Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][N:13]=1)=[O:7])C.CO.C1COCC1.O[Li].O>O>[C:14]1([C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:20])=[O:3])=[N:13][CH:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(=O)Nc1ncc(-c2ccccc2)s1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC(=O)Nc1ncc(-c2ccccc2)s1
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred solution of 5-phenyl-thiazol-2-ylamine (0.4 g, 0.0022 mol) and DIEA (0.73 g, 0.0056 mol) in chloroform (4 mL) was added mono-ethylmalonyl chloride (0.375 g, 0.0024 mol) dropwise at 0° C. and the resulting mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was then diluted with cold water and the product was extracted with chloroform. The chloroform was washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4 and evaporated under reduced pressure to afford 0.3 g (46%) of N-(5-phenyl-thiazol-2-yl)-malonamic acid ethyl ester. To a solution of N-(5-phenyl-thiazol-2-yl)-malonamic acid ethyl ester (0.292 g, 0.001 mol) in the mixture of methanol (1 mL), THF (1.5 mL) and H2O (1 mL) was added LiOH.H2O (0.084 g, 0.002 mol) and the resulting mixture was stirred for 1 hour. The reaction mixture was then concentrated. The residue was diluted with water, acidified with concentrated HCl and the product was extracted with ethylacetate. The ethyl acetate was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to afford 0.23 g (87%) of N-(5-phenyl-thiazol-2-yl)-malonamic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CS(O[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CC#N>[N+:12]([C:3]1[C:2]([O:1][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])([O-:14])=[O:13]
Reactant: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(OC2CCOCC2)c1[N+](=O)[O-]
Yield: 136.7 %

Procedure:
Methyl 3-hydroxy-2-nitrobenzoate (95 g, 0.52 mol), tetrahydro-2H-pyran-4-yl methanesulfonate (234 g, 1.3 mol) and K2CO3 (358 g, 2.6 mol) was suspend in MeCN (2 L). The mixture was heated at reflux for 20 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The mixture was filtered; the filtrate was concentrated in vacuo. The residue was purified by chromatography (petroleum ether: ethyl acetate=10:1, 5:1, 2:1) to give the title compound (200 g 100%) as a yellow oil.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([O:16][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1

Procedure:
The procedure of Example 3 is repeated using 5.11 grams of 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-ol, 2.0 ml of methacryloyl chloride and 3.10 ml of triethylamine in methylene chloride. The above-named product is isolated as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:31]=1[C:32](Cl)=[O:33]>CN(C)C1C=CN=CC=1.CC1CCCO1>[NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[N:13]([C:32](=[O:33])[C:31]3[C:30]([Cl:29])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:39])[CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: CN(C)c1ccncc1
Solvent: CC1CCCO1
Solvent: CCN(CC)CC
Product: Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(Br)cc23)c1F
Temperature: 9.300000190734863 °C
Yield: 92.93 %

Procedure:
Compound 4 (2.5 kg, 7.114 mol) obtained from Example 2 was added into a 50-liter flask and cooled to 9.3° C. To compound 4 in the 50-liter flask was added triethylamine (0.864 kg, 8.537 mol), followed by 4-dimethylaminopyridine (DMAP) (0.087 kg, 0.7114 mol) and 2,6-dichlorobenzoyl chloride (1.34 kg, 6.40 mol) in 2-methyl-THF (25 L) over a period of 2 hrs. The reaction was quenched with methanol (0.30 L at room temperature and added an aqueous NaCl solution (12.5 L, 15%) and celite (0.5 kg). The mixture was stirred and filtered through celite. The filtrate was concentrated and added 5 volumes of heptanes. The resulting solution was stirred for about 1 hr and dried with sodium sulfate (1 kg) and filtered. Compound 5 was isolated by removing the solvents under vacuum (3.47 kg, 92.93% yield). MS (ESI): M+H+=524, 525.8, 527.8. 1H NMR (DMSO-d6, δ ppm): 5.36 (2H, s), 7.01 (2H, m), 7.68 (3H, s), 8.34 (1H, brs), 8.61 (1H, brs), 8.72 (1H, d J=2.3 Hz).
Reaction SMILES: [CH2:1]([CH:5]=O)[CH2:2][CH:3]=O.[CH3:7][O:8][C:9]([CH2:11][C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:13])=[O:10].[CH3:19][NH2:20]>CO>[CH3:19][N:20]1[CH:3]2[CH2:2][CH2:1][CH:5]1[CH:11]([C:9]([O:8][CH3:7])=[O:10])[C:12](=[O:13])[CH:14]2[C:15]([O:17][CH3:18])=[O:16]
Reactant: CN
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: O=CCCC=O
Solvent: CO
Product: COC(=O)C1C(=O)C(C(=O)OC)C2CCC1N2C
Reaction time: 8 h

