 (m, 1H), 7.28-7.32 (m, 2H).
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:24]1([CH2:36][C:37]([NH2:39])=[O:38])[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1>>[CH2:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[NH:8][CH:7]=[C:6]2[C:4]1[C:3](=[O:23])[NH:39][C:37](=[O:38])[C:36]=1[C:24]1[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C(=O)c1c[nH]c2c(OCc3ccccc3)cccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2c(OCc3ccccc3)cccc12

Procedure:
Beginning with 7-(benzyloxy)indole-3-glyoxylic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[F:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[C:13]=1B(O)O.[F-].[K+]>O1CCCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([F:19])[C:13]=1[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: COC(=O)c1csc(Br)n1
Reactant: OB(O)c1c(F)cc(O)cc1F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1csc(-c2c(F)cc(O)cc2F)n1
Temperature: 120 °C
Yield: 41.1 %

Procedure:
To a suspension of methyl 2-bromothiazole-4-carboxylate (500 mg, 2.16 mmol), 2,6-difluoro-4-hydroxyphenylboronic acid (2 equiv., 767 mg) and potassium fluoride (3.3 equiv., 414 mg) in tetrahydrofuran (10 mL) and water (1 mL) was added bis(tri-tert-butylphosphine)palladium(0) (0.1 equiv., 110 mg) and the mixture was heated to 120° C. for 15 min in the microwave reactor. After in vacuo concentration, the reaction mixture was purified by CombiFlash (0 to 100% EtOAc in heptane) to provide 241 mg of the title compound as a ˜1:1 mixture with methyl 2-bromothiazole-4-carboxylate, which was used directly without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-])=O.N1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=[CH:18][CH:17]=1>>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[CH:3][C:11]1[CH:18]=[CH:17][C:14]([CH3:15])=[CH:13][CH:12]=1)[CH3:9]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(C)cc1
Temperature: 25 °C
Yield: 792 %

Procedure:
A solution of 3 (11.6 g, 96.9 mmol) and 4 (16.7 g, 126 mmol) in piperidine (958 μL, 9.69 mmol) and pyridine (39.2 mL, 485 mmol) was refluxed for 8 h under argon. The reaction mixture was cooled to room temperature and the reaction was quenched with 2 N HCl (˜250 mL). The reaction mixture was extracted with ether. The extracts were washed with water, base (NaHCO3), and water. The organic solution was dried (Na2SO4), concentrated, and chromatographed (silica, CH2Cl2) to give a colorless oil (14.6 g, 79%): 1H NMR δ 1.33 (t, J=7.2 Hz, 3H), 2.37 (s, 3H), 4.26 (q, J=7.2 Hz, 2H), 6.39 (d, J=15.8 Hz, 1H), 7.18 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.66 (d, J=15.8 Hz, 1H); 13C NMR δ 14.5 21.6, 60.6, 117.4, 128.2, 129.8, 131.9, 140.8, 144.8, 167.4; Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.76; H, 7.44.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][CH3:32])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(Cl)(=[O:35])C.CCN([CH:43]([CH3:45])C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:43][CH3:45])[C:31](=[O:35])[CH3:32])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH2:7]([O:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(C)=O
Product: CCOCC
Reaction time: 8 h
Yield: 106.9 %

