Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]([CH2:13][S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH2:17])[C:6]2[O:7][CH2:8][O:9][CH2:10][C:5]=2[CH:4]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25].C(O)C(N)(CO)CO>ClCCl.C(N(C(C)C)CC)(C)C.CN(C1C=CN=CC=1)C>[Cl:2][C:3]1[CH:12]=[C:11]([CH2:13][S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH:17][C:24](=[O:25])[C:23]([CH3:28])([CH3:27])[CH3:22])[C:6]2[O:7][CH2:8][O:9][CH2:10][C:5]=2[CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccc1SCc1cc(Cl)cc2c1OCOC2
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)Nc1ccccc1SCc1cc(Cl)cc2c1OCOC2
Reaction time: 24 h
Yield: 63.8 %

Procedure:
The product from step 1 (75 mg, 0.22 mmol) was dissolved in a mixture of dichloromethane and diisopropyl ethyl amine (4 mL , ˜40:1), PS DMAP resin (0.10 g, Argonaut 1.41 mmol/g) was added in followed by 2,2-dimethylpropanoyl chloride (0.15 mL, 1.25 mmol). The reaction was agitated for 24 hours and then treated with PS trisamine (Argonaut 4.27 mmol/g) for 6 h filtered and the solvent removed under a stream of nitrogen. The residue was chromatographed on silica to give the title product 55 mg (65%). 1H NMR (CDCl3) δ 9.87 (s, 1 H), 8.45 (dd, 1 H), 7.39 (dd, 1 H), 7.33 (dt, 1 H), 7.00 (dt, 1 H), 6.80 (dd, 2 H), 4.98 (s, 2 H), 4.77 (s, 2 H), 3.84 (s, 2 H), 1.28 (s, 9 H); MS (ESI+) for C20H22ClNO3S m/z 392 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7](=[N:14][NH:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH3:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:2]=[N-:3].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>N1C=CC=CC=1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:15]=[C:16]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[CH3:24])[O:25]1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(Cl)cc1C(=O)NN=C(CCCN=[N+]=[N-])c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(Cl)cc1C1=NN(C(=O)C(C)(C)C)C(CCCN=[N+]=[N-])(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of N′-(4-azido-1-phenylbutylidene)-5-chloro-2-methyl benzohydrazide (100 mg, 0.28 mmol) in pyridine (1 mL) was added pivaloyl chloride (70 μL, 0.56 mmol). After stirring at room temperature for 16 hours the heterogeneous mixture was treated with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed successively with 10% NaHSO4 (2×10 mL), NaHCO3 (10 mL) and brine (10 mL) then dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (9:1 hexanes/EtOAc) to afford the product (62 mg, 50%) as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>CN(C)C=O>[CH:33]1([CH2:36][N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH2:35][CH2:34]1
Reactant: BrCC1CC1
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2CC2CC2)CC1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (62%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@:10]([CH3:27])([C:13]([N:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])[CH2:9]1)C1C=CC=CC=1.C([O-])(O)=O.[Na+].[CH2:33]([O:40][C:41](Cl)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCCl.Cl>[CH3:27][C@@:10]1([C:13]([N:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])[CH2:11][CH2:12][N:8]([C:41]([O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:42])[CH2:9]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@]1(C(=O)N2C(=O)OC[C@H]2c2ccccc2)CCN(Cc2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@@]1(C(=O)N2C(=O)OC[C@H]2c2ccccc2)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
To a suspension of (R)-3-((S)-1-benzyl-3-methylpyrrolidine-3-carbonyl)-4-phenyloxazolidin-2-one (145.50 g, 399.25 mmol) and NaHCO3 (33.54 g, 399.25 mmol) in dry DCE (1000 mL) at ambient temperature was added dropwise a solution of benzylchloroformate (134.87 mL, 958.19 mmol) in DCE (100 mL) and the reaction was stirred at ambient temperature for 24 hours. The reaction was diluted with 1N HCl (500 mL) and the layers were separated. The organic layer was washed with 1M HCl (250 mL), dried (MgSO4), filtered and concentrated under reduced pressure to a thick yellow residue. The residue was purified by flash chromatography (5% ethyl acetate/DCM) to give (R)-benzyl 3-methyl-3-((R)-2-oxo-4-phenyloxazolidine-3-carbonyl)pyrrolidine-1-carboxylate (85.1 g, 208.35 mmol, 52.2% yield).
Reaction SMILES: C(O)C.[C:4]([C:6]1[C:11]2[N:12]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[O:14][C:10]=2[C:9]([CH2:18][C:19](=S)[N:20]([CH3:22])[CH3:21])=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]=1[CH3:30])#[N:5]>[Ni].O1CCCC1>[CH:15]1([C:13]2[O:14][C:10]3[C:11](=[C:6]([C:4]#[N:5])[C:7]([CH3:30])=[C:8]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:9]=3[CH2:18][CH2:19][N:20]([CH3:21])[CH3:22])[N:12]=2)[CH2:16][CH2:17]1
Reactant: Cc1c(-c2ccccc2)c(CC(=S)N(C)C)c2oc(C3CC3)nc2c1C#N
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(-c2ccccc2)c(CCN(C)C)c2oc(C3CC3)nc2c1C#N
Temperature: 50 °C
Reaction time: 5 h
Yield: 46.9 %

