Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]1[CH2:26][CH:25]1[C:27]1([OH:30])[CH2:29][CH2:28]1>>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:4]2[N:3]=[C:2]([C:23]3[S:19][C:20]([CH:24]4[CH2:26][CH:25]4[C:27]4([OH:30])[CH2:29][CH2:28]4)=[CH:21][CH:22]=3)[CH:7]=[CH:6][N:5]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: OC1(C2CC2c2cccs2)CC1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(C4CC4C4(O)CC4)s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2′-thiophen-2-yl-bicyclopropyl-1-ol (prepared by cyclopropanation of 2-thiophen-2-yl-cyclopropanecarboxylic acid methyl ester, J. Org. Chem. 1993, 502).
Reaction SMILES: P(=O)(O)(O)[OH:2].[C:6]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([C:10]1[CH:15]=[C:14]([OH:2])[C:13](=[CH:12][CH:11]=1)[OH:16])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=P(O)(O)O
Product: CC(C)(C)c1ccc(O)c(O)c1
Yield: 52 %

Procedure:
The procedure of Comparative Example 1 was repeated, except phosphoric acid was added as a reaction catalyst in an amount corresponding to 1% by weight based on the amount of para-tert.-butyl phenol used. Consequently, the conversion of para-tert.-butyl phenol was 5.3%, 4-tert.-butyl pyrocatechol was formed in a yield of 52% based on the converted butyl phenol, and the conversion of peracetic acid was 96.0%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH:25]([C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)[CH2:26][CH2:27][OH:28].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:28][CH2:27][CH2:26][CH:25]([NH:24][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:15])[CH:11]=1)=[O:23])[C:29]1[CH:30]=[N:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Reactant: NC(CCO)c1ccc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NC(CCO)c3ccc(C(F)(F)F)nc3)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylic acid (17 mg, 0.055 mmol) in N,N-dimethylformamide (0.5 mL) were added 3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (47 mg, 0.21 mmol) (WO 2008/130481), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (80 mg, 0.21 mmol) and N,N-diisopropylethylamine (80 μL, 0.46 mmol). The reaction mixture was stirred for 16 hours at 30° C. The reaction mixture was purified by preparative HPLC to afford a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([CH:15]=[N:16][C:17]([O:19][Si](C)(C)C)=[CH2:18])[CH:14]=1.C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)/[C:34](=[CH:42]/[C:43]2[C:44]([O:50][C:51]([C:54]([O:56][CH3:57])=[O:55])([CH3:53])[CH3:52])=[N:45][CH:46]=[C:47]([Cl:49])[CH:48]=2)/[C:33]1=[O:58])=O)(C)(C)C>CO>[Cl:41][C:38]1[CH:39]=[C:40]2[NH:32][C:33](=[O:58])[C:34]3([CH:42]([C:43]4[C:44]([O:50][C:51]([C:54]([O:56][CH3:57])=[O:55])([CH3:53])[CH3:52])=[N:45][CH:46]=[C:47]([Cl:49])[CH:48]=4)[CH2:19][C:17](=[O:18])[NH:16][CH:15]3[C:13]3[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=3[CH3:24])[C:35]2=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Oc1ncc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
To a toluene solution (50 mL) of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (18 mmol) was added E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-pyridin-3-ylmethylene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 6 mmol). Then the reaction mixture were heated at 130° C. for 2 h. After the solution was cooled to room temperature, methanol was added, and then the mixture was concentrated. Then a mixture of trifluoroacetic acid (10 mL) and dichloromethane (30 mL) was added. The reaction mixture was stirred at room temperature for 10 min. The solution was concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (170 mg).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH3:20])[S:5]1(=[O:22])=[O:21].[CH3:23][C@H:24]1[CH2:29][NH:28][CH2:27][C@@H:26]([CH3:30])[NH:25]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH2:3][CH2:2][N:28]3[CH2:27][C@H:26]([CH3:30])[NH:25][C@H:24]([CH3:23])[CH2:29]3)[S:5]2(=[O:22])=[O:21])=[C:14]([CH3:20])[CH:15]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1cc(Cl)ccc1N1c2ccccc2N(CCBr)S1(=O)=O
Product: Cc1cc(Cl)ccc1N1c2ccccc2N(CCN2C[C@@H](C)N[C@@H](C)C2)S1(=O)=O

Procedure:
1-(4-chloro-2-methylphenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared using 1-(2-bromoethyl)-3-(4-chloro-2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide and cis-2,6-dimethyl piperazine analogous to the conditions used general procedure V.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:18][NH2:19]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:19][CH2:18][C:17]1[CH:16]=[C:15]([F:14])[CH:22]=[C:21]([F:23])[CH:20]=1)=[O:5])[CH3:2]
Reactant: NCc1cc(F)cc(F)c1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Product: CCOC(=O)c1cnc(Cl)cc1NCc1cc(F)cc(F)c1

