Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)[C:5]([F:24])=[CH:4][N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][O:31][CH2:32][CH2:33][O:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[F:24][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:39][C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][O:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:41][CH:40]=2)=[N:3][CH:4]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COCCOCOCCOc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COCCOCOCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N(C)C(=O)OC(C)(C)C)c3)n2)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 57.5 %

Procedure:
In a 25 ml 3-Neck RBF, tert-butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)(methyl)carbamate (0.88 g), 4-(2-((2-methoxyethoxy)methoxy)ethoxy)aniline (0.901 g), Cs2CO3 (1.21 g) and Xantphose (0.144 g) were added in degassed 1,4-dioxane (10 mL) and the reaction mixture was degassed under argon for 30 minutes. Palladium(II)acetate (0.055 g) was added to reaction mixture and again it was degassed for 30 minutes. The reaction mixture was heated to 80° C. and stirred for 3.5 h. The reaction was monitored on TLC using CHCl3:methanol (9.5:0.5) as mobile phase. After completion of the reaction, reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and product was extracted with ethyl acetate (3×25 ml). Ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by using Combiflash chromatography. Product was eluted with 2% methanol in CHCl3 to give 0.8 g of tert-butyl (3-((5-fluoro-2-((4-(2-((2-methoxyethoxy)methoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)carbamate. M+1=557.9.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:12][C:11]4[N:17]=[CH:18][N:19]([C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[C:22]#[N:23])[C:10]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:29][OH:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[OH:30][NH:29][C:22](=[NH:23])[C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[N:19]1[C:10]2[C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:17]=[CH:18]1
Reactant: NO
Reactant: N#Cc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N=C(NO)c1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 300 mg (0.832 mmol) of 2-(8-phenyl-imidazo[4,5-c]quinolin-1-yl)-benzonitrile (Example 63) and 360 mg (5.19 mmol) hydroxylamine hydrochloride in 7 ml DMF, a solution of 490 mg (4.61 mmol) sodium carbonate in 2.6 ml water is added using a syringe within 3 min. After a few minutes, a precipitate starts to appear. Stirring is continued for 4 h at 70° C. (tlc-control). The reaction mixture is cooled to 0° C. and is poured into 100 ml ice-water. The compound is filtered off, washed with water and hexane, and dried at 65° C. for 16 h (high-vacuum). mp: 249-251° C. MS: 380 (M+1); HPLC: tret=6.91 min (Grad 1).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1)[CH3:2].Br[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1>>[CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[CH:4]=1)[CH3:2]
Reactant: CCc1cnc(N)s1
Reactant: BrCC1CCCO1
Product: CCc1cn(CC2CCCO2)c(=N)s1

Procedure:
A mixture of 5-ethylthiazol-2-amine and 2-(bromomethyl)tetrahydrofuran were processed using the method described in Example 2A to afford the title compound. MS (ESI) m/z 213 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:9]=[N:10][N:11]([CH2:13][CH2:14][OH:15])[CH:12]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:36][C:26]1[CH:27]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[CH:29]=[C:30]([F:31])[C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([C:8]3[N:9]=[N:10][N:11]([CH2:13][CH2:14][OH:15])[CH:12]=3)[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: OCCn1cc(-c2cccc(Br)n2)nn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(-c4cn(CCO)nn4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-[4-(6-bromopyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanol (108 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 3-chloro-6-trifluoromethylpyridazine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: [C:1]1(/[C:7](=[N:9]/[NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O)(=O)=O.O.[H][H]>CC(C)=O>[C:1]1([CH:7]([NH:9][NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C/C(=N\NC(=O)c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(NNC(=O)c1ccccc1)c1ccccc1

