Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[C:6]2[CH:12]=[CH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:5]=2[O:4]1)[CH3:2]>Cl>[CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH2:10][CH3:11])[C:6]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:5]=2[O:4]1)[CH3:2]
Reactant: CC[C@@H]1Oc2cc(C(=O)OC)ccc2N(CC)C1=O
Agent: Cl
Product: CC[C@@H]1Oc2cc(C(=O)O)ccc2N(CC)C1=O
Yield: 81.7 %

Procedure:
A mixture of (S)-2,4-diethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.90 g) in concentrated hydrochloric acid (40 ml) was stirred under reflux for a day. The concentrated hydrochloric acid was distilled off under reduced pressure to give (S)-2,4-diethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylic acid (1.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2nc3c(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4)cnn3c2=O)cc1
Temperature: 75 °C
Yield: 31.4 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (192 mg, 0.54 mmol), prepared as described in Example 1, K2CO3 (90 mg), and α-bromo-p-toluonitrile (127 mg, 0.645 mmol) in DMF (2 mL) was heated at 75° C. for 1 h. After this time, the solution was concentrated under redcued pressure. The resulting crude product was purified by reverse phase HPLC to provided the title compound, 4-((7,8-bis-(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)methyl)benzonitrile (80 mg) as a yellow solid. MS M+H=472; 1H NMR (CDCl3): δ 8.17 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.33 (m, 2H), 7.25 (m, 2H), 7.24 (m, 2H), 7.09 (m, 2H), 5.25 (2H).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]([NH2:16])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:17][CH:18]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])[C:19](Cl)=[O:20]>C(N(CC)CC)C>[CH3:7][C:8]([NH:16][C:19](=[O:20])[CH:18]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])[Br:17])([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(C)(C)C(Br)C(=O)Cl
Reactant: CC(C)(N)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(C)(C)C(Br)C(=O)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), α,α-dimethylbenzylamine (9 g) and triethylamine (7.4 g), and α-bromo-tert-amylacetyl chloride (15.5 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 15.8 g of N-(α,α-dimethylbenzyl)-α-bromo-tert-amylacetamide. M.P., 136°-137° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1>>[Cl:3][C:22]1[C:10]2[C:11](=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Temperature: 97.5 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
132 g of phosphoryl chloride are added, at 25° C., to 50 g of diethyl 2-[(4-methoxyphenylamino)methylene]malonate. The reaction medium is stirred for 15 minutes at this temperature, heated to 95-100° C. over 45 minutes, and then kept at this temperature for 4 hours. The excess phosphoryl chloride is then removed by heating at 125° C. for approximately 2 hours. The mixture is then cooled to 25° C. and 125 ml of dichloromethane are added. The medium is then stirred at 25° C. for 1 hour, and then run into 900 ml of water, over 30 minutes, while maintaining the temperature below 30° C. The pH is then adjusted to 7.5-8 by adding 172 g of a 47% sodium hydroxide solution, while maintaining the temperature at 20-25° C. The 2 phases are separated and the aqueous phase is extracted with dichloromethane. The organic phases are pooled and washed with water. The dichloromethane phase is half-concentrated and 190 ml of ethanol are added. The concentration is continued until the temperature of the reaction mass reaches 82° C. and the vapor temperature reaches 78° C. The reaction mass is cooled to 0-5° C. and then kept at this temperature for 2 hours. The precipitate is filtered off, washed with cold ethanol, and then dried at 50° C. under reduced pressure. 27.7 g (61%) of 4-chloro-3-ethoxycarbonyl-6-methoxyquinoline are obtained in the form of a yellow solid which melts at 93.7-95.7° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccccc1OCc1ccccc1
Yield: 101.1 %

Procedure:
A mixture of 2-bromophenol (1.50 g; 8.67 mmol), benzyl bromide (1.48 mg; 8.65 mmol). potassium carbonate (1.44 g; 10.41 mmol) and sodium iodide (catalytic amount) in 50 mL of acetonitrile was refluxed for 24 hours. After cooling, the solids were filtered off and the filtrate was concentrated. The crude residue was purified on a silica gel column (10% ethyl acetate hexane) to obtain 2.30 g (quantitative yield) of 2-benzyloxybromo- benzene, 1H NMR (CDCl3): δ 5.16 (s, 2H); 6.84 (t, 1H, J=7.6); 6.93 (d, 1H, J=8.3); 7.21-7.49(m, 6H); 7.56 (d, 1H, J=7.8).
