Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>CO.O.C(O)C>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][NH:15][CH:16]([CH3:17])[C:11]3=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC1=NCCn2c1ccc2-c1ccc(Cl)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC1NCCn2c(-c3ccc(Cl)cc3)ccc21
Yield: 74 %

Procedure:
6-(p-Chlorophenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine (1.0 g) was dissolved in a mixture of 100 ml of methanol and 10 ml of water under argon. The solution was treated portionwise with 0.5 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 70 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.1 g of brown oil, was dissolved in a 30-fold amount of ethanol with the addition of a 5-fold amount of methylene chloride and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 1.1 g (74%) of 6-(p-chlorophenyl)-1,2,3,4-tetrahydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:1 ); m.pt.: 196°-198° C. (dec.)
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1>[C:1]1([C:7]2[S:11][C:10]([C:12]3[C:13]4=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]4[CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)s3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
A mixture of 3-(5-phenylthiophen-2-yl)pyridin-2-amine (250 mg) in dehydrated THF (10 ml) was added to a mixture of sodium hydride (60%, 198 mg) and 2-chloroethanesulfonyl chloride (485 mg) in dehydrated THF (10 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was added to water, and the resulting precipitate was washed with water and diisopropyl ether to give the title compound (262 mg) as a yellow solid. The obtained solid was crystallized from acetonitrile to give a yellow solid.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].Cl.[CH2:6]1[C:11]2[C:12](=[O:20])[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[S:15][C:10]=2[CH2:9][CH2:8][NH:7]1.C(N(CC)CC)C.C(Cl)[Cl:29]>C(O)C.CO>[ClH:29].[CH2:1]([N:7]1[CH2:8][CH2:9][C:10]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12](=[O:20])[C:11]=2[CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCI
Reactant: ClCCl
Reactant: O=c1c2c(sc3ccccc13)CCNC2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCN1CCc2sc3ccccc3c(=O)c2C1
Yield: 60 %

Procedure:
A solution of 1.44 ml of n-propyl iodide in 10 ml of ethanol was added dropwise over 20 minutes to a refluxing solution of 2.50 g of 1,2,3,4-tetrahydro-10H-(1)-benzothiopyrano[3,2-c]pyridine-10-one hydrochloride, 3.5 ml of triethylamine in 10 ml of ethanol. The mixture was refluxed for four hours after which thin layer chromatography (SiO2 :CH2Cl2 with 10% methanol) showed no starting material. The solution was evaporated to dryness and the residue was partitioned between chloroform and dilute aqueous hydrogen chloride. The aqueous layer was adjusted to a pH of 8 by addition of sodium carbonate and was extracted three times with chloroform. The organic phase was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with methylene dichloride containing 1% of ethanol. The product was dissolved in chloroform and the solution was acidified by addition of ether saturated with hydrogen chloride. More ether was added and the mixture was filtered. The product was crystallized from ethanol and dried under reduced pressure to obtain 1.75 g (60% yield) of 1,2,3,4-tetrahydro-2-n-propyl-10H-(1)-benzothiopyrano[3,2-c]pyridin-10-one hydrochloride melting at 218° to 221° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:19]([O:21]CC)=O)[N:8]=2)=[N:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1.C1COCC1>CC(N(C)C)=O>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:19]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:21])[N:8]=2)=[N:2]1
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccc(OC)cc2n1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(Nc3cc[nH]n3)nc(C(=O)c3ccc(F)cc3)nc2c1
Reaction time: 2 h
Yield: 60 %

