Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[B:10](OC)([O:13]C)[O:11]C.Cl>C1COCC1.[Cl-].[Na+].O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([B:10]([OH:13])[OH:11])[CH:9]=[CH:8][CH:7]=1
Reactant: COB(OC)OC
Reactant: OCc1cccc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3-Bromobenzyl alcohol (2.0 g, 10.7 mmol) was dissolved in dry THF (50 ml) in a dry 100 ml flask flushed with nitrogen. The mixture was chilled in a dry ice/acetone bath. n-Butyl lithium (11 ml of a 2.13M solution in hexane, 23.5 mmol) was added. The reaction was warmed to room temperature for 1 hour, then cooled in an ice water bath. Trimethyl borate (1.3 ml, 11.2 mmol) was added and the mixture was stirred at room temperature overnight, then treated with 2N aqueous HCl to pH 2, and stirred for 3 hours. Brine (15 ml) was added, and the mixture was extracted with ethyl acetate (3×15 ml). The organic materials were combined, dried (MgSO4) then concentrated under reduced pressure which gave of 3-hydroxymethylbenzeneboronic acid (98%) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH3:12])[C:9](=O)[CH2:8][CH2:7]2.S([O-])([O-])(=O)=O.[Mg+2].[CH2:20]([NH2:23])[CH2:21][CH3:22]>ClCCl>[CH3:12][CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Br:1])[CH2:7][CH2:8][C:9]1=[N:23][CH2:20][CH2:21][CH3:22]
Reactant: CCCN
Reactant: CC1C(=O)CCc2cccc(Br)c21
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCCN=C1CCc2cccc(Br)c2C1C
Temperature: 25 °C

Procedure:
To a solution of 8-bromo-1-methyl-2-tetralone (4.05 gm, 16.9 mMol) in dichloromethane (60 mL) were added magnesium sulfate (3.0 gm, 25 mMol) and n-propylamine (2.0 mL, 24.4 mMol). The mixture was stirred at room temperature for twenty hours. The reaction mixture was filtered through a bed of celite and the filtrate concentrated in vacuo to give 1-methyl-2-n-propylimino-8-bromo-1,2,3,4-tetrahydronaphthalene as a dark residue.
Reaction SMILES: [CH3:1][CH:2]([Si:4]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[O:5]/[C:6](/C)=[CH:7]/[CH2:8]O)[CH3:3].[CH3:17][C:18](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:19].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl.CCOCC>[CH3:16][CH:14]([Si:4]([CH:2]([CH3:1])[CH3:3])([CH:11]([CH3:12])[CH3:13])[O:5][CH2:6]/[C:7](/[CH3:8])=[CH:17]/[CH:18]=[O:19])[CH3:15]
Reactant: C/C(=C\CO)O[Si](C(C)C)(C(C)C)C(C)C
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C/C(=C\C=O)CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a room temperature solution of (E)-3-[tris-(1-methylethyl)silyloxy]but-2-en-1-ol (crude from the previous step, assumed 17.6 mmol) in dichloromethane (100 mL) was added Dess-Martin periodinane (9.7 g, 22.9 mmol). The resulting suspension was stirred for 60 minutes, until the reaction was judged to be complete by TLC. The reaction mixture was diluted with Et2O and a saturated aqueous solution of NaHCO3 containing Na2S2O3 was added. This mixture was stirred vigorously until both layers became clear. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (5% Et2O/pentane) to afford the title compound as a colorless oil (3.69 g, 82% yield). IR (film) 2944, 2867, 1681, 1464, 1384, 1123 cm−1; 1H NMR (300 MHz, CDCl3) δ 10.09 (d, 1H, J=8.3 Hz, CHO), 6.28 (dd, 1H, J=1.5, 8.4 Hz, CH), 4.28 (d, 2H, J=0.9 Hz, CH2OTIPS), 2.09 (d, 3H, J=0.6 Hz, CH3C), 1.1 to 1.0 (m, 21H, TIPSO); 13C NMR 75 MHz, CDCl3) δ 191.2, 161.6, 124.1, 67.0, 18.0, 14.1, 11.9; HRMS (EI+) exact mass calculated for [M]+(C14H28O2Si) requires m/z 256.1859, found m/z 256.1862.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6]O.[O:8]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][C:11]#[N:12].[OH-].[Na+].Cl>O.CCO>[C:13]1([C:9]2[O:8][N:12]=[C:11]([NH2:6])[CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NO
Reactant: N#CCC(=O)c1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2)on1
Temperature: 25 °C

