Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:4]([CH:9]=1)[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1cc(OC)ccc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(F)cc2)c(C(=O)O)c1
Yield: 86 %

Procedure:
Methyl-2-bromo-5-methoxybenzoate (15.1 g; 0.062 mol), 4-fluorobenzene boronic acid (9.98 g; 0.0713 mol), and tris (dibenzylideneacetone)dipalladium (0) (1.0 g) were dissolved in 100 mL dimethoxyethane (DME) and 100 mL 2N sodium carbonate and stirred at reflux overnight. The reaction mixture was cooled, the DME removed in vacuo, and the resulting oil partitioned between methylene chloride and water. The aqueous layer was extracted further with methylene chloride and the combined organic extracts dried over magnesium sulfate and concentrated in vacuo. Purification of the crude material by silica gel column chromatography (gradient elution with ethyl acetate/hexane) provided 5-methoxy-[2-(4-fluorophenyl)] benzoic acid methyl ester as a colorless oil (63%). The ester (8.6 g) was hydrolyzed in refluxing 1N sodium hydroxide (72 mL) and ethanol (250 mL). The reaction mixture was cooled and extracted with ethyl acetate. The aqueous layer was then acidified, extracted with EtOAc and the extracts concentrated to afford pure 5-methoxy-[2-(4-fluorophenyl)] benzoic acid in 86% yield. The acid (6.9 g; 0.03 mol) was dissolved in 50 mL thionyl chloride and refluxed overnight. The thionyl chloride was removed in vacuo to afford 2-fluoro-7-methoxy fluorenone quantitatively as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH:10]2[CH2:12][O:11]2)=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].[OH:14][CH2:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>C(O)C>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([F:13])[CH:7]=[CH:8][C:9]=1[CH:10]([OH:11])[CH2:12][N:21]1[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@@H:16]1[CH2:15][OH:14]
Reactant: N#Cc1c(F)ccc(C2CO2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2Cl)[C@@H](CO)C1

Procedure:
2-Chloro-6-fluoro-3-(oxiran-2-yl)benzonitrile (9.1 g, 46 mmol) and (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (14.9 g, 69.1 mmol) were dissolved in ethanol (105 mL) and dispensed into 9 sealed tubes then microwaved at 140° C. for 1 h. The combined reaction mixture was concentrated and purified through a 330 g ISCO Redi-sep column with 50%-100 ethyl acetate/hexane solvent system to yield the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16]C)=[O:15])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26]C)=[O:25]>C1COCC1.CO.[OH-].[Na+]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([OH:16])=[O:15])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)OC)c4)cc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)O)c4)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of dimethyl 3,3′-(naphthalene-2,7-diyl)dibenzoate was dissolved in 60 mL of mixed solvent of THF and MeOH (v/v=1:1), 20 mL of 2N NaOH aqueous solution was added. The mixture was stirred at room temperature overnight. After the organic phase was removed, the aqueous phase was acidified with dilute hydrochloric acid to give white precipitate, which was filtered and washed with water several times. Yield: 1.71 g, 92%. 1H NMR (300 MHz, DMSO-d6): δ 7.65 (t, 2H), 7.92 (d, 2H), 7.98 (d, 2H), 8.09 (m, 4H), 8.38 (m, 2H), 8.43 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][C:3]=1[CH2:10]Br.[P:12]([O:19][CH2:20][CH3:21])([O:16]CC)[O:13][CH2:14][CH3:15]>>[Br:1][C:2]1([P:12]([O:13][CH2:14][CH3:15])(=[O:16])[O:19][CH2:20][CH3:21])[C:7]([P:12]([O:19][CH2:20][CH3:21])(=[O:16])[O:13][CH2:14][CH3:15])=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]1[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccc(CBr)c(Br)c1
Product: CCOP(=O)(OCC)C1=C(C)C=CC(C)C1(Br)P(=O)(OCC)OCC
Temperature: 180 °C

