Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CC1C=CC(N2[C:30](=[O:31])[C:29]3[C:28]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([O:32][CH3:33])[CH:26]=5)[N:21](COC)[C:20]=4[C:19]([CH2:37][CH2:38][CH3:39])=[CH:18][C:17]=3[C:15]2=[O:16])=CC=1>>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][N:5]1[C:30](=[O:31])[C:29]2[C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:32][CH3:33])[CH:26]=4)[NH:21][C:20]=3[C:19]([CH2:37][CH2:38][CH3:39])=[CH:18][C:17]=2[C:15]1=[O:16]
Reactant: CN(C)CCN
Reactant: CCCc1cc2c(c3c4cc(OC)ccc4n(COC)c13)C(=O)N(c1ccc(C)cc1)C2=O
Product: CCCc1cc2c(c3c1[nH]c1ccc(OC)cc13)C(=O)N(CCN(C)C)C2=O
Yield: 67 %

Procedure:
1.0 ml of N,N-dimethylethylenediamine was added to 300 mg of N-(4-methylphenyl)-6-methoxy-9-methoxymethyl-1-propylcarbazole-3,4-dicarboximide. The mixture was refluxed for 30 minutes and then concentrated to dryness under reduced pressure. To the residue were added 15 ml of methanol and 1.5 ml of concentrated hydrochloric acid. The mixture was refluxed for 30 minutes. The solvent was removed y distillation under reduced pressure. The residue was mixed with 50 ml of ethyl acetate and 20 ml of an aqueous saturated sodium hydrogencarbonate solution to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 180 mg (yield: 67%) of N-(2-dimethylaminoethyl)-6-methoxy-1-propylcarbazole-3,4-dicarboximide as yellow needles.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:42][CH:26]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:31][CH:30]=1.[OH-].[K+].Cl>O.O1CCOCC1>[OH:25][CH:26]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:31][CH:30]=1)[CH2:42][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: CCOC(=O)CCc1ccc(OCC2CO2)cc1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCc1ccc(OCC(O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(2-ethoxycarbonylethyl)-phenoxy]-propane are added to 80 ml of dioxane/60 ml of water and adjusted to pH 14 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: O[C:2]12[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH:6]1[CH:5]=[N:4][NH:3]2.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>ClCCl>[NH:3]1[C:2]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C:6]=2[CH:5]=[N:4]1
Reactant: CC(C)(C)OC(=O)N1CC2C=NNC2(O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate (47.0 kg, 207 mol) in dichloromethane (669 kg) at 0° C. was added a methanol solution of toluene-4-sulfonic acid monohydrate (3.7 kg, 20 mol in 38 kg MeOH) drop-wise over 2 h. The reaction was then aged for 4 h at this temperature. Then, 5% aqueous NaHCO3 (91 kg) was added and stirred at room temperature for 30 min. The layers were then separated and the aqueous extracted with dichloromethane (312 kg). The combined organics were washed with 5% brine (190 kg then 483 kg), treated with activated carbon (2.7 kg) and filtered. The resulting organics were dried with Na2SO4, filtered, and concentrated to 71-118 L. n-Heptane was then added (238 kg) and the batch further concentrated to 188-235 L. The slurry was cooled to 10-20° C., filtered, and the cake washed with n-heptane. The solids were dried under vacuum at 40-50° C. overnight to give tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[C:18]([Cl:20])[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:15]([CH3:17])[CH3:16])[CH:9]=2)=[C:5]([Cl:21])[CH:4]=1.[O:22]1[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl>[Cl:21][C:5]1[CH:4]=[C:3]([CH:19]=[C:18]([Cl:20])[C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH:15]([CH3:17])[CH3:16])[CH:9]=1)[CH2:2][N:23]1[C:24](=[O:28])[NH:25][C:26](=[O:27])[O:22]1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CBr)cc2Cl)ccc1O
Reactant: O=c1[nH]oc(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(Oc2c(Cl)cc(Cn3oc(=O)[nH]c3=O)cc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a solution of the title compound of Step B (59 mg, 0.15 mmol) and [1,2,4]oxadiazolidine-3,5-dione (16 mg, 0.15 mmol) in DMF (1.5 ml) at room temperature was added sodium carbonate (32 mg, 0.30 mmol). After stirring at room temperature for about two hours, the solution was diluted with 0.5N HCl (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (3×15 ml), brine (15 ml), dried, filtered, and concentrated. The crude product was purified by preparative TLC (22% methanol/3.5% water/74.5% chloroform) to afford the title compound (61 mg). MS (APCI−) Calc: 410.0, found: 409.1 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccc(Br)cc2)c2ccsc2S1(=O)=O
Temperature: 0 °C

Procedure:
