Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:29])[CH3:9])=[CH:4][CH:3]=1.[O:30]=[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][NH:32]1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])[O:12][C:11](=[O:29])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[CH:36][C:31](=[O:30])[NH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: O=c1ccc(B(O)O)c[nH]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 2-oxo-1,2-dihydropyridin-5-ylboronic acid following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.37 min, m/z=474(M+1); 1H NMR (CDCl3) 7.97, (dd, 1H), 7.73 (s, 1H), 7.33 (m, 2H), 7.20 (d, 2H), 7.17 (t, 2H), 6.98 (m, 3H), 5.67 (q, 1H), 3.00 (dt, 1H), 2.49 (m, 2H), 2.30 (m, 1H), 2.13 (s, 2H), 1.55 (d, 3H), 1.45 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])[C:3]([OH:5])=[O:4].[CH2:25](O)[CH3:26].S(=O)(=O)(O)O>CC1C=CC=CC=1>[CH3:25][CH2:26][O:4][C:3]([CH:2]([Cl:1])[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[N:14]=[C:15]([CH3:22])[N:16]([CH:19]([F:20])[F:21])[C:17]2=[O:18])[C:10]([F:23])=[CH:9][C:8]=1[Cl:24])=[O:5]
Reactant: CCO
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Yield: 92 %

Procedure:
To a flask was added 140 g of the 2-chloro-3-{2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorophenyl}propionic acid, obtained according to the Example 2, 160 g of ethanol, 7 g of sulfuric acid and 700 g of methyl benzene. The mixture was refluxed for 15 hours to remove water. The excess ethanol was recovered by distillation. At room temperature the mixture was washed with 200 g of water, with 200 g of a 4% (wt/wt) aqueous solution of potassium hydroxide and finally with water. The solvent was completely removed under reduced pressure to give carfentrazone-ethyl as a faint yellow transparent and viscous liquid in a yield of 92% with a purity of 98.8%.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH:41]2[CH2:46][CH2:45][C:44]3([CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)[CH2:43][CH2:42]2)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH:41]3[CH2:42][CH2:43][C:44]4([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]4)[CH2:45][CH2:46]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OC2CCC3(CCCCC3)CC2)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OC2CCC3(CCCCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 5-chloro-2-fluoro-4-(spiro[5.5]undecan-3-yloxy)benzoate, the title compound was obtained as an orange oil (0.33 g, 79%): MS (ES+) m/z 403.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:20]([C:21](=O)[C:22]=2[CH:23]=1)=[CH:19][C:18]1[C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:26])[CH:15]=2)[CH2:10][C:9]=1[CH:8]=3>COCCOCCOC>[CH3:26][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][C:18]3[C:9]([CH:10]=2)=[CH:8][C:7]2[C:20](=[CH:21][C:22]4[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:23]=4)[CH:19]=3)[CH:15]=1
Reactant: Cc1ccc2c(c1)C(=O)c1cc3c(cc1C2)Cc1ccc(C)cc1C3=O
Solvent: COCCOCCOC
Product: Cc1ccc2cc3cc4cc5ccc(C)cc5cc4cc3cc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1 gram of 3,9-dimethylpentacene-5,7(12H,14H)-dione and 10 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 15 minutes. To this was added 0.948 grams of sodium borohydride and stirring was continued at room temperature overnight. To the mixture was added 6.3 mL of methanol and stirring was continued for 1.5 hours at room temperature. To the mixture was added 15 mL of acetic acid and 10 mL of concentrated hydrochloric acid. The mixture was stirred for one hour at room temperature followed by heating for one hour at 60° C. To the mixture was added 50 mL of water and the resulting solid was isolated by filtration and washed with water. The solid was washed with tetrahydrofuran until a pale filtrate resulted. The solid was washed with heptane and dried under an atmosphere of nitrogen to give 2,10-dimethylpentacene.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][C:7]([C:22]([NH2:24])=[O:23])=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>[Pd].CO.C(Cl)Cl>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[C:7]([C:22]([NH2:24])=[O:23])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1=Cc2ccccc2-c2cc3ccc(C(N)=O)cc3n2C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)C1=Cn2c(cc3ccc(C(N)=O)cc32)-c2ccccc2C1
Reaction time: 8 h