Procedure:
The mixture of 2-bromo-α,α′-dibromo-p-xylene (68) (14.43 g, 0.042 mol) and triethyl phosphite (145 ml) was refluxed at 180° C. overnight. The excess triethyl phosphite was removed under reduced pressure, 60 ml of hexanes was added, the mixture was cooled at −78 ° C. and white solid was formed on vigorous stirring. The solid was collected by rapid filtration, washed three times with 20 ml of cool hexanes, dried in vacuo and isolated in 14.0 g (72.7%) yield as light yellow oil.1H NMR (CDCl3, 500 MHz) δppm: 7.51 (s, br, 1H), 7.40 (dd, 3J=7.7 Hz, 4J=2.2 Hz, 1H), 7.21 (d, 3J=8.0 Hz, 1H) 4.04 (m, 8H, CH2), 3.38 (d, J=21.5 Hz, 2H, CH2), 3.09 (d, J=21.5 Hz, 2H, CH2), 1.25 (m, 12H, CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[N:6][C:7]=1Cl.[CH3:10][NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:9][C:5]1[N:6]=[C:7]([N:19]([CH3:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([NH:11][CH3:10])=[O:21])[C:2]([F:1])=[CH:3][N:4]=1
Reactant: CNC(=O)c1ccccc1NC
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1N(C)c1nc(Cl)ncc1F
Yield: 26 %

Procedure:
A mixture of 5-fluoro-2,6-dichloropyrimidine (1.0 g, 6 mmol, 2.0 eq.), N-methyl-2-methylamino-benzamide (0.5 g, 3 mmol), and potassium carbonate (0.85 g, 6 mmol, 2.0 eq.) was stirred in DMF (100 mL) for 24 h. The solvent was removed under high vacuum and the residue was purified on silica gel with DCM/MeOH (9.5/0.5) to give 2-[(2-chloro-5-fluoro-pyrimidin-4-yl)-methyl-amino]-N-methyl-benzamide (230 mg, 26%): 1H NMR (300 MHz, CD3OD) δ 7.93 (dd, 1H), 7.73 (dd, 1H), 7.6 (m, 3H), 3.09 (s, 3H), 2.97 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=1.[OH-].[Na+].CO.Cl>O>[CH3:26][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCCOc1ccc(OCc2cnccc2N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)c1ccncc1COc1ccc(OCCCC(=O)O)cc1
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture containing ethyl 4-[4-[(4-dimethylaminopyrid-3-yl)methoxy]phenoxy]butanoate (25 mg), aqueous sodium hydroxide (1M, 0.2 ml), methanol (0.5 ml) and water (0.5 ml) was stirred for 3 hours then neutralised with hydrochloric acid (1M, 0.2 ml) and concentrated. The residue was dissolved in dichloromethane (5 ml), filtered, and the filtrate was concentrated to give the title compound (17 mg) as a colourless gum. NMR (d6DMSO+d4AcOH): δ 2.0(2H,q); 2.4(2H,t); 3.35(6H,s); 3.95(2H,t); 5.1(2H,s); 6.8-7.0(4H, dd+1H,m); 8.15(1H,dd); 8.3(1H,d); m/e 331(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)[OH:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.ClCCl>CO.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)=[O:24])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3C(O)c3cccc(C)n3)c2cc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(C)nc3C(=O)c3cccc(C)n3)c2cc1OC
Temperature: 25 °C
Reaction time: 144 h
Yield: 30.1 %

Procedure:
[3-(6,7-Dimethoxy-quinolin-4-yloxy)-6-methyl-pyridin-2-yl]-(6-methyl-pyridin-2-yl)-methanol (20 mg) was dissolved in methanol (0.4 ml) and dichloromethane (1.2 ml) to prepare a solution. Manganese dioxide (300 mg) was added to the solution, and the mixture was stirred at room temperature for 6 days. The reaction solution was filtered through Celite and was then washed with chloroform and methanol. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (6 mg, yield 28%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=1.[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1>[Cl:29][C:25]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([C:17]([F:16])([F:27])[F:28])[CH:26]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cnc(C(F)(F)F)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
A solution of 2,2,6,6-tetramethylpiperidin (198.8 g, 1.41 mol) in tetrahydrofuran (1.5 L) was added n-butyl-lithium (564 mL, 1.41 mol) dropwise at −78° C. Then the mixture was stirred from −78° C.˜−30° C. for 30 minutes. Then the mixture was cooled to −78° C. and a solution of 6-(trifluoromethyl)nicotinic acid (90 g, 1.47 mol) in tetrahydrofuran (2.5 L) added dropwise at −78° C., then the mixture was stirred from −78° C.-−40° C. for 1 hour. The mixture was cooled to −78° C. and a solution of hexachloroethane (222.5 g, 0.94 mol) was added to the reaction mixture dropwise. The mixture was stirred at −78° C. for 3 hours. Aqueous ammoniumchloride (1500 mL) was added to the mixture slowly at −78° C. and the mixture was stirred at room temperature for 20 minutes. The mixture was extracted with ethyl acetate (1 L*3). The combined organic layer was concentrated and the residue was purified by silica gel chromatography eluted with dichloromethane: methanol=20:1 to yield 4-chloro-6-(trifluoromethyl)nicotinic acid (Int-11) (85 g, 80%) as a brown solid.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)(=O)=O.O>CS(C)=O>[C:1]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)#[N:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C1
Reaction time: 18 h
Yield: 61.8 %