Procedure:
N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(ethylamino)ethoxy]quinazolin-4-amine (58 mg) in DCM (3 ml) was treated with acetyl chloride (15 mg) and DIPEA (39 mg) and stirred overnight. The solution was purified by chromatography using DCM to 10% 7N ammonia in methanol in DCM to give after trituration with diethyl ether N-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethyl}-N-ethylacetamide (39 mg, 61%); NMR spectrum (DMSO-d6) 1.12 (t, 3H), 1.98 (s, 3H), 3.37-3.42 (m, 2H), 3.87 (t, 2H), 4.39 (t, 2H), 5.31 (s, 2H), 7.16 (d, 1H), 7.22-7.28 (m, 1H), 7.33-7.39 (m, 2H), 7.55-7.61 (m, 2H), 7.71-7.75 (m, 1H), 7.87-7.91 (m, 1H), 7.94 (d, 1H), 8.45 (s, 1H), 8.61 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 492.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]=[C:13]([N:17]([CH:21]([CH:27]2[CH2:29][CH2:28]2)[C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)[CH2:18][CH2:19][CH3:20])[S:14][C:15]=1[CH3:16].[CH3:30]I>CC(C)=O.ClCCl>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]=[C:13]([N:17]([CH:21]([CH:27]2[CH2:29][CH2:28]2)[C:22]2[N:23]=[CH:24][N:25]([CH3:30])[CH:26]=2)[CH2:18][CH2:19][CH3:20])[S:14][C:15]=1[CH3:16]
Reactant: CI
Reactant: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1c[nH]cn1)C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1cn(C)cn1)C1CC1
Reaction time: 0.08 h

Procedure:
Add 570 mg of powdered potassium hydroxide to 856 mg of the compound of Example 42 dissolved in 10 ml of acetone. Stir for 5 minutes and then add 0.14 ml of methyl iodide. After 15 minutes at room temperature, dilute the reaction mixture in 100 ml of dichloromethane, and then wash with water and with water saturated with sodium chloride. Dry the organic phase over sodium sulphate, evaporate to dryness and then subject the residue to chromatography on a silica column, using a mixture of cyclohexane and ethyl acetate (1:1 V/V) as eluent.
Reaction SMILES: [BH3-]C#N.[Na+].Cl.[NH2:6][C:7]1[NH:11][CH:10]=[N:9][C:8]=1[C:12]([NH2:14])=[O:13].[CH2:15]([O:17][C:18]1[C:19]([CH:30]=O)=[N:20][CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[CH3:16]>CO>[CH2:15]([O:17][C:18]1[C:19]([CH2:30][NH:6][C:7]2[N:11]=[CH:10][NH:9][C:8]=2[C:12]([NH2:14])=[O:13])=[N:20][CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][O:27][CH2:28][CH3:29])[CH3:16]
Reactant: NC(=O)c1nc[nH]c1N
Reactant: CCOCCOc1ccnc(C=O)c1OCC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOCCOc1ccnc(CNc2nc[nH]c2C(N)=O)c1OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
NaCNBH3 (0.046 g, 0.73 mmol) was added in portions to a stirred solution of 5-amino-4-imidazolecarboxamide hydrochloride (0.150 g, 0.92 mmol) and 3-ethoxy-4-(2-ethoxyethoxy)pyridine-2-carbaldehyde (0.220 g, 0.92 mmol, obtained from Example 4(d)) in MeOH (1.5 mL) at r.t. over 10 minutes. The reaction mixture was stirred at r.t. for 2 days. The mixture was filtrated and the filtrate was evaporated in vacuo to give a crude of the title compound in quantitative yield. MS (ESI) m/z 364 (M+1).
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.N[C@H](C([NH:47][C@H:48]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[CH2:49]CCCNC(OCC1C=CC=CC=1Cl)=O)=O)C>O1CCCC1.C(Cl)(Cl)Cl.CO>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:47][C@H:48]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[CH3:49])=[O:5]
Reactant: C[C@H](N)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
At 0° C. the solution of 500 mg (2.326 mmol) of HCl Ala-OBzl in 5 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 500 mg (2.326 mmol) of Boc-Pro-OH, 300 mg (2.222 mmol) of 1-hydroxybenzotriazole and 480 mg (2.331 mmol) of dicyclohexylcarbodiimide in 30 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 6 h and TLC (chloroform/methanol, 30:1) indicated complete disappearance of HCl.Ala-Lys(ClZ)-OBzl. The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 80 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 30 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated to provide 782 mg (89%) of the title compound as a colorless powder. Mp100–101° C., FAB-MS (m/e) 377[M+H]+.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.B.CSC.[O:26]=[C:27]1[CH2:36][CH2:35][CH2:34][C:33]2[CH:32]=[C:31]([O:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])[CH:30]=[CH:29][C:28]1=2>C1(C)C=CC=CC=1.C1COCC1>[OH:26][CH:27]1[CH2:36][CH2:35][CH2:34][C:33]2[CH:32]=[C:31]([O:37][S:38]([C:41]([F:44])([F:42])[F:43])(=[O:40])=[O:39])[CH:30]=[CH:29][C:28]1=2
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: CSC
Solvent: Cc1ccccc1
Product: O=S(=O)(Oc1ccc2c(c1)CCCC2O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a dry three-necked flask containing (R)-2-methyl-CBS-oxazaborolidine (Aldrich, 1.94 mL, 1.0 M in toluene, 1.93 mmol, 0.05 eq) under N2 was added a solution of borane-methylsulfide (BMS) (Aldrich, 3.30 mL, 34.80 mmol, 0.9 eq) in toluene (200 mL) through an additional funnel at RT. After the addition, the reaction was cooled to 0° C. A solution of trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (11.37 g, 38.67 mmol, 1.0 eq) in THF (180 mL) was added drop-wise through an additional funnel. Following the addition, the reaction mixture was warmed to RT and stirred for additional 40 min, then quenched with MeOH. The solvent was removed in vacuo. The residue was treated with H2O (50 mL), and extracted with ether (3×150 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The title compound was obtained as an off-white solid after flash chromatography purification (16-22% EtOAc-hexane).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccc(F)cc1F
Yield: 78.5 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2,4-difluorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.0 g, 80%) as crystals.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]#[N:33])=[CH:26][CH:25]=1.[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:49][CH:50]=[CH:51][N:52]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:43]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=1[C:42]1[C:47]([C:48]2[NH:52][CH:51]=[CH:50][N:49]=2)=[CH:46][N:45]=[C:44]([NH:53][CH2:54][CH2:55][NH:56][C:24]2[N:29]=[C:28]([O:30][CH3:31])[C:27]([C:32]#[N:33])=[CH:26][CH:25]=2)[N:43]=1
Reactant: COc1nc(Cl)ccc1C#N
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1C#N

