Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19](O)=[O:20])[CH:2]=1.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([NH:22][C:19](=[O:20])/[CH:18]=[CH:17]/[C:8]3[CH:9]=[CH:10][C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:7]=3[C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:31]=2)[CH:27]=[CH:28]1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1-c1cccnc1
Reactant: Nc1ccc2cc[nH]c2c1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1-c1cccnc1)Nc1ccc2cc[nH]c2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[2-(3-pyridyl)-4-(trifluoromethyl)phenyl]prop-2-enoic acid, Example 106(b), (185 mg) and 6-aminoindole (59 mg, 0.44 mmol, Aldrich) provided, after purification by silica gel chromatography (gradient: 0-50% EtOAc in hexane), the title compound as an amorphous orange solid. MS (ESI, pos. ion) m/z: 408 (M+1).
Reaction SMILES: I[CH2:2][S:3][C:4]1[N:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.CC[O-].[Na+]>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:2][S:3][C:4]2[N:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=2)=[CH:14][CH:13]=1
Reactant: Clc1cnc(SCI)nc1
Reactant: Oc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(OCSc2ncc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
2-(Iodomethyl)thio-5-chloropyrimidine was added to a solution of p-chlorophenol (5.5 mmol) and 0.138 M NaOEt in ethanol (40 ml) and the mixture stirred at room temperature overnight. The solvent was distilled off and the mixture worked up as above; yield 64%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:14][CH2:11][C:12]#[CH:13])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of 26.6 g (189 mmol) of 4-fluoronitrobenzene, 20.8 g (377 mmol) of propargylamine, 11 g (189 mmol) of potassium fluoride, and 26 g (188 mmol) of potassium carbonate in 600 ml of dimethylsulfoxide is stirred at room temperature under a nitrogen atmosphere for twenty hours. The reaction mixture is poured into 1.5 l of water and stirred at room temperature for two hours. The yellow solid is filtered, rinsed with water, and then isopropyl alcohol. The product is dried in vacuo at 50° C. for two days to give 16.27 g (49%) 4-nitro-N-2-propynylbenzenamine; mp 150°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[NH2:17][C:18]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:17][C:18]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:8]
Reactant: CCOC(=O)c1cc(OCCN(CC)CC)ccc1N
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Product: CCOC(=O)c1cc(OCCN(CC)CC)ccc1NC(=O)COc1ccc(C(F)(F)F)cc1Cl

Procedure:
The product was obtained according to general working method I starting from 1.00 g (3.567 mmol) (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (Z2b) and 0.908 g (3.567 mmol) ethyl 2-amino-5-(2-diethylamino-ethoxy)-benzoate (Z25c).
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]O)=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=1)=[O:4].COCCN(S(F)(F)[F:38])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:38][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:2]([OH:1])([CH3:27])[C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=2)=[O:4])=[CH:19][CH:20]=1
Reactant: Cc1cc(NC(=O)C(C)(O)COc2ccc(CCO)cc2)ccc1[N+](=O)[O-]
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(CCF)cc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-hydroxy-3-[4-(2-hydroxyethylphenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide (prepared in Example 20, 300 mg, 0.0008012 mol) in dry CH2Cl2 (3 ml) was treated with Deoxo-Fluor® (195 mg, 0.0008813 mol) in dry CH2Cl2 (1 ml) at −15 to −10° C. The solution was stirred for 2 h at 0° C. and then for 3 days at room temperature. The saturated NaHCO3 solution was added and the mixture was extracted with dichloromethane. The combined extracts were washed with water, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography using dichloromethane as an eluent. Crystallization from toluene afforded the desired compound as pure crystals: m.p. 102-105° C. 1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 2.88 (2H, dt, 3JHF=24.4 Hz, 3J=6.4 Hz), 3.95 (1H, d, 2Jgem=9.8 Hz), 4.18 (1H, d, 2Jgem=9.5 Hz), 4.56 (2H, dt, 2JHF=47.4 Hz, 3J=6.4 Hz), 6.18 (1H, broad s, —OH), 6.85 (2H, d, 3J=8.5 Hz), 7.15 (2H, d, 3J=8.4 Hz), 7.88 (1H, d, 3J=9.0 Hz), 7.93 (1H, s), 8.03 (1H, d, 3J=9.0 Hz), 10.13 (1H, broad s, —NHCO—).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[NH2:29][CH2:30][CH2:31][OH:32]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([NH:29][CH2:30][CH2:31][OH:32])=[O:21]
Reactant: NCCO
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NCCO)c(=O)n(C)c1=O

