Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]([OH:28])=[O:27])=[CH:18]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]>ClCCl>[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]([O:28][C:1]([C:2]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[N:17]([C:14]4[CH:15]=[CH:16][C:11]([S:8]([CH3:7])(=[O:10])=[O:9])=[CH:12][CH:13]=4)[CH:18]=3)=[O:5])=[O:27])=[CH:18]2)=[CH:13][CH:12]=1)(=[O:9])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-n2cc(C(=O)O)c3cccnc32)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2cc(C(=O)OC(=O)c3cn(-c4ccc(S(C)(=O)=O)cc4)c4ncccc34)c3cccnc32)cc1
Temperature: 20 °C
Reaction time: 300 h

Procedure:
0.52 cm3 (6 mmol) of oxalyl chloride was added, under an argon atmosphere, to 1-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid in 15 cm3 of dichloromethane. After stirring at a temperature in the region of 20° C. for 300 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was triturated with 20 cm3 of dichloromethane, filtered and pulled dry, and then the solid was washed with 50 cm3 of distilled water to give, after drying, 0.13 g of bis[1-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic]anhydride in the form of a powder which was used directly in the following stage. IR spectrum (KBr): 3116, 2926, 1767, 1705, 1592, 1537, 1421, 1294, 1177, 1151, 1083, 999, 962, 775, 551 and 532 cm−1.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(Cl)[Cl:27]>Cl>[ClH:27].[F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Agent: Cl
Product: Fc1cc(F)c(C(F)(F)F)c(C2CCNCC2)c1
Yield: 63 %

Procedure:
A solution of tert-butyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (27, 0.590 g, 1.61 mmol) in CH2Cl2 (10 mL) and HCl (2.0 N solution in Et2O, 10 mL) stirred at ambient temperature for 18 h. The resulting solids were filtered to afford 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (28) as a white solid (0.309 g, 63%). 1H NMR (300 MHz, CDCl3) δ 7.01-6.94 (m, 1H), 6.94-6.76 (m, 1H), 3.82-3.60 (m, 2H), 3.42-3.02 (m, 3H), 2.22-1.99 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCS.[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCS
Product: CCOC(=O)C=CC1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 132.2 %

Procedure:
To a stirred solution of (S)-2-(2-ethoxycarbonyl-vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (103 mg, 0.382 mmol) in THF (2 ml) was added EtSH (85 μl, 1.15 mmol) and NaH (60% in paraffin liquid: 46 mg, 1.15 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 7 hr. The mixture was quenched with 1N HCl, extracted with AcOEt, washed with saturated aqueous NaCl, dried (MgSO4), and concentrated in vacuo to give 2-(2-ethoxycarbonyl-vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (136 mg) as a crude oil, which was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.CN(C)CCCN=C=NCC.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.O>C1COCC1.C(OCC)(=O)C>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([NH:38][C:21](=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([C:16]#[C:15][Se:14][C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:1])([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)=[CH:25][CH:24]=2)=[CH:40][CH:41]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)O)cc3)ccc21
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)Nc4ccc(O)cc4)cc3)ccc21
Yield: 63.2 %

Procedure:
A solution of 250 mg (0.63 mmol) of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)benzoic acid obtained in Example 5, 169 mg (1.25 mmol) of 1-hydroxybenzoctriazole, 240 mg (1.25 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 82 mg (0.75 mmol) of 4-aminophenol in 20 ml of THF is stirred at room temperature for 15 h. Water and ethyl acetate are then added. After stirring and separation of the phases by settling, the aqueous phase is extracted with ethyl acetate. The organic phases are then combined and washed with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified on a column of silica (ethyl acetate 20/heptane 80). 200 mg (65%) of a white solid are obtained. m.p.=202° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][C:5]=1[C:6](OCC)=[O:7])[CH3:2]>O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)(=[O:16])=[O:17])=[CH:11][C:5]=1[CH:6]=[O:7])[CH3:2]
Reactant: CCOC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1OCC
Agent: O=[Mn]=O
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C=O
Reaction time: 3 h
Yield: 47.4 %