Procedure:
To ethyl 4-(1H-pyrazol-3-ylamino)-7-methoxyquinazoline-2-carboxylate (30 mg, 0.10 mmol) in dry DMA (2.5 mL) cooled in a −20° C. cooling bath was added dropwise 1N 4-fluorophenylmagnesium bromide in THF (0.306 mL, 0.306 mmol). After 2 h additional 1 N 4-fluorophenyl magnesium bromide (0.050 mL) was added. After 2 h, the reaction mixture was quenched by addition of a saturated ammonium chloride solution. The solution was concentrated and H2O was added. The precipitate was washed with water and purified by preparative thin layer chromatography on silica gel eluting with 10% MeOH/DCM to give a solid (21 mg, 60%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.93 (s, 3H) 6.73 (br. s., 1H) 7.29 (m., 2H) 7.38 (m, 2H) 7.63 (br. s., 1H) 8.08 (m, 2H) 8.64 (m., 1H) 10.63 (br. s., 1H) 12.47 (br. s., 1H) LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH:8]=[C:9]([O:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[Cl:23])(=[O:15])=[O:14])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:24])[O:3]1.[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:26][N:5]1[C:6]2[CH:11]=[CH:10][C:9]([O:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[Cl:23])(=[O:15])=[O:14])=[CH:8][C:7]=2[C:2]([CH3:25])([CH3:1])[O:3][C:4]1=[O:24]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OC(=O)Nc2ccc(OS(=O)(=O)c3cccc(Cl)c3Cl)cc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)OC(C)(C)c2cc(OS(=O)(=O)c3cccc(Cl)c3Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a stirred solution of (4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate (0.50 g, 1.24 mmol) in dimethylformamide (DMF) (6 mL) with potassium carbonate (0.51 g, 3.72 mmol) was added methyl iodide (0.1 mL, 1.60 mmol). After stirring overnight at room temperature, the solution was then quenched with ammonium chloride solution (sat.) and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. Trituration with ether gave (1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate as a white solid (0.30 g, 59%): 1H NMR (DMSO-d6): δ 8.14 (dd, J=8.1, 1.5 Hz, 1H), 7.92 (dd, J=8.1, 1.5 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.12 (s, 2H), 7.00 (m, 1H), 3.25 (s, 3H), 1.49 (s, 6H). MS (ESI) m/z 416/418/420 ([M+H]+); Anal. calcd for C17H15Cl2NO5S: C, 49.05; H, 3.63; N, 3.36. Found: C, 49.01; H, 3.44; N, 3.15.
Reaction SMILES: [OH:1][CH2:2][C:3]([N:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])=[O:4].CN(C)C=O.[H-].[Na+].Cl[C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:21]=1>C(Cl)(Cl)Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:22]2[N:21]=[C:20]([O:1][CH2:2][C:3]([N:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])=[O:4])[C:29]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[N:23]=2)=[CH:31][CH:32]=1
Reactant: CCCN(CCC)C(=O)CO
Reactant: Fc1ccc(-c2nc(Cl)c3c(n2)CCCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)COc1nc(-c2ccc(F)cc2)nc2c1CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a mixture of 2-hydroxy-N,N-dipropylacetamide (1.8 g) and dimethylformamide (20 ml) is added sodium hydride (about 60% oily, 0.5 g) at 0 to 5° C., and the mixture is stirred at 0° C. for one hour. To the reaction mixture is added 4-chloro-2-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (2.0 g) at the same temperature, and the mixture is stirred at room temperature for four hours. To the mixture are added chloroform and ice-water, and the chloroform layer is collected, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from a mixture of diethyl ether and n-hexane to give the desired compound (2.2 g), m.p. 95-96° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([NH2:9])=[N:7][CH:8]=1.[F:15][C:16]([F:27])([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:17](Cl)=[O:18]>>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([NH:9][C:17](=[O:18])[C:16]([F:15])([F:27])[C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])=[N:7][CH:8]=1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Product: O=C(Nc1ncc(C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)C(F)(F)C(F)(F)F

Procedure:
5-(Trifluoromethyl)-3-nitro-2-aminopyridine is reacted with perfluorobutyryl chloride to yield 5-(trifluoromethyl)-3-nitro-2-(2,2,3,3,4,4,4,-heptafluorobutyramido)pyridine, which when hydrogenated yields 6-(trifluoromethyl)-1-hydroxy-2-(perfluoro-n-propyl)-1H-imidazo(4,5-b)pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O1CCCC1>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[C:4]([F:10])[CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(N)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Oc2ccccc2)c(F)cc1Cl

Procedure:
4-Chloro-2-fluoro-5-methylaniline (5 g, 31.4 mmol) was dissolved in tetrahydrofuran (100 ml) and potassium carbonate (6.0 g, 37.7 mmol) and phenyl chloroformate (5.9 g, 37.7 mmol) were added. Solution was refluxed for 3 hr and the solvent was removed under reduced pressure. Product was purified by column chromatography on silica gel (eluent, methylene chloride:hexane, 6:4; 7.15 g).
Reaction SMILES: C(=O)=O.S(=O)(=O)(O)O.[C:9]([CH2:13][OH:14])([F:12])([F:11])[F:10].C[O:16][CH:17](O)[C:18]([F:21])([F:20])[F:19]>>[C:9]([CH:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[OH:14])([F:12])([F:11])[F:10]
Reactant: OCC(F)(F)F
Reactant: COC(O)C(F)(F)F
Agent: O=C=O
Agent: O=S(=O)(O)O
Product: OC(OCC(F)(F)F)C(F)(F)F
Temperature: 75 °C