1.8 g (8.3 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are stirred for 24 hours at room temperature under nitrogen with 1.6 g (8.3 mmol) of p-bromophenylisocyanate and 0.84 g (8.3 mmol) of triethylamine in 20 ml of absolute dimethyl sulfoxide. Thereafter, the mixture is poured into 50 ml of 2-N hydrochloric acid and 20 g of ice. The separated precipitate is filtered off under suction and washed neutral with water. The filter residue is taken up in 200 ml of methylene chloride, dried over sodium sulfate, stirred with 1 g of active carbon and filtered. The filtrate is extracted with four 100 ml portions of semi-saturated sodium carbonate solution, each of the organic phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with three 100 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated, whereby the product crystallizes out. For purification, the product is recrystallized from ca 30 ml of methanol to give 3-hydroxy-2-methyl-4-(4-bromophenylcarbamoyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 197°-199° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1)([CH3:10])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:21](N=C=NCCCN(C)C)C.CO>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:21][O:18][C:17]([C:15]1[N:16]=[C:12]([S:11][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:10])[CH3:9])[S:13][CH:14]=1)=[O:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)O)cs1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-tert-Butoxycarbonyl-1-methyl-ethylsulfanyl)-thiazole-4-carboxylic acid was dissolved in methylene chloride (1200 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191.70 g), 4-dimethylaminopyridine (5.86 g) and methanol (19.47 mL) were added and the mixture was stirred at room temperature overnight. The mixture was washed with dilute hydrochloric acid (about 0.5 mol/L), saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution (each 500 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved again in ethyl acetate (700 mL), washed successively with dilute hydrochloric acid (about 0.2 mol/L), saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution (each 300 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained solid was washed with a mixed solvent (10:1, about 500 mL) of hexane and ethyl acetate, and the solid was collected by filtration. The solvent was evaporated from the filtrate and the residue was purified by silica gel column chromatography (using 500 g of Fuji Silysia BW-300, elution solvent: hexane/ethyl acetate=3/1). The obtained solid was washed with hexane and combined with the solid obtained earlier to give 2-(1-tert-butoxycarbonyl-1-methyl-ethylsulfanyl)-thiazole-4-carboxylic acid methyl ester (94.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[C:59]([O:65][CH3:66])[C:19]=1[CH:20]=[CH:21][CH:22]([S:32]([CH:35]([CH:45]=[CH:46][C:47]1[C:52]([O:53][CH3:54])=[CH:51][C:50]([O:55][CH3:56])=[CH:49][C:48]=1[O:57][CH3:58])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([NH2:44])[CH:37]=1)(=[O:34])=[O:33])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([NH2:31])[CH:24]=1>O1CCCC1>[CH3:66][O:65][C:59]1[CH:60]=[C:61]([O:63][CH3:64])[CH:62]=[C:18]([O:17][CH3:16])[C:19]=1/[CH:20]=[CH:21]/[CH:22]([S:32]([CH:35](/[CH:45]=[CH:46]/[C:47]1[C:48]([O:57][CH3:58])=[CH:49][C:50]([O:55][CH3:56])=[CH:51][C:52]=1[O:53][CH3:54])[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([NH:44][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH:37]=1)(=[O:34])=[O:33])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([NH:31][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH:24]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)c(OC)c1
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3,5-dinitrobenzoyl chloride (10 mmol) in tetrahydrofuran (40 mL) was added drop wise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in tetrahydrofuran. The solution was stirred overnight and the completion of the reaction was monitored by TLC. The solvent was removed and the residue was taken up in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to give (E)-2,4,6-trimethoxystyryl-3-(3,5-dinitrobenzamido)-4-methoxy-benzylsulfone in 80% yield (m.p. 277-279° C.). NMR (DMSO-d6) δ 3.80 (s, 3H), 3.82 (s, 6H), 3.86 (s, 3H), 4.35 (s, 2H), 6.3 (s, 2H), 7.15-9.1 (m, aromatic+vinylic), 9.8 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH4+:11].[Mn]([O-])(=O)(=O)=O.[K+]>>[Cl:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[CH:4][N:5]=[C:6]([NH2:11])[CH:7]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: [NH4+]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: Nc1cc(Cl)c([N+](=O)[O-])cn1
