Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH:9]1[NH:13][C:12](=[O:14])[CH:11]=[CH:10]1)[CH3:7].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.O1CCCC1>[C:15]1([S:21]([N:13]2[CH:9]([O:8][CH2:6][CH3:7])[CH:10]=[CH:11][C:12]2=[O:14])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC1C=CC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC1C=CC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -35 °C
Reaction time: 0.33 h
Yield: 36.5 %

Procedure:
7.37 cm3 of a 1.6M solution of n-butyllithium in n-hexane is added to a solution of 1.5 g of 1,5-dihydro-5-ethoxy-2H-pyrrol-2-one in 40 cm3 of tetrahydrofuran cooled to -35° C., operating at -35°/-30° C. The mixture is agitated for 20 minutes, then cooled to -40° C., and while maintaining the temperature between -38° C. and -40° C., a solution is added of 2.08 g of benzene sulphonyl chloride in 10 cm3 of tetrahydrofuran. The temperature is allowed to return to the ambient, the solvent is evaporated under reduced pressure, and the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane, 1--1). 1.15 g of the expected product is obtained. m.p. 117°-119° C., crystallized from ethyl ether.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[CH:14]1[C:19]([CH2:20][CH2:21]O)=[CH:18][C:17]([OH:23])=[C:16]([OH:24])[CH:15]=1.C1C(CCO)=CC=C(O)C=1.OC1C=C(CCC2C(O)=C(O)C=CC=2/C=C/C([O-])=O)C=CC=1O>>[C:1]([O:13][CH2:21][CH2:20][C:19]1[CH:14]=[CH:15][C:16]([OH:24])=[C:17]([OH:23])[CH:18]=1)(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: OCCc1ccc(O)c(O)c1
Agent: O=C([O-])/C=C/c1ccc(O)c(O)c1CCc1ccc(O)c(O)c1
Agent: OCCc1ccc(O)cc1
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccc(O)c(O)c1

Procedure:
The protocol derived from Example 14 above is applied with caffeic acid and 3-hydroxytyrosol instead of caffeic acid and tyrosol; the compound obtained is 2-(3,4-dihydroxyphenylethyl)trans-caffeoate (formula IVb2).
Reaction SMILES: Br[CH2:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]([CH:31]1[CH2:34][NH:33][CH2:32]1)=[O:30].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:27][O:28][C:29]([CH:31]1[CH2:34][N:33]([CH2:2][C:3]2[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=3)=[CH:5][CH:4]=2)[CH2:32]1)=[O:30]
Reactant: COC(=O)C1CNC1
Reactant: FC(F)(F)c1cc(SCc2ccc(CBr)cc2)ccc1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(CSc3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4-bromomethyl-benzylsulfanyl)-2-trifluoromethyl-biphenyl (185 mg, 0.4230 mmol, 1 eq.) in anhydrous DCM (7 mL) is added azetidine-3-carboxylic acid methyl ester (HCl salt, 96 mg, 0.6345 mmol, 1.5 eq.) and DIEA (0.74 mL, 4.230 mmol, 10 eq.). The mixture is stirred at room temperature for 3 h. The reaction mixture is applied directly to silica gel chromatography (gradient from 5:1 hexanes/EtOAc to 1:2 hexanes/EtOAc) to give 1-[4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzyl]-azetidine-3-carboxylic acid methyl ester.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:32]=[CH:31][CH:30]=[CH:29][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([C:26]#[N:27])[CH3:25])=[CH:19][C:18]=3[F:28])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Sn](=O)CCCC)CCC.C[Si]([N:47]=[N+:48]=[N-:49])(C)C>C1(C)C=CC=CC=1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:32]=[CH:31][CH:30]=[CH:29][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([C:26]4[NH:49][N:48]=[N:47][N:27]=4)[CH3:25])=[CH:19][C:18]=3[F:28])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C#N)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)c1nnn[nH]1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
A solution of (±)-2-(benzo[1,3]dioxol-5-yloxy)-N-[4-(1-cyano-ethoxy)-2-fluoro-benzyl]-nicotinamide (1.5 g, 3.5 mmol) in anhydrous toluene (5 mL) was transferred to a small pressure flask. Dibutyltin oxide (0.53 g, 2.1 mmol) and trimethylsilyl azide (1.7 mL, 21 mmol) were added. The tube was sealed and placed behind a blast shield. The reaction was stirred 15 min at 55° C., then warmed to 110° C. with stirring over night. The black reaction mix was cooled to 0–5° C., the pressure flask opened, and the residue taken up in methanol. Solvents were removed in vacuo and the residue taken up in ethyl acetate. The organic solution was washed twice with saturated aqueous sodium carbonate. The aqueous phases were pooled and acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The pooled organic phases were dried (MgSO4), concentrated, and loaded onto a silica gel column as a brown oil. Purification by column chromatography (5% methanol/dichloromethane) afforded product as a white solid (0.46 g, 28%).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH:4]([C:7]([O-:9])=O)[CH2:3][CH2:2]1.[NH2:17][CH:18]([CH3:28])[C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=O>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:9][C:7]([CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)=[N:17][C:18]=2[CH3:28])=[CH:26][CH:25]=1
Reactant: CC(N)C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Product: Cc1nc(C2CCNCC2)oc1-c1ccc(Cl)cc1