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and 2-aminoethanol. 1H NMR (400 MHz, CDCl3) δ ppm 3.10 (s, 3H) 3.39 (s, 3H) 3.53-3.57 (m, 2H) 3.78-3.81 (m, 2H) 6.81 (t, J=8.0 Hz, 1H) 7.47-7.52 (m, 2H) [M+H] calc'd for C15H16FIN4O4, 463. found, 463.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C.[CH3:27][S:28]([O:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])[C@H:34]([C:50](O)=[O:51])[CH2:33]1)(=[O:30])=[O:29]>C(#N)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:50]([C@@H:34]2[CH2:33][C@H:32]([O:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:36][N:35]2[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])=[O:51])[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
1.11 g of 1-(2-hydroxyethyl)piperazine, 1.29 ml of diethylcyanophosphonate and 1.18 ml of triethylamine were added, in that order, whilst ice-cooling, to a solution of 3.00 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline [prepared as described in step 54(a)(i) above] in 35 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent. To give 2.60 g of the title compound, as a powder.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].Cl.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:21]([C:22]([C:24]3[CH:41]=[CH:40][C:27]([CH2:28][NH:29][C:30](=[O:39])[CH2:31][CH2:32][CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:26][C:25]=3[CH3:42])=[O:23])[CH2:20][C:19]3[CH:18]=[N:17][N:16]([CH3:43])[C:15]=3[NH:14][C:13]=2[CH:44]=1>ClCCl.C(N(CC)CC)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:21]([C:22]([C:24]3[CH:41]=[CH:40][C:27]([CH2:28][NH:29][C:30](=[O:39])[CH2:31][CH2:32][CH:33]4[CH2:38][CH2:37][N:36]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:35][CH2:34]4)=[CH:26][C:25]=3[CH3:42])=[O:23])[CH2:20][C:19]3[CH:18]=[N:17][N:16]([CH3:43])[C:15]=3[NH:14][C:13]=2[CH:44]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1cc(CNC(=O)CCC2CCNCC2)ccc1C(=O)N1Cc2cnn(C)c2Nc2cc(Cl)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(CCC(=O)NCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ethanesulfonyl chloride (0.64 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of N-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzyl]-3-piperidin-4-yl-propionamide hydrochloride (Compound number 1108) (2.97 mg, 0.005 mmol) in dichloro-methane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then sol-vents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=613.4
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.ClC1C=CC(O[CH2:23][C:24]#[N:25])=CC=1.C(O)(=O)C.Cl>O1CCCC1>[Cl:7][C:8]1[N:9]=[C:10]([CH2:23][C:24]#[N:25])[C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CCc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 6.9 %

Procedure:
To a stirred solution of potassium t-butoxide (24.69 g, 220 mmol, 2.2 eq) in anhydrous tetrahydrofuran (150 ml) at -50° C. under nitrogen, a solution of 2-chloro-5-nitropyridine (15.85 g, 100 mmol) and (4-chlorophenoxy)acetonitrile (E. Grochowski et al., Bull. Acad. Pol. Sci. Ser. Sci. Chim., 11, 443 (1963)) (18.44 g, 110 mmol, 1.1 eq) in anhydrous tetrahydrofuran (150 ml) was added dropwise at such a rate that the reaction temperature was maintained at -40° to -50° C. with cooling in a dry ice/acetone bath. The resultant purple colored reaction mixture was then stirred at -78° C. under nitrogen for 1 hour, at which time glacial acetic acid (20 ml, 0.35 mol, 3.5 eq) was added to the reaction, and the mixture was allowed to warm to room temperature. A solution of 5% HCl (100 ml) was added to the reaction mixture and this aqueous mixture was extracted with ethyl ether (100 ml) and then with methylene chloride (2×100 ml). The extracts were combined, dried over magnesium sulfate, and passed through a silica gel filter (approximately 150 g) followed by methylene chloride (1200 ml). This filtrate was evaporated under reduced pressure, and the residual oil was chromatographed using silica gel (approximately 300 g) and eluted with 25% hexanes in methylene chloride to afford an oil (Rf =0.52 in methylene chloride) which was triturated in cold anhydrous ether to afford 6-chloro-3-nitro-2-pyridyl acetonitrile (1.37 g, 7%) as a white crystalline solid: mp, 121.5°-123.5° C. Further elution yielded another oil (Rf =0.48 in methylene chloride) which was triturated with cold anhydrous ethyl ether to afford (2-chloro-5-nitro-4-pyridyl)acetonitrile (1.87 g, 9%) as a white crystalline solid, m.p. 87°-89° C. IR (KBr) 3080, 2240, 1600, 1545, 1520, 1450, 1390, 1340, 1135 cm-1.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=1)([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(C)CC(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][N:14]2[CH2:15][CH2:16][C:11]([C:2]([OH:1])([CH3:10])[C:3]3[CH:4]=[CH:5][C:6]([F:9])=[CH:7][CH:8]=3)=[CH:12][CH2:13]2)=[CH:22][CH:23]=1
Reactant: CC(O)(C1=CCNCC1)c1ccc(F)cc1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(O)(C1=CCN(CCCC(=O)c2ccc(F)cc2)CC1)c1ccc(F)cc1