Procedure:
In a 120 mL high-pressure autoclave were charged (E)-N′-(1-phenylethylidene)benzohydrazide (119 mg) [mw. 238.28, 0.5 mmol], [Rh(cod) (S,S)-ptbp-skewphos)]OTf (5.1 mg) [mw. 1025.08, 5.0 μmol, s/c 100], and methanesulfonic acid (0.5 mg) [mw. 96.11, 5.0 μmol, 0.01 eq.]. The system was substituted with argon 7 times. 10 mL Schlenk flask was substituted with argon, pure water (9 mg) [mw. 18.02, 0.5 mmol, 1.0 eq.] and dehydrated acetone for organic synthesis (5 mL) were added, and the solution was fed into an autoclave by argon pressure supply. The system was substituted with hydrogen gas, and the mixture was stirred with hydrogen gas pressurization at 1.0 MPa for 2 hr. The system was depressurized, and analyzed by high performance liquid chromatography to find that the starting material, (E)-N′-(1-phenylethylidene)benzohydrazide, remained by 43%, and the resultant product, N′-(1-phenylethyl)benzohydrazide was produced by 45%, and the decomposed product, acetophenone, was produced by 7%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]4[CH2:30][CH2:29]4)[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37].N1C=CC=CC=1.CO>>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:36][OH:37])=[C:24]([CH:28]4[CH2:29][CH2:30]4)[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(C2CC2)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCOc1nc(C2CC2)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
Compound A (1.21 g, 2.60 mmol), hydroxylamine hydrochloride (181 mg, 2.6 mmol), pyridine (10 mL, 100 mmol), and MeOH (10 mL, 300 mmol) were combined and stirred at room temperature overnight. Additional hydroxylamine hydrochloride (20 mg) was added and the mixture evaporated to dryness. The solids were dissolved in DCM (50 mL), washed with water (2×20 mL) and saturated aqueous NaCl (10 mL), dried over Na2SO4, and evaporated to dryness to afford compound B as a white solid (1.0 g).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[H][H]>CO.[Pd]>[C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(=O)Nc1ccc(N)cc1

Procedure:
250 mg (2 mmol) of N-propionyl-4-nitroaniline are dissolved in 200 ml of methanol and combined with 0.6 g of 10% palladium/charcoal. The product is hydrogenated in a hydrogen atmosphere at 2 bar for 30 minutes. Then the catalyst is filtered off and the solvent is eliminated in vacuo.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:35][C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:17]4[C:18]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:25][CH:24]=5)=[N:19][N:20]([CH3:22])[CH:21]=4)=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:32][N:31]([CH3:33])[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([C:18]2[C:17]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:35][C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:1][N:36]6[CH2:40][CH2:39][CH2:38][CH2:37]6)=[CH:8][CH:7]=5)=[CH:10][C:11]=34)=[CH:21][N:20]([CH3:22])[N:19]=2)=[CH:24][CH:25]=1)=[O:34]
Reactant: C1CCNC1
Reactant: CN(C)C(=O)Nc1ccc(-c2nn(C)cc2-c2ccnc3[nH]c(-c4ccc(C=O)cc4)cc23)cc1
Product: CN(C)C(=O)Nc1ccc(-c2nn(C)cc2-c2ccnc3[nH]c(-c4ccc(CN5CCCC5)cc4)cc23)cc1

Procedure:
Following the procedure described for Intermediate 101 using N′-(4-{4-[2-(4-formylphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-methyl-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea and pyrrolidine provided the title compound. ESMS [M+H]+: 520.4.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:22])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:22][C:36]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:37])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g (0.66 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(pyrimidin-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.18 mL (1.32 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.11 g (0.73 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for one hour at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.21 g (68%) as a white solid; mp=121-123° C.; MS (+) ESI m/z=414 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=O.[CH3:28][O:29][NH3+:30].[Cl-].C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1>[CH3:28][O:29][NH:30][C:3](=[O:5])[CH:2]([CH3:1])[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:12]=2)[CH:7]=1
Reactant: CO[NH3+]
Reactant: CC(C(=O)O)c1ccc2cc(OCc3ccc4ccccc4n3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CONC(=O)C(C)c1ccc2cc(OCc3ccc4ccccc4n3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the acid of Example 1 (2.32 g, 6.5 mmol), 0-methylhydroxylamine hydrochloride (0.54 g, 6.5 mmol) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (1.25 g, 6.5 mmol) in tetrahydrofuran (100 ml) is added triethylamine (2.0 ml, 2 equiv). After overnight stirring at room temperature, the solvent is removed and methylene chloride is added. This is followed by sequential washings with 0.05N hydrochloric acid and water (2x). After drying over magnesium sulfate, the solvent is removed to afford a crude solid which is recrystallized from ethyl acetate to afford a white crystalline solid, 0.6 g(24%), m.p. 162°-164° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[N:13]=[C:12](O)[C:11]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)=[CH:10][N:9]=2)[CH2:5][C@@H:4]([CH3:22])[O:3]1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:12]1[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:10][N:9]=[C:8]([N:6]2[CH2:7][C@H:2]([CH3:1])[O:3][C@H:4]([CH3:22])[CH2:5]2)[N:13]=1
Reactant: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2O)ccn1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2Cl)ccn1
Temperature: 110 °C
Reaction time: 3 h
Yield: 7.1 %