Procedure:
Starting from mono-tert-butyl piperidine-1,4-dicarboxylate and 2-amino-1-(4-chlorophenyl)-propane-1-one (see J. Med. Chem. 1974, 416) (V-27) may be prepared analogously to (V-26) (see 73.1 and 73.2). Analytical HPLC-MS (method B): RT=1.30 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1.[Na]>CN(C)C=O>[Br:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: CN1CCN(C(=O)c2ccc(Cl)nc2)CC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reaction time: 18 h
Yield: 26 %

Procedure:
To a solution of (6-Chloro-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (2.00 g, 7.46 mmol) in 10 mL dimethylformamide was added 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (1.80 g, 8.95 mmol) and sodium hydiride (537 mg, 22.4 mmol). After stirring for 18 hours, this was quenched with water. This was extracted with ethylacetate. The ethylacetate layer was dired over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 0 to 5% methanol/dichloromethane) to yield 5-Bromo-1-methyl-3-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (900 mg, 1.94 mmol). MS (ESI) 406.0 (M+H)+.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][O:5][CH:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:3]1.CC1CCOC(C2C=CC(OC)=CC=2)C=1>>[CH3:1][C:2]1[CH2:3][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[O:5][CH2:6][CH:7]=1
Reactant: C=C1CCOC(c2ccc(OC)cc2)C1
Agent: COc1ccc(C2C=C(C)CCO2)cc1
Product: COc1ccc(C2CC(C)=CCO2)cc1
Yield: 35 %

Procedure:
The method of claim 5 wherein the mixture of 3-10% tetrahydro-4-methylene-2-(4-methoxyphenyl)-2H-pyran, 35-55% 5,6-dihydro-4-methyl-2-(4-methoxyphenyl)-2H-pyran, and 35-55% 3,6-dihydro-4-methyl-2-(4-methoxyphenyl)-2H-pyran is provided at a level of from about from about 0.1 to about 50 of the fragrance composition.
Reaction SMILES: [BH4-].[Na+].Br[CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:19](=[O:20])[C:14]3[N:15]=[C:16]([CH3:18])[S:17][C:13]=3[CH:12]=[CH:11][C:10]=2[CH:21]=1)[CH3:5]>O1CCOCC1.CS(C)=O>[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]2[CH:19]([OH:20])[C:14]3[N:15]=[C:16]([CH3:18])[S:17][C:13]=3[CH:12]=[CH:11][C:10]=2[CH:21]=1)[CH3:5]
Reactant: Cc1nc2c(=O)c3ccc(C(C)Br)cc3ccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2O