Temperature: -33 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
To 4-chloro-3-nitropyridine (10.0 g, 63.1 mmol) in 500 ml of liquid ammonium was added potassium permanganate (19.9 g, 126.1 mmol). The reaction was stirred at this temperature (−33° C.) for 5 hours then slowly warmed to room temperature. After evaporation of ammonia, water (1 L) was added. The solid formed was collected by filtration and washed with water (2 L). The solid was extracted with 1:1=DCM:EtOAc (5×500 ml). The solvent was removed and the resulting solid was recrystallized from EtOAc (400 ml) to give the title compound as a yellow solid (4.4 g, 33%). 1H NMR (400 MHz) 8.88 (s, 1H), 7.65 (b, 2H), 6.62 (s, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13][CH2:12]2.Br[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH:30][C:31](=[O:39])[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:22]([Cl:40])[CH:21]=1>C1(C)C=CC=CC=1>[Cl:40][C:22]1[CH:21]=[C:20]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([F:8])[CH:10]=3)[CH2:15]2)[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]=1[NH:30][C:31](=[O:39])[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(CCC1CCCC1)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Reactant: Fc1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCC1CCCC1)Nc1c(Cl)cc(N2CCc3cc(F)ccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (140 mg, 1.25 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride salt (150 mg, 0.8 mmol) and N-(4-Bromo-2-chloro-6-trifluoromethyl-phenyl)-3-cyclopentyl-propionamide (200 mg, 0.5 mmol) were then added and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12]([O:14][C:15](=[O:25])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:25])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:11])[CH:19]=1)[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CCOC(=O)COc1cccc(N)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
5-Bromo-2-fluoro-benzoic acid (250 mg, 1.14 mmol) was coupled to aniline (64)(245 mg, 1.25 mmol) using Method D. The residue was purified by column chromatography eluting with a stepped gradient of 10-15% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][C:2](CC(OO)(C)C)=O.[O:10]([C:12]([O:18][O:19][C:20]([O:26][OH:27])([CH3:25])[CH2:21][CH:22]([CH3:24])[CH3:23])(C)[CH2:13][CH:14](C)C)O.[CH:28]([O:31][CH2:32][CH3:33])=[CH:29][CH3:30]>CCCCCCCCCC(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:32]([O:31][CH:28]([O:27][O:26][C:20]([O:19][O:18][CH:12]([O:10][CH2:1][CH3:2])[CH2:13][CH3:14])([CH2:21][CH:22]([CH3:23])[CH3:24])[CH3:25])[CH2:29][CH3:30])[CH3:33]
Reactant: CC(=O)CC(C)(C)OO
Reactant: CC(C)CC(C)(OO)OOC(C)(CC(C)C)OO
Reactant: CC=COCC
Agent: CCCCCCCCCC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(CC)OOC(C)(CC(C)C)OOC(CC)OCC
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a stirred solution of 5 g of methyl isobutyl ketone peroxide containing 35.7 wt. % bis(1-hydroperoxy-1,3-dimethylbutyl)peroxide in isododecane was added 0.05 g p-toluene sulfonic acid. Then 1.8 g ethyl propenyl ether were added in 10 min, the reaction temperature being kept at 20° C. by cooling with an ice-water bath. The mixture was stirred for 20 min at 15° C. The mixture was washed with bicarbonate solution and dried over magnesium sulphate, yielding 5.8 g of product with an active oxygen content of 5.12% Chemical yield:91%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH:9]=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([C:23](=[S:25])[NH2:24])[CH:19]1[C:26]1[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[N:27]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>COCCOC>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([C:23]2[S:25][CH:8]=[CH:9][N:24]=2)[CH:19]1[C:26]1[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[N:27]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=CCCl
Reactant: Cc1cc(C2C(C(N)=S)CCN2C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: COCCOC
Solvent: c1ccncc1
Product: Cc1cc(C2C(c3nccs3)CCN2C(=O)OC(C)(C)C)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