Procedure:
Raney nickel (corresponding to 0.2 ml) was added to an ethanol (1 ml)/tetrahydrofuran (1 ml) solution of 2-(4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)-N,N-dimethylethanethioamide (I-314) (14.0 mg, 0.037 mmol), followed by stirring in an oil bath at 50° C. for 5 hours. The reaction liquid was filtered, the filtrate was concentrated, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (6.00 mg, 47%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C)C=O.O>[CH3:11][O:10][N:8]([CH3:9])[C:6]([CH:4]1[CH2:5][CH:2]([NH:1][C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:3]1)=[O:7]
Reactant: CON(C)C(=O)C1CC(N)C1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC(Nc2ncccc2[N+](=O)[O-])C1
Yield: 79.9 %

Procedure:
To a solution of 3-amino-N-methoxy-N-methylcyclobutanecarboxamide (0.606 g, 3.84 mmol) in dry dimethylformamide (15 mL) was added sodium carbonate (1.22 g, 11.5 mmol) and 2-chloro-3-nitropyridine (608 mg, 3.84 mmol). The reaction mixture was stirred and heated at reflux for 14 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL) and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (20% to 50% ethyl acetate in petroleum ether) to give N-methoxy-N-methyl-3-((3-nitropyridin-2-yl)amino)cyclobutanecarboxamide (0.86 g, 3.07 mmol, 80% yield) as yellow solid.
Reaction SMILES: C([Li])CCC.[Br-].[CH:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=O.[O:19]1[CH2:23]CC[CH2:20]1>CCCCCC>[CH3:20][O:19][CH:23]=[CH:7][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COC=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an atmosphere of argon, a solution containing butyllithium dissolved in hexane was added to a solution containing 120 g of methoxymethyltriphenylphosphoni bromide dissolved in tetrahydrofuran (THF), and the mixture was stirred for one hour at room temperature. A solution containing 50 g of methyl 4-formylbenzoate dissolved in THF was added thereto, and stirring was continued for two hours. The reaction solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 47 g of methyl 4-(2-methoxyethenyl)benzoate (45).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:15](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[C:5]([O:10][CH3:15])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Br)cc(C2CCC2)c1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1c(C=O)cc(Br)cc1C1CCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-bromo-3-cyclobutyl-2-hydroxybenzaldehyde was dissolved in N,N-dimethylformamide (30 mL), and potassium carbonate (10.79 g) and dimethylsulfuric acid (3.7 mL) were added to the solution under water cooling, and then the mixture was stirred at room temperature for 14 hours. The reaction solution was filtered and water was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1) to obtain the title compound (1.27 g) as a yellow oily substance.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:17]2[CH2:20][CH:19]([NH2:21])[CH2:18]2)=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[CH2:1]([NH:21][CH:19]1[CH2:20][N:17]([CH:16]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc(C(c2ccc(Cl)cc2)N2CC(NCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
0.134 cm3 of benzaldehyde is added, at room temperature under an argon atmosphere, to a solution of 369 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 15 cm3 of dichloromethane. The mixture is cooled to around 0° C., before gradually adding thereto 382 mg of sodium triacetoxyborohydride, and then 70 mm3 of acetic acid. After stirring for 16 hours at room temperature, the mixture is poured over 50 cm3 of a saturated aqueous sodium hydrogen carbonate solution and then extracted with twice 25 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: dichloromethane/methanol (95/5 by volume)]. 0.29 g of N-benzyl-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}amine is obtained in the form of a colorless oil [1H NMR spectrum (300 MHz, CDCl3, δ ppm):2.71 (broad t, J=7 Hz,:2 H); 3.42 (mt:2 H); 3.49 (mt:1 H); 3.70 (s:2 H); 4.25 (s:1 H); from 7.20 to 7.40 (mt:13 H)].
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(Nc2ccccc2)c2ccccc2n1