Procedure:
From 4,6-dichloropyridine-3-carboxylic acid ethylester synthesized according to the method described in US2006/0217417 and 3,5-difluorobenzylamine in a manner similar to Example 1, 6-chloro-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxylic acid ethyl ester was obtained as a light brown crystalline powder (yield 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9](O)[C:8]1=[O:15])=[O:5])[CH3:2].P(Br)(Br)([Br:18])=O.[NH4+].[OH-]>C(Cl)(Cl)Cl>[Br:18][C:9]1[C:8](=[O:15])[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12]([CH3:13])=[CH:11][N:10]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCOC(=O)Cn1c(C)cnc(O)c1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Temperature: 25 °C

Procedure:
A stirred slurry of 505 mg (2.38 mmol) of 7-3 and 756 mg (2.64 mmol) of phosphorous oxybromide in 1.7 mL of CHCl3 was stirred at 50° C. under a slow stream of Ar for 1.5 h, then allowed to cool to rt overnight. The reaction mixture was diluted with CHCl3 and ice water, basified with NH4OH, and extracted with CHCl3. The combined organic layers were dried over Na2SO4, treated with activated carbon, filtered and concentrated to give 7-4 as an orange colored solid: 1H NMR (CDCl3) δ 7.06 (s, 1H), 4.77 (s, 2H), 4.27 (q, 2H, 7.2 Hz), 2.24 (s, 3H), 1.31 (t, 3H, 7.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][O:12][S:29]([CH3:28])(=[O:31])=[O:30])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 1,2-di(t-butoxycarbonylamino)-3-hydroxypropane (3 g.) and triethylamine (2 ml.) in CH2Cl2 (30 ml.) at 0° was added methanesulphonyl chloride (1.0 ml.) with stirring. Stirring at this temperature was continued for 1 hour and the mixture was then washed with water. The organic layer was separated, dried and the solvent evaporated to give 1,2-di(t-butoxycarbonylamino)-3-methanesulphonyloxypropane (2.9 g.), m.p. 94°-96°.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[C@@H:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:20]([O:19][C:17]([C@H:4]1[CH2:3][C:2](=[O:1])[O:6][C@@H:5]1[C:7]([OH:9])=[O:8])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)O
Yield: 95.4 %

Procedure:
6.4 g of 2-benzyl 3-tert-butyl (2S,3S)-5-oxotetrahydrofuran-2,3-dicarboxylate in 80 ml of ethyl acetate was catalytically reduced with 640 mg of a 10% palladium-carbon catalyst at room temperature at atmospheric pressure of hydrogen for 3 hours. The catalyst was filtered off, and the filtrate was evaporated to dryness to give 4.39 g of the title compound as a white solid.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N)C1C=CC=CC=1.[N:20]1([CH2:29][C:30]2[CH:40]=[CH:39][C:33]([C:34](OCC)=[O:35])=[CH:32][CH:31]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1>>[C:6]1([NH:5][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[CH:21]3)=[CH:40][CH:39]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Agent: C[Al](C)C
Solvent: NCc1ccccc1
Product: O=C(Nc1ccccc1)c1ccc(Cn2cnc3ccccc32)cc1
Yield: 13 %

Procedure:
Utilising a modification of the procedure described in Example 8 employing 4 equivalents of trimethylaluminium and 4 equivalents of aniline (0.67 g, 7.2 mmol) in lieu of benzylamine with respect to 1 equivalent of ethyl 4-(1H-benzimidazylmethyl)benzoate yielded a crude product was purified by column chromatography (flash silica gel, gradient elution 0-100% ethyl acetate in hexane) and recrystallised from methanol to give N-phenyl 4-(1H-benzimidazylmethyl)benzamide (75 mg, 13%) as a white crystalline solid.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl>C1COCC1.O1CCOCC1>[CH:19]1([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([CH:2]3[CH2:15][CH2:16][CH2:5][CH2:4][CH2:3]3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: Br[Mg]C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: c1cc2ccc3c(C4CCCCC4)ccc4ccc(c1C1CCCCC1)c2c43
Temperature: 90 °C
Yield: 71 %