Procedure:
MnO2 (100 g, 1.15 mol) was loaded into a flask, followed by 1-(4-ethoxy-3-hydroxymethylphenylsulfonyl)-4-methylpiperazine (15 g, 0.05 mol, from step (b) above). This was washed with acetone (150 mL) and the suspension stirred for 3 hours. The MnO2 was filtered off onto Celite® and the filtrate concentrated under vacuum to give a pale yellow oil. This was recrystallised from toluene to give the title compound as a pale green solid (7.4 g, 47%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14]1[CH:30]=[CH:29][C:17]([O:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[C:16]([C:31]2[N:35]([CH3:36])[N:34]=[CH:33][C:32]=2[Cl:37])[CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl>ClCCl>[NH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:29]=[CH:30][C:14]([NH:13][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=2[F:1])=[CH:15][C:16]=1[C:31]1[N:35]([CH3:36])[N:34]=[CH:33][C:32]=1[Cl:37]
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc(OCCN)c(-c3c(Cl)cnn3C)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoro-4-methoxybenzoic acid (92.8 mg, 545 μmol), tert-butyl 2-(4-amino-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (200 mg, 545 μmol), HATU (207 mg, 545 μmol) and triethylamine (76.0 μL, 545 μmol) in dichloromethane was stirred at room temperature overnight. The reaction was diluted with dichloromethane and washed with water. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. To the crude product was added 2M HCl (5 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated and the title compound was obtained as a yellow oil. LCMS m/z (%)=419 (M+H, 35Cl, 100), 421 (M+H, 37Cl, 40).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:17]([OH:19])=O)[CH:14]([CH3:16])[CH3:15])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:17]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[C@H](NC(=O)CCCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)CCCc1ccccc1)C(=O)N1CCCC1
Temperature: 25 °C

Procedure:
After completion of the reaction, the mixture was extracted twice with ethyl ether to remove the unreacted acid chloride. The water phase was acidified by addition of hydrochloric acid. The resulting precipitate was extracted three times with ethyl acetate and the solvent was removed under vacuum, whereby N-(γ-phenyl)butyryl-L-valine was obtained. N-(γ-phenyl)butyryl-L-valine (1 equivalent) was then dissolved in dry methylene chloride (ca. 100 ml) together with pyrrolidine (1 equivalent), WSCD (1 equivalent) was added thereto and the mixture was continuously stirred at room temperature for one whole day and night. After the reaction the product had been washed successively with 1N hydrochloric acid, brine, saturated sodium bicarbonate and brine in that order, and had then been dried over anhydrous magnesium sulfate, the solvent was distilled off under vacuum and the residue was purified by column chromatography on silica gel, whereby the titled compound was obtained.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[C:24]1([CH3:25])[CH:26]=[CH:27][C:21]([S:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CCCCCCc1ccc(CCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
4-(4-Hexylphenyl)butanol (5.0 g) was dissolved in 20 ml of pyridine and 4.88 g of tosyl chloride was added thereto. The reaction mixture was left standing at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 2N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and saturated brine in order and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:7) to give 2.21 g of 4-(4-hexylphenyl)butyl p-toluenesulfonate as a colorless, oily substance.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[C:10]([CH:12](O)[CH3:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:26][CH:12]([C:10]1[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:11]=1)[CH3:13]
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(Br)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (444 mg, 1.23 mmol) and carbon tetrabromide (613 mg, 1.85 mmol) in tetrahydrofuran (5 mL) at 0° C. was added triphenylphosphine (485 mg, 1.85 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (4%→6% EtOAc/Hex) to give 284 mg (55%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.27 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 5.90 (q, J=7.0 Hz, 1H), 5.77 (qAB, JAB=10.4 Hz, 2H), 3.68 (m, 2H), 2.23 (d, J=7.0 Hz, 3H), 0.95 (m, 2H), −0.03 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 146.4, 134.2, 124.9, 124.7 (q, J=32 Hz), 124.6 (q, J=273 Hz), 121.6, 119.7 (q, J=4.8 Hz), 119.3 (q, J=2.9 Hz), 82.2, 68.1, 43.7, 25.5, 18.0, −1.4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:23]1[CH:24]=[CH:25][C:21]([CH2:20][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=3)[C:4](=[O:18])[CH:3]=2)=[CH:22]1
Reactant: BrCc1ccoc1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 582 mg (2.37 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 10 mL DMF is added 0.76 g (4.74 mmol) 3-bromomethyl-furan and 0.98 g (7.12 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, filtered and is directly transferred to a reverse HPLC for purification (Zorbax stable bond C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4](Cl)=[O:5].[CH3:14][OH:15]>>[CH3:14][O:15][C:4](=[O:5])[C:3]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Cl)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: CO
Product: COC(=O)c1c(Cl)cccc1[N+](=O)[O-]