Procedure:
A solution of 2,4-dichloro-quinazoline (15 g), N,N-diisopropyl-ethylamine (24.9 ml) and aniline (7.5 ml) in isopropanol (75 ml) is heated to reflux for 45 min. The cold reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is crystallized from diethylether- toluene (1:1) to give 2-chloro-4-phenylamino-quinazoline, m.p. 194-196° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[OH:17][C:18]1[C:25]([CH3:26])=[CH:24][C:21]([CH:22]=[O:23])=[C:20]([CH3:27])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:22]([C:21]1[C:20]([CH3:27])=[CH:19][C:18]([O:17][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[C:25]([CH3:26])[CH:24]=1)=[O:23]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: Cc1cc(C=O)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C=O)cc1C
Yield: 70.9 %

Procedure:
(E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (1.0 g, 3.5 mmol) was reacted with 4-hydroxy-2,5-dimethylbenzaldehyde (0.6 g, 4.2 mmol) at room temperature for 3 hours in 20 mL of acetonitrile (CH3CN) in the presence of cesium carbonate (1.7 g, 5.2 mmol) with stirring. After concentration in a vacuum to remove the reaction solvent, the residue was stirred in water (20 mL) and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum. The residue was purified by silica gel chromatography to afford (E)-methyl 2-(2-((4-formyl-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (0.88 g, yield 71%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:24][CH:25]=[O:26])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:24][CH:25]([OH:26])[CH3:27])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[Mg+]
Reactant: C[C@@H](c1ccc(F)cc1)N1CC[C@](CC=O)(c2ccc(F)cc2)OC1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(F)cc2)C(=O)O1
Temperature: -78 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
To a solution of 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-fluorophenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetaldehyde (500 mg, 1.40 mmol) in anhydrous THF (100 mL) was added CH3MgBr (5 mL, 3 mol/L) at −78° C. under nitrogen. The formed mixture was stirred for 3 h at −78° C. The reaction was quenched by water. The organic phase was separated and concentrated to give the crude product, which was purified by TLC and chiral preparative HPLC to afford (6S)-6-(4-fluorophenyl)-3-((S)-1-(4-fluorophenyl)ethyl)-6-(2-hydroxypropyl)-1,3-oxazinan-2-one (19 mg, 4%). LC-MS Method 2 tR=1.92 min, m/z=398; 1H NMR: (400 MHz, CDCl3): δ=1.02 (d, 3H), 1.48 (d, 3H), 1.84 (m, 4H), 2.01 (m, 1H), 2.14 (m, 1H), 2.29 (m, 1H), 2.84 (m, 1H), 3.83 (m, 1H), 5.54 (q, 1H), 6.74 (m, 2H), 6.82 (m, 2H), 6.99 (m, 2H), 7.21 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[NH2:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:13][CH2:12][N:11]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(N)c2)c1
Yield: 41.7 %

Procedure:
The 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (400 mg, 1.2 mmol), 3-aminophenylboronic acid (361 mg, 2.3 mmol, Aldrich Chem. Co.), Pd(0) (35 mg) and Na2CO3 (1.5 mL of a 2 M solution) were mixed in 8 mL of toluene, and the mixture was stirred at reflux for 16 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with exane:Et2O 1:1, to afford 178 mg of the title compound. MS (CI/NH3) m/z 356 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.33 (m, 2H), 3.92 (m, 2H), 4.20 (m, 1H), 4.38 (m, 1H), 4.55 (m, 1H), 6.72 (m, 1H), 6.88 (s, 1H), 6.97 (m, 1H), 7.44 (m, 2H), 8.31 (m, 1H), 8.44 (m, 1H).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1([CH3:22])[CH2:16][C:15](=[O:17])[C:14]2[C:9](=[C:10]([CH3:21])[C:11]([CH3:20])=[C:12]([OH:19])[C:13]=2[CH3:18])[O:8]1)([CH3:4])([CH3:3])[CH3:2].[CH:23]1[CH:24]=[CH:25][C:26]2OCC[C:29](=O)[C:27]=2[CH:28]=1.C(Br)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH2:29]([O:19][C:12]1[C:13]([CH3:18])=[C:14]2[C:9](=[C:10]([CH3:21])[C:11]=1[CH3:20])[O:8][C:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])[CH2:16][C:15]2=[O:17])[C:27]1[CH:28]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCOc2ccccc21
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COC(C)(C)C)O2
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(=O)CC(C)(COC(C)(C)C)O2