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]-2-methoxypyridine-3-carbonitrile was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 6-chloro-2-methoxypyridine-3-carbonitrile in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>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>[CH:13]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:15][CH2:14]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1c(F)cccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(F)cccc1C1CC1
Yield: 98.8 %

Procedure:
Methyl 2-bromo-6-fluorobenzoate (2, 11.29 g, 48.5 mmol), cyclopropylboronic acid (6.24 g, 72.7 mmol), K3PO4 (30.85 g, 145.4 mmol) and Pd(PPh3)4 (2.80 g, 2.4 mmol) were mixed under argon in a degassed mixture of toluene and water (20:1, 160 mL). The resulting brown suspension was heated at reflux for 2.5 h, cooled, filtered through Celite, and evaporated. The residue was partitioned between ethyl acetate (150 mL) and brine (150 mL). The layers were separated and organic layer was dried over magnesium sulfate and evaporated. The oily residue was suspended in hexane and the solid was removed by filtration. Evaporation of the filtrate afforded the title compound (9.30 g, 47.9 mmol, 99%) as a light brown oil.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O.CC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[C:16]([CH3:21])[CH:15]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Cl)ccc1Oc1ccc([N+](=O)[O-])cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.73 g (0.0533 moles) of 2-chloro-5-nitrobenzonitrile, 7.83 g (0.0549 moles) of 4-chloro-2-methylphenol, 7.56 g (0.0549 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from 400 ml of absolute ethanol and a small amount of acetone to give 9.60 g (62% yield) of purified 2-(4-chloro-2-methylphenoxy)-5-nitrobenzonitrile, mp 144.5°-145.5° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[F:25][C:26]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:25][C:26]1([F:32])[CH2:31][CH2:30][N:29]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:28][CH2:27]1
Reactant: FC1(F)CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC(F)(F)CC2)cn1
Yield: 98 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 4,4-difluoropiperidine hydrochloride (1 M in DMF) instead of methylamine, to the title compound (131 mg, 98%) which was obtained as a light yellow gum. MS: m/e=414.4 [M+H]+.