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]1[CH2:20]OC[CH2:17]1.C([Mg]Cl)(C)C>[Ni].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:16]([C:2]1[C:3]([CH3:15])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:20])[CH3:17]
Reactant: Cc1c(Br)cccc1C1=NC(C)(C)CO1
Reactant: C1CCOC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Ni]
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Product: Cc1c(C2=NC(C)(C)CO2)cccc1C(C)C
Temperature: 15 °C

Procedure:
A dry 3-neck 250 mL round bottom flask equipped with magnetic stirring and held under a nitrogen atmosphere was charged with 5.0 g 2-(3-bromo-2-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole, 60 mL anhydrous THF, and 100 mg Ni(dppp)Cl2. The mixture was cooled to 15° C., and isopropyl magnesium chloride (11 mL, 2M in ethyl ether) was added. A mild exotherm took place, and the mixture darkened slightly. The reaction was stirred overnight at room temperature, at which point 1H NMR indicated 50% completion. Addition of ca 75 mg Ni(dppp)Cl2 and reflux for 3 hours resulted in no further progression of the reaction. The mixture was cooled to 15° C., and an additional 13 mL of isopropyl magnesium chloride (2M in ethyl ether) and 100 mg of nickel catalyst were added and the mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH4Cl, the organic layer was removed, the aqueous layer was extracted, and the organic phases were combined and dried. The solvent was removed in vacuo to yield 3.84 g crude product as a yellow oil. Column chromatography on silica gel using 4:1 hexanes:ether as eluant yielded 0.79 g of 2-(3-isopropyl-2-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole as a colorless oil. 1H NMR (CDCl3, 200 MHz), δ (ppm): 7.5 (d, 1H), 7.37 (d, 1H), 7.22 (t, 1H), 4.13 (s, 2H), 3.23 (m, 1H), 2.5 (s, 3H), 1.45 (s, 6H), 1.22 (d, 6H). The oxazoline was suspended in 34 mL of 6N HCl and refluxed in an oil bath for 6 hours. The mixture was cooled and extracted with CH2Cl2. The extract was dried over Na2SO4 and evaporated to yield 0.76 g of 3-isopropyl-2-methyl-benzoic acid, suitably pure for the next step. 1H NMR (CDCl3, 300 MHz), δ (ppm): 7.8 (d, 1H), 7.48 (d, 1H), 7.3 (t, 1H), 3.3 (m, 1H), 2.55 (s, 3H), 1.2 (d, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39]>CN(C=O)C.C(Cl)Cl>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[N:1]([CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:2]=[CH:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6[nH]ccc6c5)sc4n3)CC2)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CCCn1ccc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(1H-Indol-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (80 mg, 0.218 mmol) was dissolved in DMF (1.1 mL) before cesium carbonate (156 mg, 0.479 mmol) was added and stirred at ambient temperature for 1 h; to the reaction mixture was added methyl 4-bromobutanoate (43 mg, 239 μmol) before it was stirred for 20 h at 80° C. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with water, washed 1 times with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give methyl 4-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-1H-indol-1-yl)butanoate after flash chromatography. MS (ESI) m/z: Calculated: 467.2; Observed: 468.4 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=3[CH3:30])([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.[CH3:31][CH:32]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:33][CH2:34]Cl.[OH-].[K+].[Na+].[I-]>C(OCC)(=O)C.C(O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=3[CH3:30])([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:34][CH2:33][CH:32]([CH3:31])[CH2:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:20][CH:21]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)CCCC(C)CCCl