Procedure:
Under an atmospheric argon gas flow, 1,6-dibromopyrene in an amount of 20 g (55.6 millimole), cyclohexylmagnesiumbromide in an amount of 117 milliliter [117 millimole, 1 mole/liter (THF: tetrahydrofuran)], (diphenylphosphinoferrocene)palladium(II)dichloride in an amount of 2.27 g (5% by mole), dried dioxane in an amount of 80 milliliter and THF in an amount of 70 milliliter were placed into a three-neck flask equipped with a cooling pipe and having a capacity of 500 milliliter, and the resultant solution was stirred with heating at a temperature of 90° C. for 8 hours. After the completion of the reaction, adding 100 milliliter of dilute hydrochloric acid, an organic layer was separated and concentrated under a reduced pressure. Then, the organic layer was passed through a silicagel short column, and after concentrating under the reduced pressure again, a precipitated crystal was separated by filtration and as a result, 7.0 g of 1,6-dicyclohexylpyrene (pale yellow powder) was obtained (the yield: 71%).
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])[C:9](=[CH:15][C:16]#[N:17])[NH:8][CH2:7][CH2:6]2.[OH-:18].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16](=[O:18])[NH2:17])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=CC#N)NCC2
Reactant: [OH-]
Agent: [Na+]
Product: COc1cc2c(cc1OC)C(=CC(N)=O)NCC2

Procedure:
Polyphosphoric acid (10.0 g) is heated to 100° C. and 1.0 g of 6,7-dimethoxy-1-cyanomethylene-1,2,3,4-tetrahydroisoquinoline is added under mechanical stirring. The reaction mixture is heated for 1 hour, poured into crushed ice and made basic with 30% sodium hydroxide. The mixture is extracted with chloroform and the extract dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure to give a white solid, yield 0.7 g, mp. 156°-158° C.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].[C:22](#[N:25])[CH:23]=[CH2:24]>N1C=CC=CC=1.O>[C:22]([CH2:23][CH2:24][N:5]1[C:4](=[O:21])[C:3]([C:1]#[N:2])=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6]1)#[N:25]
Reactant: C=CC#N
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Solvent: O
Solvent: c1ccncc1
Product: N#CCCn1nc(-c2ccccc2)c(-c2ccccc2)c(C#N)c1=O

Procedure:
4.0 grams (0.0146 mole) of 4-cyano-5,6-diphenyl-3-(2H)-pyridazinone was dissolved in 40 mls of pyridine along with 10 mls of distilled water. 2 mls of acrylonitrile was added into this solution and the mixture heated to reflux for 2 hours. The solution was cooled and the solvent distilled at reduced pressure. The residual solid was recrystallized from ethyl alcohol to give 2 grams (42%) yield of a white solid which melted at 160°-161° C. The infrared spectrum showed the C-C band at 3.3μ, the nitrile group at 4.5μ, and the carboxy groups for an amide at 6.0μ.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1I)=[O:4].[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:19][N:18]([CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:4]
Reactant: CN(N)c1ccccn1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NN(C)c1ccccn1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 5-(3,3-dimethyl-but-1-ynyl)-3-iodo-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.28 mmol), N,N-diethylenediamine (9 μL, 0.086 mmol), N-methyl-N-pyridin-2-yl-hydrazine (0.105 g, 0.86 mmol), CuI (0.01 g, 0.057 mmol), 4 Å ms (0.114 mg) and K2CO3 (0.118 g, 0.861 mmol) in DMF (3 mL) was heated to 80° C. for 16 h. The reaction was diluted with ethyl acetate, washed twice with 5% LiCl, concentrated and the crude material was purified by silica gel chromatography (0-20% EtOH in DCM) to give 5-(3,3-dimethyl-but-1-ynyl)-3-(N′-methyl-N′-pyridin-2-yl-hydrazino)-thiophene-2-carboxylic acid methyl ester in 50% yield. This was then dissolved in pyridine (5 mL) and treated with neat trans-4-methyl-cyclohexanecarbonyl chloride (0.132 g, 0.825 mmol). The reaction was heated for 16 h at 85° C. and quenched with saturated ammonium chloride solution. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude material was then dissolved in a 3:2:1 mixture of THF:MeOH:water (5 mL), treated with lithium hydroxide monohydrate (0.69 g, 1.65 mmol) and heated to 60° C. for 1 hour. The organic volatiles were evaporated under reduced pressure and the crude material was purified by HPLC to afford the title compound. MS (m/z): 454.1 [M+H]−; HPLC retention time: 3.95 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Br)=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([O:14][CH3:15])=[N:9]2)=[CH:4][CH:3]=1.C([O-])(O)=[O:17].[Na+]>CC(C)=O.O>[Br:1][C:2]1[C:11]([CH2:12][OH:17])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([O:14][CH3:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2ccc(Br)c(CBr)c2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2ccc(Br)c(CO)c2n1
Yield: 56 %