Procedure:
Hydroxylamine sulfate (2.5 g, 30.3 mmol) is added to a stirred solution of 3-oxo-3-phenylpropanenitrile (4 g, 27.6 mmol) and NaOH (1.27 g, 31.7 mmol) in H2O (25 mL)/EtOH (25 mL). The mixture is stirred at rt and then heated to 80° C. for 22 h. At this point, conc. HCl (3.39 ml, 41.3 mmol) is added and the mixture heated at 80° C. for an additional 2 h. It is then basified to pH 10 and extracted with EtOAc to give 5-phenyl-isoxazol-3-ylamine. MS (ESI) m/z 161.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[C:19]([O:25]C(C)C)=[CH:18][C:17]=2[CH3:29])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].B(Br)(Br)Br.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:41][C:42]([NH2:44])=[O:43].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([CH:22]([CH3:23])[CH3:24])[C:19]([O:25][CH2:41][C:42](=[O:43])[NH2:44])=[CH:18][C:17]=2[CH3:29])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C(C)C)c(OC(C)C)cc1C
Reactant: NC(=O)CI
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C(C)C)c(OCC(N)=O)cc1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
The ethyl (RS)-(4-cyano-phenylamino)-(4-isopropoxy-5-isopropyl-2-methyl-phenyl)-acetate (921 mg, 2.34 mmol) obtained in Example 254.2 was dissolved in CH2Cl2 and cooled to −78° C. A 1M solution of BBr3 in CH2Cl2 (9.4 ml, 9.4 mmol) was slowly added dropwise. After 15 min. the reaction mixture was left to warm to 0° C. and was stirred for 1.5 h. at 0° C. Ice-water (30 ml) was added and the mixture was stirred for 10 min. at 0° C. The organic phase was separated and the aqueous phase was extracted with CH2Cl2. The organic phase was dried, filtered and concentrated. The crude product was dissolved in acetone, Cs2CO3 (918 mg, 2.76 mmol) and iodoacetamide (447 mg, 2.41 mmol) were added and the mixture was stirred for 6 h. at room temperature. A dilute aqueous solution of KHSO4 was added and the mixture was extracted with CH2Cl2. The organic phase was dried, filtered and concentrated, and the residue was purified by chromatography (SiO2, hexane/EtOAc 1:1=>1:2). There were obtained 704 mg, (73%) of ethyl (RS)-(4-cyano-phenylamino)-(4-carbamoylmethoxy-5-isopropyl-2-methyl-phenyl)-acetate as a colorless foam.
Reaction SMILES: [BH4-].[Na+].[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[CH2:5][CH2:4]1>CO>[OH:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)[CH:9]=1
Reactant: O=Cc1cccc(OCC2CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(OCC2CC2)c1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Sodium borohydride (0.75 g, 20 mmol) was added in portions to a stirred solution of 3-(cyclopropylmethoxy)benzaldehyde (Lit: Chem. Pharm. Bull. 1975, 23, 2878) (3.5 g, 20 mmol) in methanol (80 mL). The mixture was stirred for 2 h and then quenched with water (300 mL). The product was extracted with ethyl acetate (3×150 mL) and then the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to leave 3.2 g (89%) of crude product. This material was used in the next reaction without further purification or analysis.
Reaction SMILES: I[CH2:2]CI.ICI.[Cl:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][CH:14]2[C:18](=[O:19])[CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]2[C:18]3([O:19][CH2:2]3)[CH:17]([C:20]([F:21])([F:22])[F:23])[CH2:16][CH2:15]2)=[CH:24][CH:25]=1
Reactant: O=C1C(Cc2ccc(Cl)cc2)CCC1C(F)(F)F
Reactant: ICCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ICI
Product: FC(F)(F)C1CCC(Cc2ccc(Cl)cc2)C12CO2
Reaction time: 2 h

Procedure:
Under nitrogen flow, anhydrous THF (1 ml) was combined with Sm (705 mg, 4.7 mmol), and a solution of 1,2-diiodoethane (662 mg, 2.3 mmol) dissolved in anhydrous THF (2 ml) was added dropwise with stirring. The reaction solution was stirred for 30 minutes at room temperature. Thereafter, while cooling with ice, a solution of diiodomethane (723 mg, 2.7 mmol) and 5-(4-chlorobenzyl)-2-trifluoromethylcyclopentanone (Compound (V), (Ra)Xana=H, (Rb)Xbnb=CF3, Ym=4-Cl) (432 mg, 1.6 mmol) dissolved in anhydrous THF (2 ml) was added dropwise, and stirring was continued for 2 hours at room temperature. The reaction solution was poured into a solution mixture of an aqueous solution of NaOH (NaOH (1.1 g) dissolved in 10 ml of water) and THF (10 ml), and stirring was continued for 30 minutes at room temperature. This reaction solution was combined with ice, neutralized with a 1N aqueous solution of hydrochloric acid, and then extracted with hexane. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. Silica gel chromatography (eluent; hexane: ethyl acetate=70:1) was conducted for purification to obtain the desired substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[S:29](Cl)(=[O:31])=[O:30].C(Cl)Cl>CN(C)C=O>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[S:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(NS(=O)(=O)c2c(Cl)cccc2Cl)ccc1Oc1cncc(Cl)c1
Yield: 14 %