Reactant: Cc1ccc(C)c(C2(c3ccc(O)cc3)c3cc(Br)ccc3-c3ccc(Br)cc32)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(C2(c3ccc(OCCC(C)CCCC(C)C)cc3)c3cc(Br)ccc3-c3ccc(Br)cc32)c1

Procedure:
52 g of 2,7-dibromo-9-(2,5-dimethylphenyl)-9-(4-hydroxyphenyl)fluorene were refluxed with 18 g of 3,7-dimethyloctyl chloride, 80 ml of ethanol, 7 g of KOH and 1 g of NaI for 5 days. According to TLC, the reaction was complete after this time. The solvent was stripped off, ethyl acetate was added, and the precipitate was filtered off with suction and rinsed a number of times with ethyl acetate. The organic phase was dried, and the solvent was stripped off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[CH2:12][S:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][S:13][CH3:14])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CSCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCOc1ccc(Cl)cc1C=O
Temperature: 70 °C
Yield: 65.5 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (15.6 g, 0.1 mol), chloro-methylsulfanyl-methane (9.6 g, 0.1 mol), K2CO3 (14 g, 0.1 mol) and KI (1 g, 0.006 mol) in DMF (70 mL) was heated at 70° C. for 2 h. After cooled to the room temperature, the mixture was poured into ice water. The aqueous phase was extracted with diethyl ether. The combined organic layers were washed with NaOH solution (1 N), dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow oil (14.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[S:10][CH3:11])[CH:5]=[O:6].[BH4-].[Na+].Cl.O>C1COCC1>[F:12][C:8]1[CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=[C:2]([F:1])[C:9]=1[S:10][CH3:11]
Reactant: CSc1c(F)cc(C=O)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1c(F)cc(CO)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of 3,5-difluoro-4-(methylthio)-benzaldehyde (31.3 g, 0.166 mol) in anhydrous THF (200 mL) cooled with a cold water bath was added sodium borohydride (1.6 g, 0.042 mol) in portions over 30 minutes. After stirring 1 hour at room temperature, excess dilute HCl was added, until gas evolution ceased. Water (600 ml) was added and the mixture extracted with dichloromethane (1×500 mL, 1×100 mL). The combined extracts were washed once with water, dried with magnesium sulfate, and concentrated. Purification by silica gel chromatography using 3% ethyl acetate/10% dichloromethane in hexanes initially, and eluting product with 60% ethyl acetate in hexanes gave [3,5-difluoro-4-(methylthio)-phenyl]methanol as a light yellow liquid (24.8 g, 78%). 1H NMR (CDCl3/400 MHz) 6.88-6.93 (m, 2H), 4.65 (s, 2H), 2.42 (s, 3H). HRMS m/z 190.0266 (M+H+, calcd 190.0264).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CCOCC.Cl>[F:9][C:2]([F:1])([F:8])[C:3](=[C:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:25])[OH:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1CCCc2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=C1C(=C(O)C(F)(F)F)CCc2ccccc21
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A 250 mL one neck round bottomed flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in ether (50 mL) was added over about 5 minutes The reaction mixture was stirred at room temperature for 14 hours and was diluted with 100 mL of 3N HCl. The phases were separated, and the organic layer was washed with 3N HCl and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was taken up in 70 mL of boiling ethanol/water and cooled to room temperature, whereupon crystals of 3,4-dihydro-2-[2,2,2-trifluoro-1-hydroxyethylidene]-1(2H)-naphthalenone formed which were isolated by filtration and air dried to give 32 g (81%) of pure 3,4-dihydro-2-[2,2,2-trifluoro-1-hydroxyethylidene]-1(2H)-naphthalenone: mp 48°-49° C.; 1H NMR (CDCl3) δ 2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19F NMR (CDCl3) δ-72.0. EI GC-MS M+ =242.