Procedure:
To solid 2-(cis-2,6-dimethylmorpholino)-5-(2-methylpyridin-4-yl)pyrimidin-4-ol (8.3 g, 27.6 mmol) at 20° C. was added neat phosphorus oxychloride (79 ml, 848 mmol). The reaction mixture was stirred at 110° C. for 3 hours. After cooling to 30° C., most of the phosphorus oxychloride was removed and 20 ml of dichloromethane was added. The solution was added into ice-water. The pH was adjusted to 8 using sodium bicarbonate. The dichloromethane layer was separated, washed with water, dried and evaporated. The crude product was added to a silica gel column and was eluted with dichloromethane and then dichloromethane/methanol (5:1). Collected fractions were evaporated to give the title compound (680 mg, 1.960 mmol, 7.09% yield). LC/MS [M+H]+=319/321.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:25])[C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[O:18][CH2:19][CH2:20]O.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH2:20][CH2:19][O:18][C:17]2[CH:22]=[CH:23][CH:24]=[C:15]([N:14]([CH3:13])[CH3:25])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)ccc1O
Reactant: CN(C)c1cccc(OCCO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Product: COC(=O)c1nc(Br)ccc1OCCOc1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Polystyrene bound PPh3 (0.77 g at 1 mmol/g, 0.77 mmol, 1.5 eq) was added to a solution of methyl 6-bromo-3-hydroxypicolinate (0.119 g, 0.51 mmol) and 2-(3-(dimethylamino)phenoxy)ethanol (39B) (0.093 g, 0.51 mmol) in dry DCM (5 mL). To this was added diethyl azodicarboxylate (0.134 mg, 0.77 mmol) dropwise, and the reaction mixture was stirred at rt for 4 hours, filtered to remove the resin, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 75:25-60:40, to provide the desired product methyl 6-bromo-3-(2-(3-(dimethylamino)phenoxy)ethoxy)picolinate (39C).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[I:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>CCOCC.C1COCC1>[OH:22][C:15]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([I:11])[CH:13]=2)[NH:17][C:16]1=[O:21]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COc1ccccc1[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2ccc(I)cc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3M 2-methoxyphenylmagnesium bromide (0.92 mL, 2.747 mmol) in Et2O is added drop wise to a suspension of 5-iodoisatin (300 mg, 1.099 mmol) in THF whilst cooling in ice. The mixture is then stirred at room temperature for 1 hour. The reaction mixture is quenched by adding ammonium chloride solution and extracted several times with ethyl acetate. The combined organic phases are washed several times with water, dried over MgSO4 and concentrated under reduced pressure. The precipitate is filtered off with suction, washed with very small amounts of ethyl acetate and dried. This afforded the desired product as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:6][N:7]2[CH:11]=[C:10]([N+:12]([O-])=O)[N:9]=[CH:8]2)[CH2:5][O:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[CH2:22][CH:21]([NH:27][CH:28]([CH2:32][CH2:33][CH3:34])[C:29](O)=[O:30])[CH2:20][CH2:19]2>>[CH3:1][C:2]1([CH2:6][N:7]2[CH:11]=[C:10]([NH:12][C:29](=[O:30])[C@@H:28]([NH:27][CH:21]3[CH2:20][CH2:19][C:18]4[C:23](=[C:24]([F:26])[CH:25]=[C:16]([F:15])[CH:17]=4)[CH2:22]3)[CH2:32][CH2:33][CH3:34])[N:9]=[CH:8]2)[CH2:5][O:4][CH2:3]1
Reactant: CC1(Cn2cnc([N+](=O)[O-])c2)COC1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(CC2(C)COC2)cn1