Procedure:
18.9 gm (86 mmols) of 2-chloro-6-nitro-benzoic acid chloride were added dropwise over a period of 10 minutes to 100 ml of methanol. The reaction mixture was refluxed for 4 hours and then evaporated in vacuo. The residue was treated with a little ice-cold methanol and filtered off.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=O)[O:4]C1=O.[NH3:13]>O1CCCC1>[CH3:1][NH:2][C:7]1[CH:8]=[CH:9][S:10][C:6]=1[C:5]([NH2:13])=[O:4]
Reactant: N
Reactant: Cn1c(=O)oc(=O)c2sccc21
Solvent: C1CCOC1
Product: CNc1ccsc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.60 g (14.2 mmol) 1-Methyl-1H-thieno(3,2-d)(1,3)oxazine-2,4-dione were dissolved in 30 ml tetrahydrofuran and 15.0 ml ammonia (25%) were added at 0° C. The solution was stirred for 30 min at 0° C. and for 30 min at room temperature. THF was distilled under vacuum and the remaining suspension was neutralized with diluted hydrogen chloride acid. The product was isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:10]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: N#CC1CCC1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(c2cc(Cl)nc(Cl)c2)CCC1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirring solution of 2,4,6-trichloropyridine (1.00 g, 5.48 mmol) and cyclobutanecarbonitrile (0.53 mL, 5.5 mmol) in anhydrous THF (27 mL) at −78° C. and under nitrogen was added lithium bis(trimethylsilyl)amide (6.0 mL, 6.0 mmol, 1.0 M solution in THF). The cooling bath was removed and stirring continued for 1 h. The reaction was quenched by the addition of sat. aq. NH4Cl, extracted with CH2Cl2 and organics dried over MgSO4. Following concentration, the reaction residue was purified by flash column chromatography (100:0 heptanes/EtOAc 85:15 heptanes/EtOAc) to afford the title compound as a white solid (0.995 g, 76%); 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 2H), 2.92-2.80 (m, 2H), 2.68-2.40 (m, 3H), 2.23-2.08 (m, 1H).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(OCC1C=C(Cl)N=CN=1)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: Clc1cc(COCc2ccccc2)ncn1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: c1ccc2[nH]ccc2c1

Procedure:
To a solution of 5-hydroxy indole (1.33 g, 10 mmol) and 4-benzyloxymethyl-6-chloro-pyrimidine (2.35 g, 10 mmol) in acetonitrile (20 mL) is added DBU. After 16 h at rt the solution is concentrated under reduced pressure. The residue is purified by FCC (EtOAc/Heptane from 0% to 40%) to give 546-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole. MS (ESI) m/z 447.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2>>[F:25][C:26]1[C:34]([O:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C)CC1
Yield: 69.5 %

Procedure:
Using an analogous procedure to that described in Example 237, 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (106 mg, 0.30 mmol), (prepared as described for the starting material in Example 176), was reacted with 4-fluoro-5-hydroxy-2-methylindole (60 mg, 0.36 mmol), (prepared as described for the starting material in Example 237), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (100 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[C:4]=1[C:5](=[N:7]O)[NH2:6]>CO.ClCCl.C(O)(=O)C.[Ni]>[CH3:16][O:15][C:9]1[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH2:7])=[NH:6]
Reactant: COc1cc(OC)c(C(N)=NO)c(OC)c1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(C(=N)N)c(OC)c1
Reaction time: 2 h