Reaction SMILES: Br[CH:2]([CH3:19])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])O.[Na+]>COCCOC>[CH3:19][C:2]1[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[N:20][C:3]=1[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: CC(Br)C(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(CC(=O)OCc2ccc([N+](=O)[O-])cc2)nc2ccccn12
Yield: 26.9 %

Procedure:
4-Nitrobenzyl 4-bromo-3-oxopentanoate (1.02 g) and 2-aminopyridine (436 mg) were dissolved in 1,2-dimethoxyethane (20 ml). The solution was heated for 15 hours under reflux. The reaction mixture was concentrated, to which were added 1N HCl (10 ml) and ethyl acetate (10 ml). The mixture was shaken and left standing to form two layers. To the aqueous layer was added sodium hydrogencarbonate to adjust its pH to 7, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, which was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: silica gel, 30 g, developing: ethyl acetate) to afford the title compound (0.27 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.Cl.[CH3:55][N:56]1[C:60]([C:61](Cl)=[O:62])=[CH:59][N:58]=[CH:57]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:61]([C:60]2[N:56]([CH3:55])[CH:57]=[N:58][CH:59]=2)=[O:62])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cn1cncc1C(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(=O)N1CC[C@@H](CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1-methyl-1H-imidazole-5-carbonyl chloride hydrochloride as the starting materials in 20% yield. LCMS for C28H29ClN9O2 (M+H)+: m/z=558.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:13]=1[NH2:14]>>[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:7]([C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)=[NH:8]
Reactant: CSc1ccc(C#N)cc1
Reactant: Cc1ccc(N)c(C)c1
Product: CSc1ccc(C(=N)Nc2ccc(C)cc2C)cc1
Yield: 75.2 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (18.46 g, 123 mmol) and 2,4-dimethylaniline (15 g, 123 mmol) by following the procedure described in preparation 10 (25.17 g, yield 75.2%, purity 99% by HPLC). 1H-NMR (CDCl3):δ 2.16 (s, 3H), 2.31 (s, 3H), 2.53 (s, 3H), 4.5 (bs, 2H, D2O exchangeable), 6.76-6.78 (d, 1H), 6.98-7.0 (d, 1H), 7.05 (s, 1H), 7.27-7.31 (m, 2H), 7.81-7.83 (d, 2H). MS m/z:271.3 (M+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:18])=[C:12]([S:14]([NH2:17])(=[S:16])=[O:15])[CH:13]=1)=[O:7].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>C(OCC)(=O)C.O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:18])=[C:12]([S:14]([NH2:17])(=[S:16])=[O:15])[CH:13]=2)=[O:7])[CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)CCCCCl)cc1S(N)(=O)=S
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(CCCCC(=O)c2ccc(C)c(S(N)(=O)=S)c2)CC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
A mixture of 5 g of 5-(5-chlorovaleryl)-2-methylthio-benzenesulfonamide, 3.4 g of 1-(2-methoxyphenyl)piperazine, 2.0 g of sodium carbonate and 25 ml of dimethyl sulfoxide was heated at 90° C. for 6 hours while stirring. After the reaction was finished, 100 ml of water and 100 ml of ethyl acetate were added to the reaction mixture and the stirring was continued for 30 minutes to produce crystals. The thus-produced crystals was filtered off to obtain 6.0 g of the titled compound (yield: 80.5%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[CH3:14]>>[Cl:1][C:2]1[N:3]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:13][CH3:14])=[CH:17][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Yield: 37 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-ethoxyphenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-ethoxyphenyl)-1H-indole-3-carboxaldehyde (37% yield) as a off white solid. ESI/MS 300 (M+H); RT=3.56 min.
Reaction SMILES: [CH3:1][C:2]1[N+:6]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:15])=[N:12][C:13]=2[NH2:14])=[CH:5][S:4][C:3]=1[CH2:16][CH2:17][OH:18].Cl.[Cl-].[CH3:21][C:22]1([S:34]([O-:37])(=[O:36])=[O:35])[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:24](=[O:25])[CH2:23]1.[Na+]>O>[CH3:21][C:22]1([S:34]([OH:37])(=[O:36])=[O:35])[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:24](=[O:25])[CH2:23]1.[CH3:1][C:2]1[N+:6]([CH2:7][C:8]2[CH:9]=[N:10][C:11]([CH3:15])=[N:12][C:13]=2[NH2:14])=[CH:5][S:4][C:3]=1[CH2:16][CH2:17][OH:18]
Reactant: CC1(S(=O)(=O)[O-])CC(=O)c2ccccc2C1=O
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CC1(S(=O)(=O)O)CC(=O)c2ccccc2C1=O

Procedure:
25 g of thiamine hydrochloride (vitamin B1) was dissolved in 50 g of water; to said solution of 25 g of powdery sodium menadione bisulfite was added within about half an hour. After half an hour of agitation, the reaction mass became opalescent and the adduct began to precipitate. After an hour, the precipitate was filtered, washed and dried. 25 g of a white product having the following analysis was obtained.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C@@H:28]([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[CH3:30][N:29]1[C:22]2[N:23]([C:24](=[O:26])[N:25]=[C:20]([O:16][CH2:15][C:12]3[CH:13]=[CH:14][C:7]([O:6][C:5]4[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=4)=[C:8]([CH:11]=3)[C:9]#[N:10])[CH:21]=2)[CH2:27][C@@H:28]1[CH3:31]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)cc1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(F)cc4)c(C#N)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 2-(4-fluorophenoxy)-5-(hydroxymethyl)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.