Procedure:
1-(3-Methyl-oxetan-3-ylmethyl)-4-nitro-1H-imidazole was reduced and then coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 433.3 m/z (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=O)[C:12]([OH:14])=O)=[CH:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.Cl.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][C:43](=[NH:48])[O:44]C(C)C)=[CH:34]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:42]2[C:43](=[O:44])[NH:48][C:12](=[O:14])[C:11]=2[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:34]1
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
A stirred solution of 406 mg (2 mmol) of 1-methyl-3-indolylglyoxylic acid in 20ml of dichloromethane was treated with 202 mg (2 mmol) of triethylamine and 273 mg (2 mmol) of isobutyl chloroformate. After 0.5 hour, the solution was added dropwise to a stirred solution of 533 mg (2 mmol) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride and 808 mg (8 mmol) of triethylamine in 50 ml of dichloromethane. The solution obtained was heated to reflux under nitrogen for 18 hours, cooled and treated with 1.9 g (10 mmol) of p-toluenesulfonic acid. After 1 hour, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel using dichloromethane/ethyl acetate (8:1) for the elution to give 107 mg(30% ) of 3,4-bis-(1 -methyl-3-indolyl)-1H-pyrrole-2,5-dione in the form of an orange colored solid of melting point >310° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:20](Cl)(=[O:22])=[O:21])=[N:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:22])=[O:21])=[N:18][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2-AMINOTHIAZOLE (0.29 g, 0.0029 mol) in Pyridine (2 mL, 0.02 mol) was added portionwise 5-Bromo-pyridine-2-sulfonyl chloride (0.50 g, 0.0019 mol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure, diluted with Ethyl acetate, washed with 1.0 N HCl, H2O and brine, dried with anhydrous sodium sulfate, filtered and concentrated to give the product was obtained as a yellow solid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[NH2:25])\[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]4([CH2:24][CH2:23][CH2:22][CH2:21]4)[C:16](=[O:20])[NH:17]3)=[CH:13][CH:12]=2)[CH:5]=1.[C:26](OC(=O)C)(=O)[CH3:27]>>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[N:25]=[C:26]([CH3:27])[O:1][N:2]=2)=[CH:5][C:6]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3([CH2:21][CH2:22][CH2:23][CH2:24]3)[C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(/C(N)=N\O)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Product: Cc1nc(-c2ccc(C)c(-c3ccc4c(c3)NC(=O)C43CCCC3)c2)no1
Temperature: 130 °C
Yield: 30.9 %

Procedure:
A mixture of (E)-N′-hydroxy-4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzimidamide (preparation 54, 31 mg, 0.09 mmol) and acetic anhydride (0.03 mL, 0.28 mmol) was heated in a sealed tube 130° C. for 1 h. The solvent was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution, brine, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (8:2 hexanes/ethyl acetate to ethyl acetate) to yield the title compound (0.01 g, 32%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([N+:24]([O-:26])=[O:25])[C:18]=2Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([N+:24]([O-:26])=[O:25])[C:18]=2[OH:30])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2Cl)CC1
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2O)CC1
Yield: 31.6 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, 1-[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl-2,6-dichloro-3-nitrobenzene (200 mg, 0.45 mmol), 60% NaH (54 mg, 1.35 mmol) and water (8μL, 0.45 mmol) were reacted to form the desired product (60 mg, 32%). EI-MS (m/z) 420.1, 422.1 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br.Br[CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20]>>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH2:16][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: CN(C)CCCBr
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Agent: Br
Product: CN(C)CCCn1cnc(-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and (3-bromopropyl)dimethylamine hydrogen bromide according to the procedure for the preparation of Example 35, part A. [M+H] Calc'd for C14H17N5, 256. Found, 256.