Procedure:
The reaction of succindialdehyde of the formula (3) with the organic amine of the formula (4) and the acetonedicarboxylic acid ester of the formula (5) is per se well known. For example, when each of the substitu-ents R and R″ is a methyl group (Me), a methanolic solution containing dimethyl 1,3-acetonedicarboxylate is added to a methanol solution of succindialdehyde in an ice bath under a nitrogen atmosphere, a methanolic solution containing methylamine is added dropwise thereto in an ice bath and stirred overnight, and the solvent is distilled off to obtain dimethyl 8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1a: R′=Me and R=Me in the formula (1)) in a yield of 70-90 mol %.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][C:17](=[O:19])[NH:16][N:15]=1.CI>CN(C=O)C>[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][C:17](=[O:19])[N:16]([CH3:1])[N:15]=1
Reactant: CC(C)(C)[O-]
Reactant: O=c1[nH]nc(-c2ccccc2O)o1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(-c2ccccc2O)oc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of 3.8 g of potassium t-butoxide in 60 ml of dry DMF under a N2 atmosphere was added portionwise 6 g of the product of Example 10 while maintaining the reaction temperature at 10°-20° C. with external cooling. After stirring at 25° C. for one hour, 9.6 g of methyl iodide was added dropwise at 10°-20° C. with external cooling. After stirring at room temperature for 16 hours, the suspension was poured into excess ice-water and filtered. The residue was recrystallized from 2-propanol to yield 4.6 g of the subject compound; m.p. 160°-162° C.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.B(F)(F)F.CCOCC.[F:20][C:21]1[CH:22]=[C:23]2[C:40](=[CH:41][CH:42]=1)[O:39][C:26]1([CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[CH2:25][C:24]2=[O:43].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:25]1[C:26]2([CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:30][CH2:31]2)[O:39][C:40]2[C:23](=[CH:22][C:21]([F:20])=[CH:42][CH:41]=2)[C:24]1=[O:43])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(F)ccc1O2
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C1C(=O)c2cc(F)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 22 %

Procedure:
To triethyl orthoformate (20.2 mL, 121.5 mmol) in dry dichloromethane (115 mL) under argon at −10° C. was added drop-wise BF3.OEt2 (15.4 mL, 121.5 mmol). The solution was allowed to warm to 0° C. and was stirred for 10 minutes. After, the solution was cooled to −78° C. prior to the slow drop-wise addition of tert-butyl 6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (13.6 g, 40.5 mmol) in dichloromethane (10 mL). iPr2NEt (24.7 mL, 141.7 mmol) was added drop-wise over 30 minutes, and the mixture was slowly warmed to room temperature and was stirred at 25° C. for 2 hours. The reaction mixture was diluted with the addition of dichloromethane (200 mL) followed by saturated aqueous sodium bicarbonate solution (200 mL). The mixture was shaken in a separatory funnel and separated. The organic layer was washed with additional sodium bicarbonate solution (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to yield a residue that was purified by silica gel column chromatography (0-25% EtOAc/hexanes gradient) to give tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (3.9 g, 22%). ESI-MS m/z calc. 437.2. found 438.7 (M+1)+. Retention time 2.14 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=2[N+:20]([O-])=O)[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[NH2:20][C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][C:10]=1[NH:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:23])([F:1])[CH2:3][CH2:4]1
Reactant: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-(4-{[(4,4-Difluorocyclohexyl)methyl]amino}-3-nitrophenyl)acetamide (1.48 g, 4.52 mmol) was dissolved in 50 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken in a Parr hydrogenation apparatus under H2 atmosphere (45 psi) at rt for 24 h. The solution was filtered through Celite and the solvent was evaporated. Yield: 1.32 g (98%); 1H NMR (400 MHz, CDCl3) δ 1.31-1.43 (m, 2 H), 1.64-1.73 (m, 2 H), 1.74-1.82 (m, 1 H), 1.89-1.93 (m, 1 H), 1.93-1.96 (m, 1 H), 2.08-2.17 (m, 5 H), 3.00 (d, J=6.64 Hz, 2 H), 3.27-3.46 (m, 2 H), 6.55 (d, J=8.40 Hz, 1 H), 6.70 (dd, J=8.40, 2.34 Hz, 1 H), 7.01 (s, 1 H), 7.13 (d, J=2.34 Hz, 1 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(Cl)Cl>[C:27]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH3:20])=[C:7]([CH:18]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])(=[O:29])[CH3:28]
Reactant: COc1ccc(CO)cc1C(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(COC(C)=O)cc1C(=O)OCc1ccccc1
Yield: 99 %