Procedure:
10% Palladium on carbon (77 mg, 0.07 mnol) was added to a solution of 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-3-methoxy-N6-(2-methoxyethyl)-N6-methyl- (65 mg, 0.11 mmol) in MeOH/CH2Cl2 (1:1, 4 mL) and the reaction mixture was vacuum flushed with nitrogen (3×) and then with hydrogen (3×). The reaction was stirred under a balloon of hydrogen overnight, filtered through a pad of celite and concentrated to yield 5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-N6-(2-methoxyethyl)-N6-methyl- (60 mg, 0.10 mmol, 92%) as a light yellow solid. Mixture of atrope diastereomers. 1HNMR (300 MHz, CD3OD) δ 8.10-7.92 (m, 1H), 7.91-7.83 (m, 1H), 7.62-7.51 (m, 1H), 7.42-7.33 (m, 1H), 7.10-6.84 (m, 2H), 4.67-4.44 (m, 1H), 3.93-3.86 (m, 3H), 3.84-3.21 (m, 1H), 3.06-2.86 (m, 8H), 2.83-2.64 (m, 2H), 2.18-1.19 (m, 10H). LCMS: m/e 611 (M+H)+, ret time 2.12 min, column C, 2 minute gradient.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([NH2:49])(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([NH2:49])(=[O:47])=[O:48])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(N)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(O)cc(NS(N)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 70 %

Procedure:
N-[3-hydroxy-5-(4-{[(1S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]sulfamide (38 mg, 0.05 mmol) was treated with trifluoroacetic acid (760 μl, 9.86 mmol) and a solution of ammonia (7N in methanol, 780 μl, 5.32 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 20 mg (63% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9](I)[C:8]([O:12][CH2:13][O:14][CH3:15])=[C:7](Br)[CH:6]=1)[CH3:2].C(O[C:21](=O)[C:22]1[CH:27]=[C:26](Br)[C:25](OCOC)=[C:24](Br)[CH:23]=1)C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH3:4])[CH:6]=2)[C:8]([O:12][CH2:13][O:14][CH3:15])=[C:7]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[CH:27]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(OCOC)c(I)c1
Reactant: CCOC(=O)c1cc(Br)c(OCOC)c(Br)c1
Product: CCOC(=O)c1cc(-c2cccc(C)c2)c(OCOC)c(-c2cccc(C)c2)c1

Procedure:
3,5-Bis-(3-methylphenyl)-4-methoxymethoxybenzoic acid ethyl ester was prepared as a white solid (4.2 g, 30%) in a similar manner to Step 1 of Example 143 from a 2:1 mixture of 3-bromo-4-methoxymethoxy-5-iodobenzoic acid ethyl ester and 3,5-dibromo-4-methoxymethoxybenzoic acid ethyl ester. 1H NMR (CDCl3) δ 1.17 (t, J=8.18 Hz, 3H); 2.4 (s, 6H); 2.66 (s, 3H); 4.36 (quartet, J=8.18 Hz, 2H); 4.40 (s, 2H); 7.11-7.20 (m, 2H); 7.20-7.40 (m, 6H); 8.00 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[O:23]=[C:24]1[CH2:29][O:28][CH2:27][CH2:26][N:25]1[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(Cl)CCl>CN(C=O)C>[O:23]=[C:24]1[CH2:29][O:28][CH2:27][CH2:26][N:25]1[C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[CH:34][CH:35]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (26 mg, 0.082 mmol) and 4-(3-oxo-morpholin-4-yl)phenylamine (23 mg, 0.12 mmol) in DMF (3 mL), EDC (39 mg, 0.20 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (27 mg). MS 493.2 and 495.2 (M+H, Cl pattern).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].C(Cl)(=O)C(Cl)=O.[NH4+:29].[OH-]>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][C:11]([NH2:29])=[O:13])=[CH:5][C:4]=1[C:19]([F:22])([F:20])[F:21])#[N:2]
Reactant: CC(C)(C)CN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)CN(CC(N)=O)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2-dimethylpropyl)glycine (1.13 g, 3.58 mmol) in CH2Cl2 (10 mL) at 0° C. was added oxalyl chloride (0.33 mL, 3.76 mmol), followed by DMF (0.01 mL, 0.2 mmol). The resulting solution was stirred 5 min in the cooling bath, 20 min at rt and 1 h at reflux under N2. After cooling to rt, the solution was slowly poured into NH4OH (10 mL of a 30 wt % solution) at 0° C., stirred 30 min, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (×2), combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was recrystallized from IPA/hexanes, affording 0.642 g of the title compound as a colorless, amorphous solid. The mother liquor was concentrated and purified by flash chromatography (EtOAc/hexanes), affording an additional 0.241 g of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.9 Hz, 1H), 7.07 (d, J=2.5 Hz, 1H), 6.85 (dd, J=8.9, 2.6 Hz, 1H), 5.70 (bs, 1H), 5.59 (bs, 1H), 4.12 (s, 2H), 3.38 (s, 2H), 1.03 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:30]3[CH2:29][CH2:28][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:32][CH2:31]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 36 (495 mg) was reacted with Boc-piperazine via General Procedure B-3 to give tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5](/[CH:6]=[CH:7]/[C:8](=[N:17][OH:18])[NH2:9])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: NO
Reactant: N#CC=Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(/C=C/c1ccc(Cl)c(C(F)(F)F)c1)=NO
Yield: 40.1 %