Procedure:
3.4 g of 2,4,6-trimethoxybenzamidoxime are dissolved in 120 ml of a methanol/dichloromethane/acetic acid mixture (2/2/1; (v/v/v)) in an autoclave and hydrogenation is carried out at a pressure of 2×106Pa in the presence of 1 g of Raney nickel. After hydrogenation for 2 hours, the catalyst is separated out and the mixture is concentrated to dryness.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([O:27]CC)=[O:26])[C:17]2=[O:33])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C1SC(N2CCN(CC3C=C(C=CC=3)C(OC)=O)C2=O)=NC=1C)=O)C1C=CC=CC=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:17]2=[O:33])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Agent: COC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Product: Cc1nc(N2CCN(Cc3cccc(C(=O)O)c3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 85 %

Procedure:
Following the procedure as described in Example 25, making variations as required to replace ethyl 3-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate with methyl 3-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate, the title compound was obtained as a colorless solid in 85% yield: mp 143-145° C. (methanol/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.55 (t, J=5.9 Hz, 1H), 7.89-7.87 (m, 2H), 7.58-7.46 (m, 2H), 7.37-7.20 (m, 5H), 4.51 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 4.04-3.98 (m, 2H), 3.50-3.3.45 (m, 2H), 2.47 (s, 3H); MS (ES+) m/z 451.2 (M+1).
Reaction SMILES: O.[OH-].[Li+].C([O:11][C:12]([C:14]1([C:45](=[O:53])[NH:46][N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=[C:30]([C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[C:34]([F:44])[CH:33]=4)[O:29][N:28]=3)=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>O.O1CCCC1>[F:44][C:34]1[CH:33]=[C:32]([C:30]2[O:29][N:28]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([CH2:20][N:17]4[CH2:16][CH2:15][C:14]([C:45](=[O:53])[NH:46][N:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)([C:12]([OH:13])=[O:11])[CH2:19][CH2:18]4)=[CH:22][CH:23]=3)[N:31]=2)[CH:37]=[CH:36][C:35]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(NN1CCCCC1)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)NN2CCCCC2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 70 °C

Procedure:
A solution of lithium hydroxide monohydrate (0.031 g, 0.000735 mol) in demineralized water (2 mL) is added to a solution of 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(piperidine-1-ylcarbamoyl)-piperidine-4-carboxylic acid benzyl ester (0.165 g, 0.000245 mol) in tetrahydrofuran (10 mL). The reaction mixture is heated at 70° C. for 2 hrs. Tetrahydrofuran is removed under reduced pressure and the residue is acidified with 2N HCl (pH ˜5). The solid mass thus formed is filtered and washed with acetone (5 mL) to furnish 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(piperidine-1-ylcarbamoyl)-piperidine-4-carboxylic acid [91, MS (ES+)=584.23].
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]3=[O:25])[C:11]([F:13])=[CH:12][C:7]=2[N:6]=[C:5]1[C:26]([F:29])([F:28])[F:27])[C:2]#[CH:3].[C:30](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:30][N:16]1[C:17]([C:21]([F:22])([F:23])[F:24])=[CH:18][C:19](=[O:20])[N:14]([C:10]2[C:11]([F:13])=[CH:12][C:7]3[N:6]=[C:5]([C:26]([F:27])([F:28])[F:29])[N:4]([CH2:1][C:2]#[CH:3])[C:8]=3[CH:9]=2)[C:15]1=[O:25]
Reactant: C#CCn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C#CCn1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 69.1 %

Procedure:
A solution of 0.6 gram (0.001 mole) of 3-[1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil, 0.4 gram (0.003 mole) of potassium carbonate, and 0.17 mL (0.003 mole) of methyl iodide in 30 mL of acetone was stirred at ambient temperature for about 18 hours, after which the reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in diethyl ether and washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to an oily residue, which was subjected to column chromatography on silica gel. Elution was accomplished using 1:3 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of 1-methyl-3-[1-(2-propyn-1-yl)-2-trifluoromethyl-5-fluorobenzimidazol-6-yl]-6-trifluoromethyluracil, mp 104°-105° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(C1C=C(B(O)O)C=CC=1)(=O)C>>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: OB(O)c1ccncc1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: CC(=O)c1cccc(B(O)O)c1
Product: O=C(NC1CC1)c1cn(-c2cccc(-c3ccncc3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of Step 5 of Example 1 but substituting N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and 4-pyridineboronic acid for 3-acetylphenylboronic acid the title compound was obtained as a white solid.