Procedure:
A 250 mL round bottom flask was equipped with a thermometer, magnetic stir bar, addition funnel and dry ice condenser leading to a receiver cooled with an isopropanol cold bath held at about −30° C. by the addition of portions of dry ice as needed. Sulfuric acid (175 g) was placed in the 250 mL flask and CF3CH2OH (Aldrich, 57.8 g, 0.578 mole) placed in the receiver. Trifluoroacetaldehyde methyl hemiacetal (Alfa Aesar, 50 g, 90% purity, 0.346 mole) was placed in the addition funnel and added rapidly dropwise to the sulfuric acid solution which was heated to 75° C. as the addition proceeded. The aldehyde began to distill from the sulfuric acid solution at a pot temperature of about 64° C. After the completion of the addition the sulfuric acid solution was held at 75° C. for an additional hour. The receiver had gained 26.3 g in weight and this solution was used without purification in the next step.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25](N)=[CH:24][C:23]=3[F:29])[CH:13]=2)=[N:10][CH:11]=1.[C:30]1([NH:36][C:37]([C:39]2([C:42]([OH:44])=O)[CH2:41][CH2:40]2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC[N:47](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25]([N:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:37]([C:39]4([C:42]([NH2:47])=[O:44])[CH2:40][CH2:41]4)=[O:38])=[CH:24][C:23]=3[F:29])[CH:13]=2)=[N:10][CH:11]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(-c5ccc(C6OCCO6)cn5)sc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
To intermediate 38 (0.46 g, 1.1 mmol) in dry DMF (20 mL) was added 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (40) (0.46 g, 2.2 mmol) [US 2007/0004675 A1], DIPEA (0.98 mL, 5.6 mmol) and HATU (1.07 g, 2.81 mmol) and the mixture was stirred at r.t. for 18 h. The mixture was then partitioned between ethyl acetate and water; the organic phase was collected, washed with water, 1M NaOH, saturated NH4Cl, and brine, dried (anhydrous MgSO4), filtered and concentrated. Silica gel chromatography (2% methanol in ethyl acetate) afforded intermediate 41 (0.23 g, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.37 (s, 1H), 9.98 (s, 1H), 8.68 (s, 1H), 8.53 (d, J=5.3 Hz, 1H), 8.40 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.97 (dd, J=8.2, 2.0 Hz, 1H), 7.90 (dd, J=13.1, 2.0 Hz, 1H), 7.62 (d, J=7.6 Hz, 2H), 7.53-7.46 (m, 2H), 7.30 (t, J=7.4 Hz, 2H), 7.06 (t, J=7.4 Hz, 1H), 6.66 (d, J=5.3 Hz, 1H), 5.88 (s, 1H), 4.11-3.97 (m, 4H), 1.47 (br s, 4H). MS (m/z): 597.2 (M+H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([OH:20])(=[O:19])=[O:18])=[C:13]([NH2:21])[CH:12]=1.[N:22]#[C:23][NH2:24].[OH-].[Na+].Cl>>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([NH:24][C:23]#[N:22])[N:4]=2)=[CH:12][C:13]=1[NH2:21])([OH:20])(=[O:18])=[O:19]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N#CN
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CNc1nc(Cl)nc(Nc2ccc(S(=O)(=O)O)c(N)c2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
19 parts of cyanuric chloride are dispersed in 200 parts of ice water, and 18.8 parts of 1,3-diaminobenzene-4-sulfonic acid are added. The mixture is initially stirred at 0° to 5° C. and a pH of 2.5 for two hours and then at 0° to 5° C. and a pH of 4 for 30 minutes, and 4.25 parts of cyanamide are then added. The pH is brought to 10 by means of aqueous sodium hydroxide solution, the mixture is gradually heated to 50° to 60° C., stirred in this temperature range and at this pH for about 90 minutes, and then brought to a pH of 7 by means of hydrochloric acid. The 2-sulfo-5-(2'-chloro-4'-cyanamido-s-triazin-6-yl)aminoaniline compound thus obtained is diazotized directly in its synthesis solution in the usual manner by first adding 20 parts by volume of an aqueous 5N sodium nitrite solution and adding the mixture slowly to a mixture of 50 parts by volume of aqueous concentrated hydrochloric acid and 600 parts of ice. Stirring is continued for 2 hours, excess nitrous acid is destroyed, if necessary, by means of sulfamic acid, and the diazonium salt suspension obtained is then added to an aqueous solution of 36.2 parts of 1-[4'-(β-sulfatoethylsulfonyl)phenyl]-3-methyl-5-pyrazolone; the coupling reaction is carried out at 15° to 25° C. and a pH of 4.5 to 5.5, and the synthesis solution is then clarified at 40° to 50° C. by means of kieselguhr and filtration.
Reaction SMILES: C[Mg]Cl.[CH2:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:7]=1[C:15]1[CH:20]=[CH:19][C:18](CC=O)=[CH:17][CH:16]=1)[CH3:5].C([O:27][CH2:28][CH3:29])(=O)C.[CH3:30]CCCCCC>O1CCCC1>[CH2:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:7]=1[C:15]1[CH:20]=[CH:19][C:18]([C:28]([OH:27])([CH3:29])[CH3:30])=[CH:17][CH:16]=1)[CH3:5]
Reactant: CCOC(C)=O
Reactant: CCCCCCC
Reactant: CCc1c(-c2ccc(CC=O)cc2)[nH]c2nccnc12
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CCc1c(-c2ccc(C(C)(C)O)cc2)[nH]c2nccnc12
Reaction time: 1 h
Yield: 109 %