Procedure:
12.1 g (0.05 mol) of 4-chloro-3-trifluoromethylcinnamonitrile are added to a solution consisting of 7.2 g (0.10 mol) of hydroxylamine hydrochloride and 7.3 g (0.10 mol) of sodium carbonate in 100 ml of water and 100 ml of ethanol. The mixture is heated at reflux temperature until the reaction is complete (24 hours) and the whole batch is subsequently stirred into 250 ml of water. The solid material which separates off during this process is filtered off with suction, washed with a little water and dried. 5.3 g (39.3% of theory) of (E)-4-chloro-3-trifluoromethylcinnamamide oxime are obtained.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[I-].[NH2:8][N+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH3:17].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[C:19]#[CH:20].C(Cl)Cl>CN(C=O)C>[CH2:15]([C:10]1[N:9]2[N:8]=[CH:20][C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]2[CH:13]=[CH:12][CH:11]=1)[CH2:16][CH3:17]
Reactant: CCCc1cccc[n+]1N
Reactant: C#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1cccc2c(C(=O)OCC)cnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
Next, 2.41 g (22.7 mmol) of Na2CO3 were added to a solution of 5.0 g (18.9 mmol) of 1-amino-2-propylpyridinium iodide in 20 ml of DMF, followed by stirring at room temperature for 1 hour. Ethyl propiolate (3.71 g; 37.9 mmol) was added further, followed by stirring at room temperature for 20 hours. After the reaction, the reaction mixture was treated in a similar manner to the preparation of the 7-ethyl derivative, whereby 1.45 g (6.25 mmol) of the title compound were obtained as crystals from CH2Cl2 :hexane=1:1 eluate fractions (yield: 33% - 9% in two steps).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:29])=[C:6]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]=[C:10]3[N:16]([C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[C:17](=[O:20])[NH:18][CH2:19][C:9]=23)[CH:7]=1.[S:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31]1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[N:16]1[C:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:35]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)=[O:36])[CH:3]=[CH:4][C:5]=3[CH3:29])[C:9]=2[CH2:19][NH:18][C:17]1=[O:20]
Reactant: O=C(O)c1ccsc1
Reactant: CSc1nc(-c2cc(N)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CSc1nc(-c2cc(NC(=O)c3ccsc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compounds 5-(5-amino-2-methylphenyl)-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.205 g, 0.5 mmol), 3-thiophenecarboxylic acid (0.0647 g, 0.5 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.107 g, 0.55 mmol), 4-(dimethylamino)pyridine (0.002 g, 0.016 mmol), and triethylamine (0.14 mL, 1 mmol), were dissolved in chloroform (10 mL) and stirred under argon at room temperature for 16 h. The reaction was not complete. An additional 3-thiophenecarboxylic acid (0.13 g, 1.0 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.107 g, 0.55 mmol) were dded and heated to 40° C. for 17 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water (3×), brine (1×), dried over anhydrous Na2SO4, filtered and evaporated. The crude product was flash chromatographed on silica gel (10 g) eluted with 0-5% MeOH/CH2Cl2 to give the title compound as a solid. LC-MS m/z 524 (M+H)+, 2.2 min (ret. time).
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[C:10]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:42][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[C:10]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCNCC3)c2n1
Yield: 88.6 %