Procedure:
Next, benzyl 5-hydroxymethyl-2-methoxybenzoate and 100 ml of methylene chloride were mixed and, after pyridine (660 ml, 8.16 mmol), acetic anhydride (460 ml, 4.88 mmol) and N,N-dimethylaminopyridine (25 mg, 0.205 mmol) were added under stirring and cooling with ice, the mixture was stirred overnight. The reaction mixture was washed with 1 mol/l hydrochloric acid, aqueous solution of sodium hydrogencarbonate and brine, then dried over anhydrous sodium sulfate and concentrated to obtain 1.27 g (99%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)Cc2csc(-c3cnn(C(C)(C)C)c3-c3ccc(F)cc3)n2)CC1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 1-methylpiperazine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([Cl:16])=[O:13])=[N:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Product: COC(=O)c1ccc(C(=O)Cl)nc1
Temperature: 80 °C

Procedure:
A mixture of pyridine-2,5-dicarboxylic acid 5-methyl ester (150 mg, 0.828 mmol) and thionyl chloride (1 mL) was heated at 80° C. for 5 h. The thionyl chloride was evaporated under reduced pressure, the residue was dried in high vacuum and used crude for the next reaction.
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].O=S(=O)=O.[F:10][C:11]([F:18])([F:17])[C:12]([F:16])=[C:13]([F:15])[F:14]>>[C:12]1([F:16])([C:11]([F:18])([F:17])[F:10])[S:2](=[O:5])(=[O:3])[O:1][C:13]1([F:15])[F:14]
Reactant: O=S(=O)(O)O
Reactant: FC(F)=C(F)C(F)(F)F
Agent: O=S(=O)=O
Product: O=S1(=O)OC(F)(F)C1(F)C(F)(F)F
Temperature: -45 °C
Reaction time: 0.15 h
Yield: 66 %

Procedure:
A 100 mL Parr™ reactor was charged with 63.8 g of 65% oleum (0.52 mole SO3), cooled to -45° C., evacuated, and then charged with 62 grams (0.44 mole) liquid hexafluoropropene from a cold trap (-78° C.). The reaction mixture was allowed to warm to room temperature. At 20° C. a slight exotherm was observed which increased to a maximum temperature of 56° C. and a pressure of 965 kPa over a 9 minute period. Following the exotherm the reactor was held at 42° C. for 6 hours while the mixture was agitated. The reactor was then vented of excess HFP (with the recovery of 0.7 g HFP) and the contents of the reactor were decanted to yield 103.8 grams (g) of a two phase reaction product. The upper layer (90.6 g) was separated from the lower layer, washed with concentrated sulfuric acid to remove residual SO3 and then distilled to give 63.3 grams of HFP suitone (66% yield with respect to the consumed olefln) with boiling point (b.p.) 45°-50° C. NMR analysis of a higher boiling fraction (b.p. 50°-167° C., yield 25 g) revealed a mixture oftetrafluoropropionic acid derivatives and fluorosulfonic acid. A small portion of this fraction was refluxed in methanol for one hour to give tetrafluoropropionic acid methyl ester (yield 12% based on hexafluoropropene consumed). HFP sultone, after heating with concentrated sulfuric acid for 17 hours at 40° C., was recovered by distillation with 95% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][C:14]2[N:15]=[CH:16][S:17][CH:18]=2)[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:49]=[C:48]([CH3:50])[C:44]([C:45](O)=[O:46])=[C:43]([CH3:51])[N:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:40][C:41]1[CH:49]=[C:48]([CH3:50])[C:44]([C:45]([NH:1][CH2:2][CH2:3][CH:4]([N:6]2[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][C:14]3[N:15]=[CH:16][S:17][CH:18]=3)[CH2:8][CH2:7]2)[CH3:5])=[O:46])=[C:43]([CH3:51])[N:42]=1
Reactant: CC(CCN)N1CCC(NCc2cscn2)CC1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc(C)c1C(=O)NCCC(C)N1CCC(NCc2cscn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
Following general procedure E: to a stirred solution of [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-thiazol-4-ylmethyl-amine (0.320 g. 1.19 mmol), EDCI (0.252 g, 1.31 mmol) and HOBt (0.177 g, 1.31 mmol) in DMF (5 ml) was added 6-chloro-2,4-dimethyl-nicotinic acid (0.243 g, 1.31 mmol) followed by DIPEA (343 μL, 1.78 mmol) and the resulting mixture was stirred at 25° C. for 16 hours. Standard workup and purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 93:5:2) afforded 6-chloro-2,4-dimethyl-N-(3-{4-[(thiazol-4-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (0.42 g, 81%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12](COCC[Si](C)(C)C)[CH:13]=[CH:14][N:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Cl.C([O:28][C:29](=[NH:44])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][C:36]([N+:40]([O-:42])=[O:41])=[CH:37][CH:38]=2)[N:33]([CH3:43])[CH:32]=1)(C)C.Cl.[CH2:46]([OH:48])[CH3:47]>>[NH:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:47]3[C:46](=[O:48])[NH:28][C:29](=[O:44])[C:30]=3[C:31]3[C:39]4[C:34](=[CH:35][C:36]([N+:40]([O-:42])=[O:41])=[CH:37][CH:38]=4)[N:33]([CH3:43])[CH:32]=3)=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC(C)OC(=N)Cc1cn(C)c2cc([N+](=O)[O-])ccc12
Reactant: Cn1ccc2ccc(-c3nccn3COCC[Si](C)(C)C)cc21
Agent: Cl
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc(-c3ncc[nH]3)cc21