Procedure:
To a cooled (˜5° C.) solution of methylmagnesium chloride (3M in THF; 81.3 mL, 244 mmol, 10 equiv.) in tetrahydrofuran (116 mL), was added a solution of compound 4 (6.5 g, 24.4 mmol) in tetrahydrofuran (348 mL) drop-wise, over ninety minutes, keeping the temperature at about 0° C. by the rate of addition. A bright yellow solution was observed on addition. After one hour, TLC (ethyl acetate/n-heptane 1/1) showed no starting material present and a new spot moving at a lower Rf. The batch was quenched by the careful addition of a saturated, aqueous solution of sodium bicarbonate (about 660 mL). A thick mass ensued and ethyl acetate (250 mL) and water (250 mL) were added to the mixture. The aqueous layer was removed and re-extracted with ethyl acetate (2×250 mL). The ethyl acetate fractions were combined, washed with water (2×200 mL) and concentrated on the Buchi at a bath temperature of 40° C. and from 80 to 10 torr, to give 7.5 g (109%) of 1 as a light-beige solid: 1H NMR (DMSO-d6, FIG. 2) δ 12.0 (1H, s), 8.35 (1H, d, J=3.5 Hz), 8.2 (1H, d, J=3.5 Hz), 7.6 (4H, s), 5.1 (1H, s), 2.9 (2H, q, J=8 Hz), 1.5 (6H, s), 1.3 (3H, t, J=8 Hz).
Reaction SMILES: [S:1]1[C:5]([CH:6]([NH:8][C:9]2[C:10]([CH3:21])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH3:7])=[CH:4][C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:17]3[CH:18]=[CH:19][C:14]([C:13]4[O:12][N:11]=[C:10]([CH3:21])[C:9]=4[NH:8][CH:6]([C:5]4[S:1][C:2]5[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=5[CH:4]=4)[CH3:7])=[CH:15][CH:16]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1cc2ccccc2s1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)c4cc5ccccc5s4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (1-benzo[b]thiophen-2-yl-ethyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13]([CH:23]2[CH2:25][CH2:24]2)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:26]([N:28]([CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:27].CN1C(=O)CCC1>CO>[CH:23]1([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:4]2[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=[C:2]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:28]([CH2:36][CH3:37])[CH2:26][CH3:27])=[CH:34][CH:33]=3)[CH:3]=2)[CH2:25][CH2:24]1
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCN(CC)c1ccc(Nc2cc(N(Cc3ccc(OC)cc3)C3CC3)c3ncc(C#N)n3n2)cc1
Yield: 12.2 %