Potassium carbonate (700 mg, 5.20 mmol) and 2-chloroacetaldehyde (400 mg, 5.20 mmol) were added sequentially to a solution of 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-3-thiocarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 1.04 mmol) in DME (10 mL) at rt under an atmosphere of N2. The reaction mixture was stirred at room temperature for 16 h then filtered under vacuum. The filtrate was concentrated and the residue dissolved in DME (10 mL) prior to cooling to 0° C. Trifluoroacetic anhydride (655 mg, 3.12 mmol) and pyridine (575 mg, 7.28 mmol) were added and reaction mixture was stirred at rt for 4 h. The mixture was concentrated and the residue was diluted with DCM (20 mL). The solution was washed with water (2×30 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified using column chromatography (DCM to 9:1 DCM/MeOH) to afford 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-3-thiazol-2-yl-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (200 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24](Cl)=[O:25]>>[Br:18][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1sccc1Br
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4sccc4Br)nc23)CC1
Yield: 49.2 %

Procedure:
Beginning with 0.37 gm (1.6 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.45 gm (2.0 mMol) 3-bromo-2-thiophenecarbonyl chloride, 0.33 gm (49%) of the title compound were prepared essentially by the procedure described in Example 8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:11])=[N:6][C:5]=1[CH2:12][O:13][CH3:14].[N+:16]([O-])([OH:18])=[O:17].O>CC(O)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([OH:10])=[C:8]([N+:16]([O-:18])=[O:17])[C:7]([OH:11])=[N:6][C:5]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1nc(O)cc(O)c1C(=O)OC
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COCc1nc(O)c([N+](=O)[O-])c(O)c1C(=O)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4,6-Dihydroxy-2-methoxymethyl-nicotinic acid methyl ester (15.9 g, 74.75 mmol) is dissolved in AcOH (60 mL) and cooled to 0° C. in an ice bath. Nitric acid (70%, 4.73 mL) is added dropwise. The resulting solution is stirred at room temperature overnight. Water (200 mL) is added to the mixture and a white precipitate forms. The precipitate is collected and dried in a vacuum oven to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][CH3:23])[N:3]=1.O.[NH2:25][NH2:26].CCOC(C)=O>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:25][NH:26]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][CH3:23])[N:3]=1
Reactant: CC[C@@H]1CCCN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC[C@@H]1CCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To 4-{2-amino-6-[(2R)-2-ethyl-1-pyrrolidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (50 mg, 0.161 mmol) in ethanol (4 mL) was added hydrazine monohydrate (1 mL, 20.40 mmol), and the reaction mixture was stirred overnight at 100° C. into a sealed tube. The reaction was poured onto water and EtOAc, and the organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting solid was dissolved in ethanol (˜2 mL), and treated with hexanes until the solution became cloudy. The mixture was roto-evaporated (˜½ original volume) until a heavy precipitate was observed. The solution was decanted and the solid was dried under vacuum at 40° C. to afford the title compound (30 mg, 58%) as a pale yellow solid. LC-MS (ES) m/z=324 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (t, J=7.3 Hz, 3H), 1.37 (m, 1H), 1.7-2.0 (m, 5H), 3.40 (m, 1H), 3.50 (m, 1H), 4.00 (m, 1H), 5.38 (bs, 2H), 5.97 (bs, 2H), 6.23 (s, 1H), 7.51 (dd, J=8.6, 1.0 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.89 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:27])[C:24](Cl)=[O:25].[CH2:29]([OH:31])[CH3:30]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([C:23](=[O:27])[C:24]([O:31][CH2:29][CH3:30])=[O:25])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc(Cn2ccc3ccc(-c4ccccc4)cc32)cc1
Reactant: CCO
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3ccccc3)ccc12
Yield: 77 %

Procedure:
Ethyl (1-benzyl-6-phenyl-1H-indol-3-yl)(oxo)acetate was prepared from, 1-benzyl-6-phenyl-1H-indole (1.90 g, 6.71 mmol), oxalyl chloride (1.8 mL, 20 mmol), and ethanol (4 mL). Purification by flash chromatography, using 5-12.5% ethyl acetate in hexane as an eluant, yielded the title compound as a light yellow solid (1.98 g, 77%), mp: 121-123° C. Mass spectrum (+ES, [M+H]+) m/z 384; 1HNMR (500 MHz, DMSO-d6): δ 8.7 (s, 1H), 8.25 (d, 1H, J=8.2 Hz), 7.9 (d, 1H, J=0.46 Hz), 7.7 (d, 2H, J=7.9 Hz), 7.65 (dd, 1H, J=8.2 H and 0.76 Hz), 7.45 (t, 2H, J=7.6 Hz), 7.35-7.4 (m, 5H), 7.25-7.35 (m, 1H), 5.65 (s, 2H), 4.35 (q, 2H, J=7.1 Hz), and 1.35 ppm (t, 3H, J=7.1). Elemental Analysis for C25H17NO3: Calculated: C, 78.31; H, 5.52; N, 3.65. Found: C, 77.93; H, 5.40; N, 3.58.