Procedure:
A solution of sodium borohydride (0.31 g) and the product from step (x) (1.35 g) in 1,4-dioxan (40 ml) and dimethyl sulphoxide (10 ml) was stirred at room temperature for 18 hours. The reaction was quenched with water (4 ml) before solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate which was washed with saturated aqueous sodium bicarbonate and saturated brine. The organic phase was collected, dried (MgSO4) and evaporation of solvent under reduced pressure gave a yellow oil which was purified by chromatography, eluting with 20% isohexane in ethyl acetate.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]3)[C:10]2=[O:24])=[C:6]([F:27])[CH:5]=1.[C:28]([O:34][CH2:35]Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].Cl>CS(C)=O.O>[Br:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21](=[O:22])[N:20]([CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:19](=[O:23])[NH:18]3)[C:10]2=[O:24])=[C:6]([F:27])[CH:5]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C(=O)OCN1C(=O)NC2(C1=O)C(=O)N(Cc1ccc(Br)cc1F)c1ccccc12
Reaction time: 0.08 h

Procedure:
Ethanolic potassium hydroxide solution (1 M; 5.2 ml) was added to a solution of 1'-(4-bromo-2-fluorobenzyl)-spiro-[imidazolidine-4,3'-indoline]-2,2',5-trione (2.0 g.) in dimethyl sulphoxide (10 ml.). The solution was stirred for 5 minutes and then chloromethyl pivalate (0.75 g.) was slowly added. After the addition was completed, the reaction mixture was further stirred for 16 hours; and then poured into water (100 ml.). The aqueous mixture was carefully acidified (concentrated hydrochloric acid). The precipitate which formed was washed with water, air dried and recrystallised twice from 2-propanol to give 1'-(4-bromo-2-fluorobenzyl)-1-(pivaloyloxymethyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, as a white solid (0.75 g.), m.p. 220°-222° C.
Reaction SMILES: [CH3:1]COCC.[Li]C.[Br:8][C:9]1[CH:20]=[CH:19][C:12]([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1>C1COCC1.[Cu]I>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([CH3:1])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1
Reactant: COC(=O)C=Cc1ccc(Br)cc1
Reactant: CCOCC
Agent: [Cu]I
Agent: [Li]C
Solvent: C1CCOC1
Product: COC(=O)CC(C)c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
A flask under nitrogen atmosphere was charged with CuI (2.77 g, 14.54 mmol) and ether (50 mL). The slurry was cooled to 0 C in an ice-water bath before a solution of MeLi in THF (1.6M, 18.2 mL, 29.1 mmol) was added dropwise over 20 minutes. A clear solution formed. A solution of methyl 4-bromocinnamate (3.19 g, 13.2 mmol) in THF (30 mL) was added dropwise via syringe over 30 minutes, and the resulting reaction mixture was stirred at 0 C for 2 hours. Then the reaction was quenched with ammonium chloride and worked up. The resulting crude product was purified by MPLC (0 to 15% ethyl acetate in hexanes) to afford methyl 3-(4-bromophenyl)butanoate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11]([NH:12][C:13](=[O:21])[CH2:14][CH2:15]1)=[CH:10][C:9]3=[O:22].C([N-]C(C)C)(C)C.[Li+].[CH3:31][Si:32](Cl)([CH3:34])[CH3:33]>C1COCC1>[CH3:31][Si:32]([CH3:34])([CH3:33])[O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11]([N:12]([Si:32]([CH3:34])([CH3:33])[CH3:31])[C:13](=[O:21])[CH2:14][CH2:15]1)=[CH:10][C:9]3=[O:22]
Reactant: C[C@]12CC[C@H]3[C@@H](C(=O)C=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](C(=O)C=C4N([Si](C)(C)C)C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
17β-Hydroxy-4-aza-androst-5-ene-3,7-dione (40.000 g, 131.84 mmol) prepared in Example 18A or otherwise obtained is prepared in solution at −78° C. in dry THF (300 mL). Lithium diisopropylamide solution (2.0 M in heptane/THF/ethylbenzene; 135.0 mL, 270.0 mmol) is added under an inert atmosphere and the deprotonation reaction occurs while stirring at −78° C. over 60 minutes. Trimethylsilyl chloride (35.00 mL, 275.8 mmol) is added, and stirring is continued for an additional 15 minutes and then the solution is allowed to warm to room temperature. After stirring an additional 2 hours, the reaction mixture is filtered through Celite® and the filtrate is evaporated to dryness. The residue is redissolved in ether (500 mL) and the resultant slurry is filtered again through Celite®. The solvent is evaporated to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[O:12]=[C:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]2[C:8](=[N:9][CH:10]=[CH:11][C:2]=2[C:24]2[CH:25]=[CH:26][C:21]([S:18]([NH2:17])(=[O:20])=[O:19])=[CH:22][CH:23]=2)[NH:7]1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: NS(=O)(=O)c1ccc(-c2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Yield: 1.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 171 using Compound 83 (100 mg, 0.43 mmol) and 4-(aminosulphonyl)benzeneboronic acid (174 mg, 0.87 mmol) to provide 177 (2 mg, 2% yield) as a grey solid. LC-MS (M+H=352, obsd.=352).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]([CH3:15])([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].Br[C:23]#[N:24]>C1COCC1.CCOC(C)=O>[CH3:14][C:6]([CH3:15])([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][CH:2]1[CH2:3][O:4][C:23]([NH2:24])=[N:1]1
Reactant: N#CBr
Reactant: CC(C)(Cc1ccccc1)CC(N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccccc1)CC1COC(N)=N1
Reaction time: 17 h
Yield: 54.3 %

