Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[Na].[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][C:21]#[N:22])[CH:16]=3)[C:11]2=[O:23])=[CH:7][CH:6]=1.Br[CH2:27][CH2:28]Br.C(OC(=O)C)C>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]4([C:21]#[N:22])[CH2:28][CH2:27]4)[CH:16]=3)[C:11]2=[O:23])=[CH:7][CH:6]=1
Reactant: COc1ccc(CN2CCc3cc(CC#N)ccc3C2=O)cc1
Reactant: BrCCBr
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCc3cc(C4(C#N)CC4)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To a suspension of sodium hydrate (0.228 g, 60%, 5.72 mmole) in 15 ml DMF was added nitrile (IV) (1.2 g, 3.9 mmole) and after stirring for 15 minutes at room temperature 1,2-dibromo-ethane (1.1 g, 5.8 mmole) in 1.5 ml DMF was added. The resulting mixture was stirred 0.5 hour at room temperature and then more sodium hydrate (0.114 g, 2.86 mmole) was added and the reaction mixture heated for about 10 minutes at 30-35° C. After cooling the mixture was partitioned between ethylacetate and brine, the organic layer was dried over sodium acetate and concentrated in vacuo. Purification by silica gel column chromatography with 30%-50% ethylacetate in hexane afforded compound (V) 1 g (77% yield).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:2][NH:3][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(CCCS(C)(=O)=O)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCCCS(C)(=O)=O
Reaction time: 2 h

Procedure:
Ethereal HCl (22.5 ml, 1 M solution) was added to a stirred solution of N-methyl-N-(3-mesylpropyl)-N-(benzyloxycarbonyl)amine (Method 14; 5 g) in methanol (100 ml). 10% Pd/C (1.25 g) was added and the mixture was stirred under an atmosphere of hydrogen for 2 hrs. The catalyst was removed by filtration and the filtrate evaporated to dryness. Trituration with ether gave the product as a white solid. NMR (DMSO-d6+d4-acetic acid) 2.11 (m, 2H), 2.59 (s, 3H), 3.0 (s, 3H), 3.05 (t, 2H); m/z 152.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:22][OH:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>C(#N)C.[Ag]=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:22][O:23][CH3:24])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)CC[C@@H](CO)NC(=O)OCc1ccccc1
Agent: O=[Ag]
Solvent: CC#N
Product: COC[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 19 h
Yield: 71.2 %

Procedure:
To a solution of tert-butyl (4S)-4-{[(benzyloxy)carbonyl]amino}-5-hydroxypentanoate (4.0 g, 12.4 mmol) in acetonitrile (80 ml) were added silveroxide (14.3 g, 61.7 mmol) and methyliodide (7.7 ml, 124 mmol), and the mixture was stirred for 19 hours. After removal of the insoluble materials, the solvent was removed in vacuo and the residue was purified with silica gel chromatography to give tert-butyl (4S)-4-{[(benzyloxy)carbonyl]amino}-5-methoxypentanoate (2.98 g, 71%).
Reaction SMILES: [OH-].[Sr+2].[OH-].Cl.[C:5]([OH:17])(=[O:16])[CH:6]([CH:8]([CH2:12][C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])O>O>[CH2:12]([C:13]([OH:15])=[O:14])/[C:8](/[C:9]([OH:11])=[O:10])=[CH:6]\[C:5]([OH:17])=[O:16]
Reactant: O=C(O)CC(C(=O)O)C(O)C(=O)O
Agent: Cl
Agent: [OH-]
Agent: [Sr+2]
Solvent: O
Product: O=C(O)/C=C(\CC(=O)O)C(=O)O
Reaction time: 3 h
Yield: 60.5 %

Procedure:
Thirty one grams (0.1 mole) of the product prepared in Example I-B is mixed with 300 mls water. 79 grams of strontium hydroxide (0.65 mole) is added slowly at 65°-70° C. while maintaining the pH at 10-10.5. The mixture is stirred for an additional three hours after the addition of the strontium hydroxide. The solution is cooled and 180 grams of 10% hydrochloric acid is added slowly to a pH of 1.3. The acidified solution is next evaporated to dryness in vacuo. The residue is extracted with acetone and the acetone extract is filtered and evaporated to dryness. There is thus obtained 23 g of residue containing 45.7% (60.5% yield) trans-aconitic acid and 10.7% of a mixture of the lactones of isocitric acid and alloisocitric acid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:10]#[N:11].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:10]#[N:11]
Reactant: [C-]#N
Reactant: BrCc1ccccc1Br
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCc1ccccc1Br
Temperature: 60 °C
Yield: 80.9 %