Procedure:
Potassium cyanide (5.80 g, 89.0 mmol) was added to a solution of tert-butyl (3S)-3-[(methylsulphonyl)oxy]-1-pyrrolidinecarboxylate (preparation 78) (9.35 g, 35.3 mmol) in dimethylsulphoxide (100 ml), and the reaction stired at room temperature for 18 hrs, and then at 100° C. for a further 24 hrs. The cooled mixture was poured into water and extracted well with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (20:80) as eluant to give the title compound as an oil, (4.28 g, 62%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35](Cl)[N:34]=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[C:35]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:34]=[CH:33][N:32]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COc1ccc(Sc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)cc1F
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Sc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)cc1F
Yield: 69.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((3-fluoro-4-methoxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (203 mg, 0.43 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (102 mg, 0.66 mmol) and DIEA (230 μl, 1.32 mmol) in 10 ml of tert-BuOH were heated at 80° C. for 72 h. After evaporation of the solvent under reduced pressure, the residue (158 mg, 35% yield) was used in the next synthetic step without further purification. Purity 50%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+].C([O-])([O-])=O.[K+].[K+].C[N:22](C)CCN>[Cu-]=O.C(O)CO>[NH2:22][C:2]1[N:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CC(C)(C#N)c1cccc(Br)n1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Product: CC(C)(C#N)c1cccc(N)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 894.2 %

Procedure:
A heavy walled resealable tube was loaded, under an argon atmosphere, with copper (I) oxide (159 mg, 1.11 mmol), 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile (5000 mg, 22.2 mmol), ammonium hydroxide 28% solution (26.9 mL, 444 mmol), K2CO3 (614 mg, 4.44 mmol), N,N-dimethylethylenediamine (196 mg, 244 μA, 2.22 mmol) and ethyleneglycol (44.4 mL). The reaction was heated to 60° C. with stirring for 6 h. After cooling down, the reaction mixture was extracted with dichloromethane (3×25 mL), combined organics dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (silica gel 50 μm, 40 g, Analogix) eluting with 0 to 5% over 20 min (10% ammonium hydroxide in methanol)/dichloromethane, obtained 2-(6-aminopyridin-2-yl)-2-methylpropanenitrile (3.2 g, 89.4% yield) as a white solid. 1H NMR (CHLOROFORM-d) δ: 7.34-7.46 (m, 1H), 6.81 (d, J=7.2 Hz, 1H), 6.40 (d, J=7.9 Hz, 1H), 4.67 (br. s., 2H), 1.63-1.68 (m, 6H); LC-MS 162.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:34])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[NH:16][C:15]1=[O:33])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[CH2:36][C:37]1[C:46]2[C:41](=[CH:42][C:43]([O:47][CH3:48])=[CH:44][CH:45]=2)[O:40][C:39](=[O:49])[CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:48][O:47][C:43]1[CH:42]=[C:41]2[C:46]([C:37]([CH2:36][N:16]3[C:15](=[O:33])[C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:34])[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[C:18]4[CH:29]=[CH:30][CH:31]=[CH:32][C:17]3=4)=[CH:38][C:39](=[O:49])[O:40]2)=[CH:45][CH:44]=1
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2c(CBr)cc(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(CN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c4ccccc43)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a rt solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (60 mg, 121 μmol) in DMF (302 μl) was added 4-(bromomethyl)-7-methoxycoumarin (35.8 mg, 133 μmol), cesium carbonate (47.2 mg, 145 μmol), and sodium iodide (21.7 mg, 145 μmol). The reaction was stirred at rt for 8 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((7-methoxy-2-oxo-2H-chromen-4-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (44.3 mg, 54%) as a white solid. MS m/z 707 (MNa)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:28]1[C:4](=[O:3])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:29]1=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: CC(C)(C)N=C=O
Product: COc1cccc2c1ncc1c(=O)n(C(C)(C)C)c(=O)n(C3CCCC3)c12
Yield: 49 %

Procedure:
3-tert-Butyl-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (18 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and tert-butyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 368 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](C#N)=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH3:12][N:13]1[C:17]([C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cc1cccn1C
Reactant: Cc1ccc(C(=O)C#N)cc1
Product: COC(=O)Cc1ccc(C(=O)c2ccc(C)cc2)n1C
Yield: 398.8 %