Procedure:
The title compound was prepared using the procedure described in Example 3, beginning with 0.1 g of the aniline of Example 1 and 2,6-dichlorobenzenesulfonyl chloride and using dimethylformamide as solvent in place of CH2Cl2. After workup, 0.024 g (14%) of the title sulfonamide was obtained
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:22]1(C)C=CC(S(OCC)(=O)=O)=C[CH:23]=1>C(O)C>[CH2:22]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1)[CH3:23]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1ccc2c(c1)ccn2C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CCC(n2ccc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-piperidin-4-yl-1H-indole (0.6 g, 3 mmol) in 5 mL of dry ethanol was added anhydrous potassium carbonate (680 mg, 4.9 mmol). After stirring for 15 minutes at ambient temperature, ethyl p-toluenesulfonate (0.48 mL, 4.5 mmol) was added. The reaction was heated under reflux for 24 hours with stirring, quenched with water, extracted with methylene chloride (2×), dried and evaporated to give a residue. The residue was chromatographed on silica gel with toluene/acetone (50:50) to yield 360 mg straw colored material (53% of theory).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C(Cl)(=O)C([Cl:29])=O>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([Cl:29])=[O:25])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCCCC(=O)O
Product: CCOCc1nc2cnc3cccnc3c2n1CCCCCC(=O)Cl

Procedure:
The method described in Part D of Example 53 was used to treat 6-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]hexanoic acid (3.23 g, 9.4 mmol) with oxalyl chloride (3.29 mL, 37.7 mmol) to obtain 6-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]hexanoyl chloride. The reaction was complete in two hours.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>CS(C)=O>[N+:27]([C:18]1[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:17]=1[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])sc2ccccc12
Yield: 129.4 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (5.0 g), 4-fluoro-3-nitrobenzotrifluoride (5.1 g) and dimethyl sulfoxide (65 ml), ethyl 2-(2-nitro-4-trifluoromethylanilino)benzo[b]thiophene-3-carboxylate (12 g) was obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (50 ml), 18% hydrochloric acid (50 ml) and tin(II) chloride-dihydrate (10.9 g), ethyl 2-(2-amino-4-trifluoromethylanilino)benzo[b]thiophene-3-carboxylate (2.8 g) was obtained.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:20]=[C:21]([C:24](Cl)=[O:25])[S:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(Cl)Cl.[OH:30][CH:31]([CH2:36][CH3:37])[C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C>CCOCC>[CH2:2]([NH:18][C:19]1[CH:20]=[C:21]([C:24]([O:30][CH:31]([C:32]([O:34][CH3:35])=[O:33])[CH2:36][CH3:37])=[O:25])[S:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCC(O)C(=O)OC
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OC(CC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10 g. of 4-hexadecylamino-2-thiophenecarbonyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several protions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 4-(hexadecylamino)-2-thiophenecarboxylate as a white solid.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C@H:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]3[CH2:36][CH2:35][O:34][C:33]3=[O:37])=[CH:30][C:25]=2[CH2:24][CH2:23][O:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:18][CH2:19][CH2:20][C@H:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][N:32]3[CH2:36][CH2:35][O:34][C:33]3=[O:37])=[CH:30][C:25]=2[CH2:24][CH2:23][O:22]1
Reactant: CC(C)(C)[Si](OCC[C@@H]1OCCc2cc(CN3CCOC3=O)ccc21)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1OCCN1Cc1ccc2c(c1)CCO[C@H]2CCO
Temperature: 25 °C

Procedure:
To a stirred solution of 3-{[(1S)-1-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]methyl}-1,3-oxazolidin-2-one (0.22 g, 0.43 mmol) in dry THF (30 ml) was added tetrabutylammonium fluoride (1M solution in THF) (0.51 mL, 0.51 mmol) and the reaction stirred at room temperature under nitrogen over the weekend. The reaction was quenched by addition of water and extracted with dichloromethane. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluting with methanol/dichloromethane (1:9), to yield the title compound as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[CH:24]([C:28](=O)[CH3:29])[CH2:25][C:26]#[N:27]>C(#N)C>[CH2:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:24]([CH2:25][C:26]#[N:27])=[C:28]([CH3:29])[N:1]=2)[CH:4]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)C(Cl)CC#N
Reactant: Nc1ccc(NCc2ccccc2)cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(NCc3ccccc3)cn2c1CC#N