Procedure:
N-Boc-protected 3-[2-(aminoethyl)phenyl]-2-propenoic acid (Compound 23) was prepared as outlined in Scheme IV. A mixture of o-bromobenzyl bromide (10.45 g; 41.81 mmol) and sodium cyanide (2.55 g; 52.25 mmol) in 100 ml of DMSO was heated at 60° C. for 5 hours. After being cooled, the reaction mixture was diluted with 200 ml of water and 200 ml of ethyl acetate. The layers were separated and the aqueous layer was extracted with any additional 100 ml of ethyl acetate. The combined organic layers were dried and concentrated, and the residue was purified on a flash column, eluting with 10% ether/hexane to obtain 6.63 g (81%) of 2-bromobenzyl cyanide 19, 1H NMR (CDCl3): δ 3.83 (s, 2H); 7.18 (m, 1h); 7.29 (t, 1H); 7.52 (d, 1H);
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:18]O>>[I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: CO
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)c(C)cc1C
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 5-iodo-2,4-dimethylbenzoic acid (compound 2.1, 10 g, 32.60 mmol, 1.00 equiv, 90%) and sulfuric acid (10 mL) in methanol (100 mL) was stirred overnight at 80° C. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was diluted with 200 mL of ethyl acetate. The resulting mixture was washed with 3×50 mL of water, 2×50 mL of sodium bicarbonate (aq. sat.), followed by 2×50 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 9.2 g (88%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:24])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[F:1][C:2]1[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:24])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Reaction time: 7 h
Yield: 79.9 %

Procedure:
To a mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.05 mmol) in anhydrous methanol (1 mL) and anhydrous THF (1 mL) at ambient temperature under nitrogen atmosphere was added zinc dust (33 mg, 50 mmol) and ammonium chloride (27 mg, 50 mmol). The reaction mixture was stirred for 7 h before the catalyst was filtered off and the filtrate was concentrated in vacuo to give a solid which was partitioned between chloroform and water. The aqueous phase was extracted twice with chloroform. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the desired compound (16 mg, 87%) as a solid. 1H NMR (CDCl3) δ 7.86-7.83 (m, 1H), 7.50-7.38 (m, 2H), 7.09-7.00 (m, 1H), 6.56-6.45 (m, 1H), 4.14 (t, 2H, J=5.5 Hz), 2.99-2.38 (m, 18H); MS(ESI+) m/z 401.4 (M+H)+.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1.CCOCC>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C#CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C#CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 5-hexynyl alcohol (102 mmoles) in pyridine (150 ml), under argon, was cooled to 0° C. and p-toluenesulfonyl chloride (204 mmoles) was added. The reaction mixture was kept at about 4° C. for 18 hours, poured into ice-water and then taken up in ether. The ether extract was washed with cold 10% hydrochloric acid, water and brine. The organic layer was dried and concentrated in vacuo to give 5-hexynyl p-toluenesulfonate. A solution of phenylacetylene (97 mmoles) in tetrahydrofuran (200 ml) containing a trace of triphenylmethane was cooled to 0° C. and then n-butyl lithium (37.3 ml of 2.6 moles in hexane) was added dropwise. The resulting solution was stirred at 0° C. for 10 minutes and hexamethylphosphoramide (21 ml) was added dropwise. After stirring for 10 minutes a solution of 5-hexynyl p-toluenesulfonate (97.1 mmoles) in tetrahydrofuran (200 ml) was added. The reaction mixture was stirred at room temperature for 18 hours, diluted with ether and the organic layer was washed with water and brine. The dried organic solution was concentrated and the product was purified by flash chromatography to give 1-phenylocta-1,7-diyne. A mixture of this compound (43 mmoles), 2-bromobenzaldehyde (35.8 mmoles), cuprous iodide (0.5 mmoles) and bis(triphenylphosphine) palladium (II) chloride (0.7 mmoles) in triethylamine (100 ml) was heated in an oil bath (95° C.) for one hour. The reaction mixture was cooled to 0° C., filtered and the filtrate was concentrated. The residue was dissolved in ether, washed with 10% hydrochloric acid, water and brine. The organic layer was dried and concentrated to give a product which was purified by flash chromatography to yield 2-(8-phenyl-1,7-octadiynyl)benzaldehyde. A solution of this compound (24.1 mmoles) in ethyl acetate (100 ml) and 10% palladium on charcoal (1 g) was hydrogenated (40 psi of hydrogen) at room temperature for 15 minutes. The catalyst was filtered off and the filtrate concentrated to give the 2-(8-phenyloctyl)benzaldehyde.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH2:12]O)[CH:9]=[N:10][CH:11]=1>CCOCC>[Br:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][Cl:3])[CH:7]=1
Reactant: OCc1cncc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: ClCc1cncc(Br)c1
Temperature: 4 °C
Yield: 99 %