Procedure:
A mixture of 5.0 g (0.034 mole) of 4-methylbenzoylcyanide and 0.8 g (0.005 mole) of methyl 1-methyl-pyrrole-2-acetate was added over 4 hours from a heated addition funnel to a sample of 3.8 g (0.025 mole) of methyl 1-methylpyrrole-2-acetate at 180° through which nitrogen was bubbled. The mixture was heated for six more hours after the addition was complete. The reaction was cooled and dissolved in methylene chloride-toluene. The organic solution was washed with 10 percent sodium hydroxide solution and saturated brine and dried (MgSO4). The solvent was evaporated in vacuo and the residue recrystallized twice from methanol to give 5.41 g (69 percent yield) of white crystalline methyl 1-methyl-5-(4-methyl-benzoyl)-pyrrole-2-acetate, mp 118°-120° C. The solid state IR spectrum was identical to authentic material.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[N:4][N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:9][CH:8]([N:7]([C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: Cc1nnc(NC(C)C)s1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1nnc(N(C(=O)c2ccccc2)C(C)C)s1

Procedure:
N-(5-methyl-1,3,4-thiadiazol-2-yl)-1-methylethylamine (5 g, 0.032 mole) in pyridine (100 ml) was treated with benzoyl chloride (4.1 ml). The reaction mixture was stirred and heated to reflux for 51/2 hours. The pyridine was removed under reduced pressure and the residue treated with water and extracted with ether (× 3). The ethereal solution was dried, filtered and evaporated to dryness and the residue recrystallised from ether/petrol ether (40°-60° C.) to give the title compound as a pale yellow crystalline solid m.p. 82.5°-83.5° C.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[C@H:3]([NH:27]C(=O)OCC1C=CC=CC=1)[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][N:16]=1)=[O:14])=[O:5]>CO.[Pd]>[CH3:1][C:2]([CH3:39])([CH3:38])[C@H:3]([NH2:27])[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][N:16]=1)=[O:14])=[O:5]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccccc2)cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[C@H](N)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccccc2)cn1
Reaction time: 18 h
Yield: 92.8 %

Procedure:
phenylmethyl [(1S)-2,2-dimethyl-1-({(1S,4S)-5-[(5-phenyl-2-pyridinyl)carbonyl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)propyl]carbamate (1.3 g, 2.47 mmol) was dissolved in methanol (40 ml). Next, 5% Pd/C (200 mg) was added under nitrogen. The reaction was hydrogenated at 45 psi under a hydrogen atmosphere for 18 h at room temperature. The reaction mixture was filtered and the filtrate concentrated to afford the title compound (0.9 g) as a yellow oil. LCMS (m/z): 393.1 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:41])[NH:10][C:11]1[CH:16]=[C:15]([C:17]([C:19]2[C:24]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=3)(=[O:28])=[O:27])=[CH:23][C:22]([Cl:40])=[CH:21][N:20]=2)=[O:18])[CH:14]=[CH:13][N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:16]=[C:15]([C:17]([C:19]2[C:24]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:36]([F:37])([F:39])[F:38])[CH:30]=3)(=[O:28])=[O:27])=[CH:23][C:22]([Cl:40])=[CH:21][N:20]=2)=[O:18])[CH:14]=[CH:13][N:12]=1)=[O:41]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(NC(=O)CNC(=O)OC(C)(C)C)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc(NC(=O)CN)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ({-4-[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-pyridin-2-ylcarbamoyl}-methyl)-carbamic acid tert-butyl ester (45 mg) in CH2Cl2 was added TFA (200 L). The resulting mixture was stirred at room temperature for 3 h, concentrated under reduced pressure and the residue was re-dissolved in MeCN and purified by HPLC to provide 2-amino-N-{4-[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-pyridin-2-yl}-acetamide. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.48-8.46 (m, 1H), 8.19 (s, 1H), 8.08 (br m, 3H), 7.89 (s, 1H), 7.78-7.76 (m, 2H), 7.55 (d, J=7.6 Hz, 1H), 7.28-7.26 (m, 1H), 3.85 (s, 2H), 2.43 (s, 3H); MS m/z 528.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[N+:23]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O>CO.O1CCCC1.[Fe]>[NH2:23][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:14]=1[O:13][C:12]1[CH:26]=[CH:27][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of the product of Example 43A (0.73 g, 2.0 mmol), iron powder (1.12 g, 20 mmol) and ammonium chloride (1.08 g, 20 mmol) in methanol (20 mL), tetrahydrofuran (20 mL), and water (10 mL) was heated at 80° for 48 hours. After cooling to room temperature, the mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum then purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (670 mg, 100%).