Procedure:
Reaction of the above carbamate (165 mg, 0.282 mmol) with an excess of TFA (2 mL) in CH2Cl2 (10 mL) at room temperature for 1.5 hrs, followed by treatment with aq. NH3 gave 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-9-(4-piperidinyl)-9H-purine (121 mg, 88%), which was used in the next step without further purification: 1H NMR (CDCl3) δ 7.87 (s, 1H), 7.81 (dd, J=8.4, 0.5 Hz, 1H), 7.48 (t, J=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.54 (tt, J=12.0, 4.1 Hz, 1H), 4.38 (br s, 4H), 4.07 (s, 3H), 3.88 (t, J=4.8 Hz, 4H), 3.30 (d, J=12.4 Hz, 2H), 2.86 (dt, J=12.4, 2.3 Hz, 2H), 2.20 (dd, J=11.8, 2.2 Hz, 2H), 2.04 (dq, J=12.3, 4.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[C:13]([C:16]3[N:17](COCC[Si](C)(C)C)[N:18]=[CH:19][CH:20]=3)=[CH:14][N:15]=[C:8]1[C:7]([NH:29][CH2:30][CH2:31][CH2:32][O:33][P:34](=[O:51])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[N:6]2.Cl.[Na]>C(O)C.C(O)(C)C>[N:18]1[NH:17][C:16]([C:13]2[N:9]3[C:10]4[C:5]([N:6]=[C:7]([NH:29][CH2:30][CH2:31][CH2:32][O:33][P:34](=[O:51])([O:43][CH2:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)[O:35][CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:8]3=[N:15][CH:14]=2)=[CH:4][C:3]([C:2]([F:1])([F:53])[F:52])=[CH:12][CH:11]=4)=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1cnc2c(NCCCOP(=O)(OCc3ccccc3)OCc3ccccc3)nc3cc(C(F)(F)F)ccc3n12
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CC(C)O
Product: O=P(OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(-c3ccn[nH]3)cnc12)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.4 %

Procedure:
To a stirred solution of phosphoric acid dibenzyl ester 3-{7-trifluoromethyl-1-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]-imidazo[1,2-a]quinoxalin-4-ylamino}-propyl ester (966 mg; 1.26 mmol; 1.0 eq) in absolute ethanol (7 mL) at 0° C., is added a 4N solution of hydrogen chloride in isopropanol (3.5 mL). The solution is stirred for 5 minutes at 0° C., warmed-up to room temperature and stirred for two additional hours. The reaction mixture is basified with an aqueous solution saturated with sodium hydrogenocarbonate (35 mL). The aqueous layer is extracted three times with ethyl acetate (3×40 mL). The combined organic phases are dried over sodium sulphate, filtered and concentrated under vacuum. Purification by two successive silica gel chromatography (elution with ethyl acetate) afforded the title compound (392 mg; 0.61 mmol; 48%) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br-].[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([Zn+])=[N:31][CH:32]=1>O1CCOCC1.[Zn]>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([C:2]2[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:23])([F:21])[F:22])[CH:14]=2)[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])=[N:31][CH:32]=1
Reactant: Cc1ccc([Zn+])nc1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: [Br-]
Agent: [Zn]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)nc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-bromo-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoate (1.2 g, 2.8 mmol) in 0.6 mL of dioxane under N2 was added 5-methyl-2-pyridyl zinc bromide (0.5M, 11.3 mL, 5.67 mmol). The reaction was heated to 70° C. for two hours. An additional 0.5 equivalents of zinc reagent was added and the mixture stirred at 70° C. overnight. The mixture was cooled and concentrated. The crude material was taken up in EtOAc and sat. NaHCO3 and sat. Rochelle's salt added. The organic layer was extracted and washed with Rochelle's salt (2×) followed by brine. The final organic layer was dried over Na2SO4, filtered and concentrated to 1.01 g of crude material. Purification using automated flash chromatography (SiO2, 120 g, 0-5% MeOH/DCM) gave, upon concentration, title product. LC-MS (M+H)=436.1
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]>>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: COc1ccccc1I
Reactant: Clc1ccc2cc[nH]c2c1
Product: COc1ccccc1-n1ccc2ccc(Cl)cc21

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-2-methoxybenzene: ESMS m/e: 257.9 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.C([O:13][C:14]1[CH:23]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[C:21]([Cl:28])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=O)C>>[N+:1]([C:23]1[C:22]([NH:24][C:25](=[O:27])[CH3:26])=[C:21]([Cl:28])[CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:14]=1[OH:13])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c([N+](=O)[O-])c1O
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 90 ml concentrated HNO3 and 10 ml concentrated H2SO4 cooled to -10° C. is added portionwise over 5 minutes 10.9 g (38.2 mmol) methyl 2-acetoxy-4-acetylamino-5-chlorobenzoate. The mixture is stirred another 5 minutes and poured into ice water (400 ml). The ppt. which forms is filtered, washed (H2O) and dried to obtain methyl 3-nitro-4-acetylamino-5-chlorosalicylate; m.p. 166°-69° C.