Procedure:
A mixture of 2.0 g of 4-(α-hydroxy-α-methyl-4-fluorobenzyl)-1,2,5,6-tetrahydropyridine, 2.5 g of 4'-fluoro-4-chlorobutyrophenone, 3.0 g of sodium carbonate, a crystal of sodium iodide, in 100 ml of 4-methyl-2-pentanone is stirred and refluxed for 72 hours. It is cooled, filtered, and the filtrate evaporated under reduced pressure. Diethyl ether is added to the residue and the resulting solution extracted with 5% aqueous hydrochloric acid. The aqueous solution is made basic with ammonium hydroxide and extracted with diethyl ether. The extract is dried, evaporated and the residue recrystallized from isopropanol, to give the 4'-fluoro-4-[4-(α-hydroxy-α-methyl-4-fluorobenzyl)-1,2,5,6-tetrahydropyridyl]-butyrophenone melting at 95°.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35].O>CN(C=O)C>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:23][CH2:24][N:25]2[C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]2=[O:34])[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
1-(2,3-Dichlorophenyl)piperazine hydrochloride (3.16 g, 11.8 mmol) and potassium carbonate (4.08 g, 29.5 mmol) were added to the solution of 2-(2-bromoethyl)isoindoline-1,3-dione (3 g, 11.8 mmol) in DMF (20 ml). The reaction mixture was stirred for overnight at room temperature. After reaction complete, water (40 ml) was added and then normal work-up was taken. The residue was purified with normal phase preparative column to afford title compound (3.87 g, 81% yield) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([OH:12])=[O:11].[CH3:13][C:14](O)([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][C:14]([CH3:16])([CH3:15])[CH3:13])=[O:11]
Reactant: Cc1cc(O)c(C(=O)O)c(=O)o1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(C(=O)OC(C)(C)C)c(=O)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.4 %

Procedure:
In 18 ml of toluene, 0.51 g of 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylic acid, 0.67 g of 2-methyl-2-propanol and 0.07 g of 4-dimethylaminopyridine were dissolved, and 0.58 g of WSC was added and the mixture was stirred at room temperature for 16 hours. Subsequently, water was poured into the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The resultant organic layer was washed with a saturated solution of sodium chrolide, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to obtain 0.22 g of tert-butyl 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylate (Compound No. 7).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[Cl:8][C:9]1[C:14](Cl)=[N:13][CH:12]=[CH:11][N:10]=1>>[Cl:8][C:9]1[C:14]([O:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: OCc1ccco1
Reactant: Clc1nccnc1Cl
Product: Clc1nccnc1OCc1ccco1
Yield: 68 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step 1, starting from 2-furanmethanol (4.18 g, 42.7 mmol), 2,3-dichloropyrazine (2.05 g, 13.8 mmol) and KO-t-BuO (1.82 g, 16.2 mmol). The product, which was obtained as a yellowish oil in 68% yield, was used directly in the next step.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:37])([CH3:36])[C:34]#[N:35])=[CH:29][CH:28]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:34]([C:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]4[N:10]([CH:25]=[C:7]([NH:6][C:4]([CH:1]5[CH2:3][CH2:2]5)=[O:5])[N:8]=4)[N:11]=3)[CH:17]=2)=[CH:32][CH:31]=1)([CH3:37])[CH3:36])#[N:35]
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C#N)c1ccc(NC(=O)c2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)cc1
Yield: 56.2 %