Procedure:
To a stirred solution of (RS)-2-amino-4,4-dimethyl-5-phenyl-pentan-1-ol (0.97 g) at r.t. in THF (15 ml) under an argon atmosphere were added K2CO3 (0.78 g) and a solution of BrCN (0.59 g) in THF (10 ml). The mixture was stirred for 17 h. The suspension was diluted with EtOAc and washed with H2O. The aqueous phase was back-extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on Isolute® Flash-NH2 silica gel from Separtis (gradient: cyclohexane ->CH2Cl2->CH2Cl2/MeOH 9:1) to give (RS)-4-(2,2-dimethyl-3-phenylpropyl)-4,5-dihydro-oxazol-2-ylamine (0.59 g) as an off-white sticky solid. MS (ISP): 233.2 ([M+H]+))
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:13]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]([CH3:28])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:25][CH:26]([N:22]1[CH2:23][CH2:24][CH:19]([N:14]2[CH:15]=[CH:16][C:17](=[O:18])[C:12]([C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[CH:9][CH:10]=3)=[N:13]2)[CH2:20][CH2:21]1)[CH3:28]
Reactant: CC(C)=O
Reactant: O=c1ccn(C2CCNCC2)nc1-c1ccnn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCC(n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1-Phenyl-1H-pyrazol-5-yl)-1-piperidin-4-ylpyridazin-4(1H)-one (0.20 g), acetone (0.23 mL) and acetic acid (1.0 mL) were dissolved in THF (10 mL), sodium triacetoxyborohydride (0.66 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and neutralized with saturated sodium hydrogen carbonate. Sodium chloride was added to saturation, and the mixture was extracted with ethyl acetate/THF. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, THF) and recrystallized from ethyl acetate/hexane to give the title compound (0.15 g).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1B(O)O)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: COc1cc(OC)c(C=O)cc1Br
Product: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Yield: 79 %