Procedure:
A microwave tube was charged with 1G (30 mg, 0.085 mmol), N1,N1-diethylbenzene-1,4-diamine (139 mg, 0.85 mmol), and NMP (1 mL). The mixture was irradiated in a microwave for three cycles of 15 min. (300W), 120° C. The crude reaction mixture was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min., 30 min. gradient, monitored at 220 nm) to afford 244A, (5 mg, 9.0% yield). HPLC: Rt=3.896 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=482.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]([NH:22][OH:23])=[NH:21])=[CH:19][C:13]=2[N:12]=1.[CH3:24]CCCCCC>C(OCC)(OCC)OCC.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[N:21]=[CH:24][O:23][N:22]=3)=[CH:19][C:13]=2[N:12]=1
Reactant: N=C(NO)c1ccc2[nH]c(-c3cc([N+](=O)[O-])ccc3Cl)nc2c1
Reactant: CCCCCCC
Agent: Cl
Solvent: CCOC(OCC)OCC
Product: O=[N+]([O-])c1ccc(Cl)c(-c2nc3cc(-c4ncon4)ccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A stirred solution of 2-(2-chloro-5-nitro-phenyl)-N-hydroxy-1H-benzoimidazole-5-carboxamidine (5.29 g; 16.0 mmol) in triethyl orthoformate (50 ml) was heated to 80° C. Concentrated hydrochloric acid (3 drops) was added and heating continued for a further two hours. After cooling to room temperature, heptane (50 ml) was added which caused a precipitate to form. The solid was filtered off and washed with more heptane to afford 2-(2-chloro-5-nitro-phenyl)-5-[1,2,4]oxadiazol-3-yl-1H-benzoimidazole (3.30 g, 62%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[CH:5][CH:4]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=2)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[CH:8][CH:7]=1)=[O:18]
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccc(NC(=O)c2ccccc2C)cc1
Product: Cc1ccccc1C(=O)Nc1ccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)cc1
Yield: 74.9 %

Procedure:
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-2-methyl-benzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound (109 mg, 75%).
Reaction SMILES: CC1(C)[O:6][C:5](=O)[C@H:4]([C@H:8]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][C@H:16]2[CH3:27])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:3]1.[NH2:29][OH:30]>CC(O)C.O>[OH:30][NH:29][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][C@H:16]1[CH3:27])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C[C@@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Reactant: NO
Solvent: CC(C)O
Solvent: O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 47.5 %

Procedure:
To a solution of (5S)-2,2-dimethyl-5-((1R)-3-methyl-1-{[(2R)-2-methyl-4-(2-pyridinyl)piperazinyl]carbonyl}butyl)-1,3-dioxolan-4-one (517 mg; 1.33 mmol; 1.0 eq) in iPrOH (2.0 mL) was added an aqueous solution of hydroxylamine (391.5 μl; 6.64 mmol; 5.0 eq.) and the resulting reaction mixture was stirred at RT for 40 min. HPLC analyses showed the presence of 2 diastereoisomers (75/25). This reaction mixture was dissolved in water (6 mL) and directly purified by reverse-phase chromatography (major diastereoisomer as the first eluted peak, gradient starting from 100% H2O up to 75% H2O in ACN in 5 min, then isocratic 75% H2O in ACN for 25 min; flow: 50 mL/min) to give the title product (4) as a white powder (230 mg; 47%). 1H NMR (CD3OD, 300 MHz) δ 8.10 (m, 1H), 7.58 (m, 1H), 6.84 (m, 1H), 6.69 (m, 1H), 4.84-4.70 (m, 1H), 4.60 (m, 1H), 4.48 (m, 0.4H), 4.19 (m, 1H), 4.13-3.98 (m, 2H), 3.71-3.55 (m, 0.6H), 3.30-3.07 (m, 2H), 3.05-2.82 (m, 1H), 1.94-1.76 (m, 1H), 1.55-1.38 (m, 3H), 1.35 (d, 1.3H, J=6.7 Hz), 1.23 (d, 1.7H, J=6.7 Hz), 0.93 (m, 6H). M+(ESI): 365.2, M−(ESI): 363.2. HPLC (Condition B), Rt: 2.4 min (HPLC purity: 97.6