Procedure:
A mixture of 2-amino-5-benzylamino pyridine (4.0 g), triethylamine (2.1 g),3-chloro-4-oxopentanenitrile (2.7 g) and acetonitrile (50 ml) is stirred and heated under reflux for 18 hr. The solvent is removed in vacuo, and the residue is dissolved in chloroform (200 ml). The solution is washed with water (4×100 ml), dried over anhydrous potassium carbonate and the chloroform is removed in vacuo. The residue is chromatographed on silica gel (200 g) using chloroform as the eluant. The product is obtainedand crystallized from acetonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:11](=[NH:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:11](=[N:24][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1cc(N=C(c2ccccc2)c2ccccc2)ccc1F
Temperature: 25 °C
Yield: 103.9 %

Procedure:
Add 5-bromo-2-fluoro-benzonitrile (0.5 g, 2.5 mmol), benzophenone imine (0.543 g, 3 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 60 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 50 mg, 0.05 mmol], and Cs2CO3 (1.6 g, 4.9 mmol) in 1,4-dioxane (20 mL). Stir the reaction under N2 at 110° C. for 16 hrs. Cool to room temperature, filter the solid, and concentrate the filtrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:3) affords the title compound (0.78 g, 99%). MS: (M+1): 301.
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[O:14]=[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=2)[N:16]1[CH2:29][C:30](O)=[O:31]>>[C:7]([C:4]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[C:2]([NH:1][C:30](=[O:31])[CH2:29][N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:25]([F:26])([F:28])[F:27])=[CH:19][CH:18]=3)[CH:23]=[CH:24][C:15]2=[O:14])[S:6][CH:5]=1)#[N:8]
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: N#Cc1csc(N)c1-c1nccs1
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-c1nccs1

Procedure:
The title compound was prepared from 5-amino-4-(thiazol-2-yl)thiophene-3-carbonitrile (271 mg, 1 mmol) and 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.76 mmol) according to protocol A. The crude product was purified by column chromatography (35% EtOAc/hexanes) and HPLC to give N-(4-cyano-3-(thiazol-2-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide (24.mg) as a white solid with an m/z of 461.1 and retention of 7.348 min using the [7] LCMS method. 1H-NMR (300 MHz, CDCl3) δ 13.21 (s, 1H), 7.93 (m, 2H), 7.86 (dd, J=8.9, 1.8 Hz, 1H), 7.58 (s, 1H), 7.54 (d, J=3.4 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.31 (d, J=3.3 Hz, 1H), 7.00 (d, J=9.6 Hz, 1H), 5.35 (s, 2H). 13C-NMR (75 MHz, CDCl3) δ 165.3, 161.7, 161.0, 140.8, 140.0, 139.9, 129.4, 128.0, 126.5, 122.7, 120.4, 117.8, 115.9, 115.0, 114.7, 106.0, 46.3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(Cl)[Cl:11]>>[Cl:11][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCl
Product: O=Cc1ccc(O)c(Cl)c1
Reaction time: 14 h
Yield: 79.8 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (5.0 g, 40.0 mmol) in DCM (50 mL) SOCl2 (3.30 mL, 40.0 mmol) was added slowly at 0° C. After the addition was completed, the reaction mixture was brought to RT and stirred for 14 h. The reaction mixture was then quenched with water (50 mL), neutralized with a saturated NaHCO3 solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography to afford 3-chloro-4-hydroxybenzaldehyde (5.0 g, 77%) as a brown solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=2)=[O:8])=[CH:5][C:4]=1[O:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])[CH2:34][CH2:33]1.[C:46]1([CH:52](Cl)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:46]1([CH:52]([NH:2][C:3]2[CH:27]=[CH:26][C:6]([C:7]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:10]=3)=[O:8])=[CH:5][C:4]=2[O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[CH2:34][CH2:33]2)[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(N)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(NC(c3ccccc3)c3ccccc3)c(OCCCN3CCN(c4ccccc4OC)CC3)c2)c2ccccc21
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Ethyl 4-{3-{4-amino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate hydrochloride (2.0 g) was dissolved in N,N-dimethylformamide (10 ml), and diphenylmethyl chloride (1.2 ml) and potassium carbonate (1.3 g) were added to the solution. The mixture was stirred at 90° C. for five hours. The reaction mixture was cooled and diluted with ethyl acetate (200 ml). The resultant mixture was sequentially washed with water and saturated brine, and dried and evaporated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby obtain 1.13 g of ethyl 4-{3-{4-diphenylmethylamino-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])=[CH:12]2.CN(C)C=O.ClCCl.Cl>C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:22](=[O:23])[CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=3)=[O:19])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
4-Hydroxypiperidine (0.83 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (0.8 mmol) were coupled according to procedure A (dimethylformamide- dichloromethane reaction solvent) with the following workup: the reaction mixture was stirred with ethyl acetate and aqueous 2N HCl, the resulting suspension filtered and the collected solid washed successively with aqueous 2N HCl, aqueous 2N NaOH, ether and dried : Yield 180 mg, 68%; TSPMS 336/338 (MH+, 100%);