Procedure:
Ex-32A: 2-(5-Formyl-2,4-dimethoxyphenyl)indole-l-carboxylic acid tert-butyl ester was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and N-Boc-indole-2-boronic acid in a similar manner as Ex-1A, 79% yield, yellow oil. 1H-NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.15 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.45 (d, J=8 Hz, 3H), 7.27–7.35 (m, 1H), 7.19–7.27 (m, 1H), 6.52 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][N:20]4[CH:24]=[C:23]([C@:25]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:26][CH3:27])[N:22]=[N:21]4)=[CH:16][CH:17]=3)[N:12]=[C:11]([C:33]#[N:34])[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=[O:36].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][N:20]4[CH:24]=[C:23]([C@:25]([OH:32])([C:28]([F:31])([F:29])[F:30])[CH2:26][CH3:27])[N:22]=[N:21]4)=[CH:16][CH:17]=3)[N:12]=[C:11]([C:33]([NH2:34])=[O:36])[CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4cc(Cl)cc(Cl)c4)cc(C#N)nc3c2)nn1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4cc(Cl)cc(Cl)c4)cc(C(N)=O)nc3c2)nn1)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of (S)-4-(3,5-dichlorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carbonitrile (30 mg, 0.059 mmol) in acetone (1.5 mL) and water (1 mL) was added sodium percarbonate (28 mg, 0.18 mmol). After 1.5 h at 50° C., the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 524 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16](Cl)=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>CS(C)=O.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(-c2ccnc(OCc3ccccc3)c2)c(Cl)n1
Reactant: COCCN
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCNc1nc(C(F)(F)F)ccc1-c1ccnc(OCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
-(2-(Benzyloxy)pyridin-4-yl)-N-(2-methoxyethyl)-6-(trifluoromethyl)-pyridin-2-amine. To a 2.5-mL microwave vial was added 3-(2-(benzyloxy)-pyridin-4-yl)-2-chloro-6-(trifluoromethyl)pyridine (0.50 g, 1.37 mmol) and 2-methoxyethylamine (0.59 g, 6.58 mmol, Fluka) in 2 mL of DMSO. The vial was sealed and left to stir at 40° C. for 3 d and then heated at 120° C. for 5 h. The reaction mixture was allowed to cool to room temperature and was diluted with EtOAc (20 mL). The organic layer was washed with saturated NaCl (2×30 mL), dried over Na2SO4, filtered, and concentrated to afford a yellow oil. The crude material was purified by normal phase column chromatography (gradient: 5%-20% EtOAc/Hexanes) to give 3-(2-(benzyloxy)pyridin-4-yl)-N-(2-methoxyethyl)-6-(trifluoromethyl)pyridin-2-amine as a clear oil [MS (ESI, pos. ion) m/z: 404 (M+1)].
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:22][C:23]1[C:24](=[O:30])[NH:25][C:26](=[O:29])[NH:27][CH:28]=1.N1C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18]([N:27]2[CH:28]=[C:23]([F:22])[C:24](=[O:30])[NH:25][C:26]2=[O:29])=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3cc(F)c(=O)[nH]c3=O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (75 mg, 0.25 mmol), 5-fluorouracil (75 mg, 0.58 mmol), and 0.5 mL of pyridine in 2.0 mL of THF was stirred at room temperature for 1 h and filtered. The solid was then washed with THF, acetone, methanol, and ether to give 34 mg (36%) of 1-{3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl}-5-fluoro-1H-pyrimidine-2,4-dione as a light yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 12.22 (d, J=4.69 Hz, 1H, CONHCO), 12.19 (s, br, 1H, NH-1′), 8.33 (d, J=6.64 Hz, 1H, H-6″), 7.92-7.94 (m, 1H, H-4), 7.74-7.76 (m, 1H, H-7), 7.71 (s, 1H, H-vinyl), 7.26-7.29 (m, 2H, H-5, 6), 6.16 (s, br, 1H, H-4′), 2.47 (s, 3H, CH3), and 2.35 (s, 3H, CH3).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=[CH:10][C:2]1=2.[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:10]1[C:2]2[O:1][CH2:6][CH2:5][O:4][C:3]=2[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: CC(=O)Nc1cccc2c1OCCO2
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(Br)c2c1OCCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.5 %

Procedure:
To a solution of N-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acetamide (5.5 g, 28.5 mmol) in chloroform (20 mL) cooled at −20° C. was slowly added a solution of bromine (1.6 mL, 30 mmol) in chloroform (5 mL) so that the reaction temperature was maintained below −10° C. The reaction was stirred at 0° C. for 10 minutes, and then quenched immediately with water. The mixture was extracted with dichloromethane; the combined extracts were washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (dichloromethane) to afford the product N-(8-bromo-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acetamide (5 g, yield 64%). 1H NMR (400 MHz, CDCl3) δ ppm 9.23 (s, 1H), 7.46-7.48 (d, 1H, J=8.8 Hz), 7.04-7.06 (d, 1H, J=9.2 Hz), 4.32-4.40 (m, 4H), 2.07 (s, 3H).