Procedure:
3.5 g of the crude product from Example 4 were converted to the above chromanone, using 7 g of benzyl bromide, 3 of Na2CO3 and 15 ml of dimethylformamide, by a method similar to that of Example 9. Yield (after purification three times by chromatography): 20%; melting point: 51°-62° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][C:25]([NH:27][NH2:28])=[O:26].O>CO>[Cl:1][CH:2]1[C:10](=[C:11]=[N:28][NH:27][C:25](=[O:26])[CH3:24])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: CC(=O)NN
Solvent: O
Solvent: CO
Product: CC(=O)NN=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Yield: 55.3 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 109 mg, 0.29 mmol) was dissolved in MeOH (5 mL) to which was added acethydrazine (85 mg, 1.1 mmol). The resulting solution was heated on a 45 C oil bath for 16 h, then cooled to room temperature and poured into 15 mL of water. The resulting suspension was cooled to 4 C, then filtered and the solids rinsed with cold water (25 mL). The solids were dissolved in DMF (0.5 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a white crystalline solid, which was recrystallized from acetone/MeOH to yield 70 mg (56%) of 4.32 as a white microcrystalline solid which is an inseparable mixture of isomers in a ratio of 60:40: mp 270-271 C; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): (major isomer) δ 11.25 (s, 1H, D2O exch.), 8.56 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 5.94 (d, 1H), 5.40-5.36 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.13 (s, 1H), 3.98 (s, 1H), 3.70 (s, 2H), 2.24 (s, 3H); (minor isomer) δ 11.41 (s, 1H, D2O exch.), 8.56 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 5.94 (d, 1H), 5.40-5.36 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.42 (q, 1H), 4.13 (s, 1H), 3.98 (s, 1H), 3.70 (s, 2H), 1.95 (s, 3H). 13C-NMR (125 MHz, DMSO-d6): (major isomer) δ 171.39, 135.98, 133.15, 129.73, 126.01, 124.96, 123.86, 121.69, 115.41, 108.31, 88.78, 86.09, 71.41, 69.66, 61.10, 20.36; (minor isomer) δ 165.24, 138.70, 133.12, 129.82, 126.06, 124.96, 123.99, 122.17, 115.33, 108.51, 88.78, 86.09, 71.41, 69.66, 61.10, 21.67. HRMS (ES) m/z calcd. for C16H16Cl3N3O5.Na 458.0053, found 458.0043. Anal calcd for C16H16Cl3N3O5: C, 44.01; H, 3.69; N, 9.62. Found: C, 43.76; H, 3.75; N, 9.67.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 27 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.69 (t, 1H, J=5.2 Hz), 7.52 (s, 1H), 7.38 (d, 1H, J=8.0 Hz), 7.30–7.27 (m, 4H), 7.20 (t, 1H, J=8.0 Hz), 7.00–6.95 (m, 4H), 6.89 (d, 1H, J=8.0 Hz), 4.90 (s, 1H), 3.37 (dd, 2H, J=6.0, 11.6 Hz), 3.05 (d, 2H, J=11.2 Hz), 2.55 (t, 2H, J=6.8 Hz), 2.49 (m, 1H), 2.33 (t, 2H, J=7.2 Hz), 2.17 (m, 2H), 1.79–1.69 (m, 8H), 0.97 (t, 3H, J=7.6 Hz); ESMS m/e: 534.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.ClC(N(C)C)=C(C)C.Cl.[NH2:18][CH2:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]#[N:28])=[O:21].C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:27]([C@@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:20](=[O:21])[CH2:19][NH:18][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])#[N:28]
Reactant: N#C[C@@H]1CCCN1C(=O)CN
Reactant: O=C(O)c1c[nH]nn1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#C[C@@H]1CCCN1C(=O)CNC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1H-1,2,3-triazole-4-carboxylic acid (0.092 g, 0.814 mmol) was dispersed in dry dioxane (3 mL) in a round bottom flask with nitrogen. To this 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.151 ml, 1.139 mmol) was added and the reaction was stirred for 30 minutes at room temperature. The starting material dissolves over time. Then (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile hydrochloride (0.247 g, 1.302 mmol) with N-ethyl-N-isopropylpropan-2-amine (0.307 ml, 1.709 mmol) was added and the mixture was stirred for 2 h, evaporated to dryness and redissolved in ethyl acetate. Followed by washing with 0.1N citric acid and saturated sodium bicarbonate and brine. After drying over sodium sulfate, filtration and evaporation, the product was purified using column chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].CN.[CH2:16]([N:18](CC)CC)C>ClCCl.O>[CH3:16][NH:18][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCN(CC)CC
Agent: CN
Solvent: ClCCl
Solvent: O
Product: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (30 g, 0.14 mol) in dichloromethane (500 mL) was slowly added a solution of methylamine in water (30%, 15.3 g) and triethylamine (38 mL, 0.27 mol) respectively. The mixture was stirred at room temperature for 1 hour and then evaporated. The residue was subjected to silica gel chromatography to afford the product N-methyl-2-nitrobenzenesulfonamide (26 g, yield 90%).