Procedure:
To a cooled solution of thionylchloride (41 ml, 344 mmol) at 0° C. was added cautiously (highly exothermic) portionwise (5-bromo-pyridin-3-yl)-methanol (10 g, 44.5 mmol). After complete addition the mixture was heated to reflux for 1 h to complete the reaction. After cooling, ether (50 ml) was added and the mixture cooled to 4° C. The precipitated solid was filtered off and washed with cold ether then dried at 50° C. under vacuum for 2 h to afford the title compound (9.1 g, 84%) as a light yellow solid. MS: m/e=206.9 (M+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl.O>[CH3:22][S:23]([O:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:3]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 2.5 °C
Yield: 91.2 %

Procedure:
To a solution of tert-butyl N-[(1S,3R)-3-hydroxycyclopentyl]carbamate (3.0 g, 14.91 mmol, 1.00 equiv) and triethylamine (3.0 g, 29.65 mmol, 1.99 equiv) in dichloromethane (50 mL) was added methanesulfonyl chloride (2.2 g, 19.21 mmol, 1.29 equiv) dropwise with stirring at 0-5° C. After addition was completed, the reaction mixture was warmed to room temperature and stirred at room temperature for 2 h. The mixture was diluted with 50 mL of water and extracted with 2×50 mL of ethyl acetate. The combined organic layers was washed with 2×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.8 g (91%) of tert-butyl N-[(1S,3R)-3-(methane sulfonyloxy)cyclopentyl]carbamate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:2]=1[NH2:1]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1cccc(O)c1N

Procedure:
To a solution of 2 g (13.1 mmol) of 2-amino-3-hydroxybenzoic acid in 60 mL of CH3OH at 0° C. was bubbled HCl gas until the solution was saturated. The reaction was heated at reflux for 12 h. The reaction mixture was concentrated and dissolved in 30 mL of water. The solution was neutralized with sat'd NaHCO3 solution and extracted with EtOAc. The organic fractions were dried over MgSO4, filtered and the filtrate was concentrated to give 1.8 g of the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)cc(C=O)c1
Temperature: 105 °C
Reaction time: 7 h
Yield: 94.3 %

Procedure:
In a three-necked flask with a capacity of 3 liters, 253.11 g of methyl 5-bromo-3-(hydroxymethyl)benzoate were placed and mixed with 2000 ml of toluene, and the resultant mixture was agitated to prepare a solution. The resultant solution was mixed with 44 g of manganese dioxide, and the resultant reaction mixture liquid was heated to a temperature of 105° C. and agitated for 7 hours. The resultant reaction mixture liquid was allowed to be cooled to room temperature and filtered to remove a solid fraction therefrom, and the resultant filtrate was concentrated. The target compound, methyl 5-bromo-3-formylbenzoate was obtained in an amount of 236.79 g which corresponded to a yield of 94.3%.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([O:17]C)=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)[Br:20]>ClCCl>[BrH:20].[NH2:2][C:3]1[C:4]([OH:17])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1c(N)cccc1-c1csc(C(=O)O)c1
Reactant: BrB(Br)Br
Agent: Br
Solvent: ClCCl
Product: Nc1cccc(-c2csc(C(=O)O)c2)c1O
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
4-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 51b (360 mg, 1.45 mmol) was dissolved in 5 mL of dichloromethane followed by dropwise addition of boron tribromide (2.8 mL, 5.6 mmol). The reaction mixture was reacted at room temperature for 4.5 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched with 5 mL of methanol. The mixture was concentrated under reduced pressure. The residue was diluted with 10 mL of ethyl acetate and stirred for 0.5 hours. The mixture was filtered and the filter cake was dried to obtain the title compound 4-(3-amino-2-hydroxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 51c (80 mg, yield 17.5%) as a grey solid.
Reaction SMILES: [ClH:1].O(CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=C[CH:4]=1.Cl.[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47](OC)=[CH:46][CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=1[CH2:3][CH3:4])[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: CCc1ccccc1OCC(O)CNC(C)(C)Cc1ccc(OC)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M−15, 1), 237 (16), 236 (100), 163 (5), 121 (17), 114 (7), 91 (6), 77 (7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][NH:15][C:14](=O)[C:13]=3[CH:12]=[CH:11]2)=[CH:5][CH:4]=1.P(Cl)([Cl:34])(OC1C=CC=CC=1)=O>>[Cl:34][C:14]1[C:13]2[CH:12]=[CH:11][N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:18]=2[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: CCOC(=O)c1c[nH]c(=O)c2ccn(Cc3ccc(OC)cc3)c12
Product: CCOC(=O)c1cnc(Cl)c2ccn(Cc3ccc(OC)cc3)c12