Procedure:
Using 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (100 mg, 0.30 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (57 mg, 0.36 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (63 mg, 0.33=mol), 4-(dimethylamino)pyridine (54 mg, 0.44 mmol) and pyridine (3.0 mL) as starting materials and in the same manner as in Example 318, the title compound (81 mg, 57%) was obtained as a white powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:21])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: NC1CCN(CCN2C(=O)COc3ccc(Cl)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(Cl)cc54)CC3)nc2N1
Yield: 20.7 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 56) (0.8 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (150 mg, 0.84 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21 to give 78 mg (21%) product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:11][CH2:12][CH2:13][OH:14].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>O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:11][CH2:12][CH2:13][OH:14])=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1cncc(Br)c1
Reaction time: 72 h

Procedure:
5-Bromonicotinic acid (0.020 g, 0.10 mmol), 2-aminoethanol (9.16 mg, 0.15 mmol), HATU (0.046 g, 0.12 mmol), DIPEA (0.052 g, 0.40 mmol), and dioxane (2 mL) were added to a 20 mL vial. The vial was sealed and placed on a heater/shaker for 3 days at 40° C. The reaction mixture, containing the title compound, was used without purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:4]=1.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[C:22]([O:26][CH2:27][CH2:28][CH2:29][CH:30]=O)[CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17]1>>[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:22]3[N:23]=[C:24]4[C:19]([CH2:18][CH2:17][C:16](=[O:15])[NH:25]4)=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)[N:4]=1
Reactant: Cc1ccnc(N2CCNCC2)n1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: Cl
Product: Cc1ccnc(N2CCN(CCCCOc3ccc4c(n3)NC(=O)CC4)CC2)n1

Procedure:
In a manner similar to that of other examples above, 4-methyl-2-piperazin-1-yl-pyrimidine hydrochloride (U.S. Pat. No. 6,303,603) was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 397.2 (Exact Mass: 396.23).
Reaction SMILES: C([BH3-])#N.[Na+].[N:5](=[C:7]([CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[N:15]([CH3:24])[C:13]1=[O:14])[OH:6].Cl>CO.CCOCC>[OH:6][NH:5][CH:7]([CH3:25])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[N:15]([CH3:24])[C:13]1=[O:14]
Reactant: CC(CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)=NO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)NO
Reaction time: 3 h

Procedure:
Sodium cyanoborohydride (62.84 mg, 1 mmol) was added to a solution of 1-(5-oximinohexyl)-3,7-dimethylxanthine (Klein, J. P.; Leigh, A. Oxime Substituted Therapeutic Compounds, U.S. Pat. No. 5,770,595 (Jun. 23, 1998)) (293 mg, 1 mmol) in methanol (10 ml). 1 M hydrogen chloride in ether was added to pH 4-5. After stirring for 3 hours, the mixture was concentrated under reduced pressure. 1 N aqueous sodium hydroxide solution to pH 9-10 (10 ml). The mixture was extracted with 10% methanol-dichloromethane (3×50 ml). The combined extracts were washed with water (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-dichloromethane to provide 1-(5-(N-hydroxy)aminohexyl)-3,7-dimethylxanthine (180 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]([C:19](=[O:24])N(OC)C)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[C:26]([NH:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[CH3:39])([CH3:29])([CH3:28])[CH3:27]>>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])[C:19](=[O:24])[CH2:39][C:33]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=1[C:31](=[O:40])[NH:30][C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)ccc1C(=O)NC(C)(C)C
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1CC(=O)[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-1-(methoxy-methyl-carbamoyl)-2-(2,4,5-trifluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.4 g, 3.4 mmol) and N-tert-butyl-4-chloro-2-methyl-benzamide (2.3 g, 10 mmol) followed by purification by silica gel flash column chromatography gives the title compound.
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]([CH3:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[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:13]=[C:14]([C:19]#[N:20])[CH:15]=[C:16]([CH2:18][Br:21])[CH:17]=2)[O:9][N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(CBr)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-methylphenyl)-1,2,4-oxadiazole (0.5 g, 1.91 mmol), N-bromosuccinimide (0.339 g, 1.91 mmol), and benzoyl peroxide (0.0010 g, 0.04 mmol) in carbon tetrachloride (25 mL) was heated at 80° C. for 18 hours. After this time the reaction mixture was cooled and diluted with dichloromethane. The organic solution was washed with water and brine to afford 0.595 g (91%) of 3-(2-pyridyl)-5-(3-bromomethyl-5-cyanophenyl)-1,2,4-oxadiazole.