Procedure:
A suspension of 7-bromo-8-bromomethyl-2-methoxyquinoline (35.2 g; prepared according to WO 2007/081597) and NaHCO3 (14.63 g) in acetone (430 mL) and water (430 mL) was refluxed for 6 h. The org. solvent was removed under reduced pressure and the aq. layer was extracted twice with EA. The combined org. layers were sequentially washed with water and brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was crystallized from TBDME, affording an off-white solid (16.01 g; 56% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4](=[O:18])[C:3]=1[N:19]=O.[H][H]>[Pd].C(O)C>[NH2:19][C:3]1[C:4](=[O:18])[N:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: CCCn1c(N)c(N=O)c(=O)n(CC(=O)OCC)c1=O
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(N)c(N)c(=O)n(CC(=O)OCC)c1=O

Procedure:
6-Amino-3-carboethoxymethyl-5-nitroso-1-propyluracil (2.84 g, 10 mmol) is slurried with 75 mL of absolute ethanol and 100 mg of 10% palladium-on-carbon. The mixture is hydrogenated at 25° C. and an initial pressure of 60 p.s.i. of hydrogen in a Parr apparatus. After uptake of hydrogen is completed the mixture is filtered and the filtrate concentrated to give the diaminouracil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]([NH:19][NH2:20])(=[O:18])[CH3:17]>S(Cl)(Cl)=O.C(Cl)(Cl)Cl>[C:16]([NH:19][NH:20][C:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:15])(=[O:18])[CH3:17]
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: CC(=O)NN
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)NNC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 111.5 g (0.5 mole) of 5-(p-chlorophenyl)furoic acid in 500 ml of thionyl chloride was heated at reflux for 1-11/4 hr. After slight cooling, the reaction mixture was filtered and the filtrate was concentrated in a water bath at reduced pressure to a creamy solid. The solid was dissolved in 400 ml of chloroform. To this chloroform solution under stirring at room temperature was added a suspension of 74 g (1 mole) of acetyl hydrazine in 900 ml of chloroform. Addition was completed in about 20 min. White creamy solid separated fairly readily while the temperature rose to about 45°. The mixture was allowed to stir at ambient temperature overnight.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH2:24]([S:31][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(SCc2ccccc2)c(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
67.6 g of 2-chloro-3,5-dinitrobenzotrifluoride are dissolved in 150 ml of N,N-dimethylformamide (DMF) and the mixture is treated with 35.9 g of solid potassium carbonate, treated dropwise with 31 g of benzylmercaptan in 200 ml of DMF with stirring at 0° C., and subsequently stirred for a further 16 hours at room temperature, while cooling.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[C:8]([NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]3[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:39](O)=[O:40])[CH:33]=4)[NH:28]3)[CH:22]=2)=[CH:17][CH:16]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:8]([NH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]3[C:36]([CH3:38])([CH3:37])[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:39]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:40])[CH:33]=4)[NH:28]3)[CH:22]=2)=[CH:19][CH:20]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)NC(=O)c1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(-c2cccc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To a suspension of 60% sodium hydride (87 mg, 2.1 mmol) in N,N-dimethylformamide (1.5 mL) was added methanesulfonamide (210 mg, 2.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-tert-butylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.22 mmol) and 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3′-(6-methanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-biphenyl-4-carboxylic acid tert-butylamide (23 mg, 20%) as a white solid: LC/MS m/e calcd for C30H35N3O4S (M+H)+: 534.70, observed: 534.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:11][C:7]=2[C:6]([C:20]#[N:21])=[CH:5][N:4]=1.C1C(=O)N([Br:29])C(=O)C1>C(OCC)(=O)C>[Br:29][C:11]1[C:7]2[C:6]([C:20]#[N:21])=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])[CH:10]=1
Reactant: COc1ncc(C#N)c2ccn(COCC[Si](C)(C)C)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: COc1ncc(C#N)c2c(Br)cn(COCC[Si](C)(C)C)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-4-carbonitrile (1.34 g) in ethyl acetate (20.15 mL) was added NBS (1.97 g) at room temperature, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.30 g).
Reaction SMILES: [CH3:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[C:19]([O:22][C:23](=O)C)(=O)[CH3:20].C(OC(OCC)OCC)C>>[CH3:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[C:12]([F:18])[C:3]=1[C:4]([C:6](=[CH:23][O:22][CH2:19][CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1c(F)cc(F)c(F)c1C
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Yield: 90 %

Procedure:
To ethyl 2-methyl-3,4,6-trifluorobenzoylacetate (3.2 g) are added acetic anhydride (3.0 g) and triethoxymethane (2.7 g) and the mixture is refluxed for 1 hour. After concentrating, ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (3.5 g) is obtained.