Procedure:
Prepared in a similar manner to Example 243(e) using ethyl 1-{[4-(methyloxy)phenyl]methyl}-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (14.45 g) and phenyl dichlorophosphate (100 ml) to afford the title compound as a yellow oil (7.2 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15]>C1COCC1>[CH3:11][C:12]([CH3:17])=[CH:13][C:14]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([Br:3])[CH:5]=1)=[O:15]
Reactant: CC(C)=CC(=O)Cl
Reactant: Nc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Nc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a suspension of NaH (4.15 g, 173 mmol, 60% in oil) in 50 ml of THF was cannulated a solution of 20.322 g (118 mmol) of 3-bromoaniline in 50 ml of THF. The resulting mixture was stirred at 0° C. for 45 min and warmed to room temperature over a period of 15 min. To this solution was added through cannulation 13.123 g (173 mmol) of 3,3-dimethylacryloyl chloride. The mixture was stirred at room temperature for 24 h and thereafter slowly poured into ice water. The resulting mixture was extracted with methylene chloride (twice), dried over MgSO4 and concentrated to yield a solid. The solid was purified by recrystallization in hexane/EtOAc (2:1) to give the title compound as a light brown solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12>CO.[Pt]=O>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12
Reactant: c1cn2ccnc2cn1
Agent: O=[Pt]
Solvent: CO
Product: c1cn2c(n1)CNCC2
Yield: 99 %

Procedure:
The title compound was prepared from imidazo[1,2-α]pyrazine (500 mg, 4.20 mmol, from Step A) and platinum oxide (250 mg) in methanol (50 mL), using a procedure analogous to that described in Example 1, Step B. Concentration gave the title compound (512 mg) as a viscous oil. 1H NMR (500 MHz, CD3OD) δ 3.37 (t, 1H, J=5.5 Hz), 4.18 (t, 2H, J=5.6 Hz), 4.88 (s, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.33 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To methyl 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylate (32 g, 68.6 mmol) in a 1 L round-bottom flask under nitrogen in tetrahydrofuran (THF) (600 mL) was added water (150 mL), then lithium hydroxide (2.464 g, 103 mmol). After 22 min the slightly cloudy mixture was filtered and the THF was evaporated off to give a slight suspension. The aqueous mixture was cooled in an ice-bath and taken to pH 6 using 2M hydrochloric acid. This mixture was stirred for 10 min in an ice-bath, the pH re-checked but not much material seemed to have come out of solution. So the pH was further reduced to pH 5 and this seemed to bring more material out of solution. The solid was collected by vacuum filtration, washed with water then dried under high vacuum at 40° C. to give 19.2 g (62%) of a white solid that the Lab HPLC showed to be 98.7% pure with a retention time of 1.76 min. LC-MS m/z 453 (M+H)+, 0.72 min (ret time) [split peak].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(O)c1ccc(CBr)cc1
Yield: 71.1 %

Procedure:
A mixture (suspension) of p-toluic acid (13.6 g, 98 mmol), N-bromosuccinimide (17.8 g, 99 mmol) and benzoylperoxide (0.2 g, 0.826 mmol) in dry benzene (100 ml) was heated at reflux for 21 h. After evaporation of the solvent in vacuo, the white residual solid was suspended in boiling water (100 ml), collected by filtration and washed with boiling water (4×100 ml). The crude dried product was crystallized from hot MeOH, yielding 15.0 g (69.7 mmol, 71.1%) of p-bromomethylbenzoic acid as white crystals mp 223°-225° C.; 1Hmr (DMSO-d6) δ: 4.75 (2H, s, --CH2Br), 7.47-7.62-7.88-8.02 ppm (4H, A2'B2', aromatic Hs); ir (nujol) νmax :2500-2600(br.--CO2H), and 1670cm-1 (C=O --CO2H).
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1)(OCC)=O.[CH3:22][NH:23][C:24](=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:27].C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:22][N:23]1[C:24](=[O:32])[C:25]2[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:27]=[C:1]1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:20][CH:21]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: CCOC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1C
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in any of Examples 16-22 (100 g, 0.32 M), N-methyl anthranilamide (58.7 g, 0.39 M), xylene (100 ml) and p-toluenesulfonic acid (200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 10-15 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (29 g, Y-23%, P=98%)