Procedure:
3-[6-(1H-Imidazol-2-yl)-1-methyl-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione was prepared from 1-methyl-6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-indole and 2-(1-methyl-6-nitro-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride followed by deprotection using aqueous hydrochloric acid in ethanol.
Reaction SMILES: Br[C:2]1[C:3](=[O:33])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:60][O:61][C:62]1[N:67]=[CH:66][C:65](B(O)O)=[CH:64][CH:63]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]3)=[CH:7][CH:8]=2)[C:3](=[O:33])[C:2]=1[C:65]1[CH:66]=[N:67][C:62]([O:61][CH3:60])=[CH:63][CH:64]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cn1
Yield: 77 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[3-(4-(methylsulfonyl)piperazin-1-yl)propoxy]-1H-inden-1-one obtained in Step 1 of Example 108 as a starting material instead of 6-(2-morpholino ethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])[CH2:6][CH3:7].[I-].C[N+](C)(C)[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([CH3:35])=[CH:31][C:32]=2[CH3:34])[N:27]([CH3:36])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C@H:5]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][C:30]([CH3:35])=[CH:31][C:32]=3[CH3:34])[N:27]([CH3:36])[CH:26]=2)[C:9]1=[O:19])[CH2:6][CH3:7]
Reactant: Cc1cc(C)c2c(C[N+](C)(C)C)cn(C)c2c1
Reactant: CC[C@H](CC(=O)OC)n1c(=O)[nH]c2cccnc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](CC(=O)OC)n1c(=O)c2ncccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Temperature: 65 °C
Yield: 35.3 %

Procedure:
A mixture of 1.75 g of (R)-3-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-pentanoic acid methyl ester, 2.5 g of trimethyl-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-ammonium iodide and 1.7 g of potassium carbonate in 50 mL of N,N-dimethylformamide is heated at 65° C. for 3 h. The resulting mixture is diluted with water and the product is extracted with ethyl acetate. The organic layer is washed with brine, dried (sodium sulfate) filtered and concentrated. The residue is purified by flash chromatography on silica gel to give 1.0 g (35%) of (R)-3-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl]-pentanoic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[C:38]([C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][C:41]=1B(O)O)#[N:39].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:38]([C:40]1[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[CH:42][C:41]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2)#[N:39]
Reactant: N#Cc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 100 °C
Yield: 1.4 %

Procedure:
A pressure vessel was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D) (150 mg, 0.288 mmol), potassium carbonate (199 mg, 1.441 mmol), (2-cyano-4-(trifluoromethyl)phenyl)boronic acid (124 mg, 0.576 mmol), tetrakis(triphenylphosphine)palladium(0) (33.3 mg, 0.029 mmol), dioxane (1922 μl) and water (961 μl). The reaction was heated in a microwave to 100° C. for 60 min. Additional (2-cyano-4-(trifluoromethyl)phenyl)boronic acid (124 mg, 0.576 mmol) and tetrakis(triphenylphosphine)palladium(0) (33.3 mg, 0.029 mmol) were added and the resulting mixture was heated in a microwave at 100° C. for an additional hour. After heating the mixture was allowed to cool to room temperature, the organic layer was separated and the organic layer was concentrated. The resulting product was purified by MPLC (40 g silica gel column, eluting with 0% to 50% EtOAc in heptane) to afford a white solid that was further purified by reverse phase HPLC (Column: Xbridge 19×100 mm, 5 μm, Waters, Milford, Mass., Flow rate: 40 mL/min, Mobile phase: 0.1% NH4OH in ACN and water). The fractions containing product were dried under a vacuum to afford 5-(2-cyano-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (2.1 mg, 0.004 mmol) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.58 (d, J=8.76 Hz, 1H) 7.69-7.74 (m, 1H) 7.75-7.83 (m, 2H) 7.87 (d, J=8.01 Hz, 1H) 8.16-8.24 (m, 2H) 8.34 (d, J=8.34 Hz, 1H) 8.52-8.57 (m, 2H); m/z (ESI) 461.0 (M+H)+.