Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:5][CH2:4]1)[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[C:25]1[C:34]2[N:33]=[CH:32][CH:31]=[N:30][C:29]=2[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.ClC1C=C(OC)C=CC=1B(O)O>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[C:11]([NH:12][C:35]([C:28]3[C:29]4[N:30]=[CH:31][CH:32]=[N:33][C:34]=4[C:25]([C:18]4[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=4[Cl:16])=[CH:26][CH:27]=3)=[O:36])[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2cccc(N)c2)CC1
Reactant: COc1ccc(Cl)c(-c2ccc(C(=O)O)c3nccnc23)c1
Agent: COc1ccc(B(O)O)c(Cl)c1
Product: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cc(OC)ccc4Cl)c4nccnc34)c2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-(4-ethylpiperazin-1-yl)-aniline (Step 2.1) and 8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid. The latter compound was synthesized as described in Steps 1.2-1.7 but using 2-chloro-4-methoxyphenylboronic acid in Step 1.4. Title compound: ESI-MS: 502.1 [M]+; tR=3.57 min (System 3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:7][C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([OH:19])=O)=[C:12]3[N:11]=[CH:10][C:9]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:4][S:5][CH:6]=1.[CH:34]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH2:36][CH2:35]1>>[CH3:1][C:2]1[C:3]([NH:7][C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH:40][S:37]([CH:34]4[CH2:36][CH2:35]4)(=[O:39])=[O:38])=[O:19])=[C:12]3[N:11]=[CH:10][C:9]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:4][S:5][CH:6]=1
Reactant: Cc1cscc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: NS(=O)(=O)C1CC1
Product: Cc1cscc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-methyl-3-thienylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.11 mmol) obtained in step 2 and cyclopropanesulfonamide (0.048 g, 0.44 mmol), the title compound (0.005 g, 8%) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([CH2:20][CH2:21][CH:22]([NH:27]C(=O)OC(C)(C)C)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][C@@H:14]5[CH2:35][O:36][CH2:37][CH2:38][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([CH2:20][CH2:21][CH:22]([NH2:27])[C:23]([CH3:26])([CH3:24])[CH3:25])[CH2:15][C@@H:14]5[CH2:35][O:36][CH2:37][CH2:38][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NC(CCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(N)CCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 193 using tert-butyl (1-((R)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-4,4-dimethylpentan-3-yl)carbamate (PREPARATION x78) in CH2Cl2 (0.5 mL) and trifluoroacetic acid (0.5 mL) (11.7 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (s, 9H), 1.51-1.75 (m, 1H), 1.91-2.08 (m, 1H), 3.02-3.39 (m, 4H), 3.53-3.65 (m, 6H), 3.80-3.96 (m, 1H), 3.97-4.16 (m, 2H), 4.60-4.76 (m, 1H), 6.96-7.12 (m, 1H), 7.20-7.33 (m, 1H), 7.47-7.88 (m, 4H), 11.33-11.59 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C24H32N6O, 421.27 found 421.4.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4](SC2C=CC=CC=2)[N:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]N)[CH:30]=1.C[N:38](C=O)C>>[NH2:38][C:4]1[C:5]([C:20]#[N:21])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:7]([C:8]#[N:9])=[C:2]([NH:1][CH2:35][C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: NCc1cccnc1
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCCO2
Product: N#Cc1c(N)nc(NCc2cccnc2)c(C#N)c1-c1ccc2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
100 mg (0.26 mmol) of 2-amino-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(phenyl-sulfanyl)-3,5-pyridinedicarbonitrile and 56 mg (0.52 mmol) of 3-picolylamine in 8 ml of DMF are heated at 100° C. After 3 hours, another 224 mg (2.08 mmol) of 3-picolylamine are added, and the mixture is heated at 100° C. for another 4 hours. After dilution with water, the mixture is extracted three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The concentration residue is purified by preparative HPLC on reversed-phase silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:23]#[C:24][CH2:25][OH:26])=[CH:17][C:16]=3[F:27])=[O:11])=[CH:4][CH:3]=1>C(Cl)Cl.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:17][C:16]=3[F:27])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCO)cc2c1O
Yield: 66 %

Procedure:
A suspension of the title compound of Example 53 (0.300 g) and 10% Pd/C (0.03 g) in 25 mL of 3:1 CH2Cl2 /MeOH is hydrogenated at atmospheric pressure overnight. The reaction is filtered through celite. The filtrate is condensed. The crude product is recrystallized from EtOAc/hexanes to yield 0.200 g of the desired product as a pale-yellow solid.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:3]([C:12](O)=[O:13])=[C:2]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CS(Cl)(=O)=O.[CH2:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:26]([N:33]1[CH2:38][CH2:37][N:36]([C:12]([C:3]2[C:4](=[O:5])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[O:1][C:2]=2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:35][CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)c1c(-c2ccccc2)oc2ccccc2c1=O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(c1c(-c2ccccc2)oc2ccccc2c1=O)N1CCN(Cc2ccccc2)CC1

Procedure:
6 g of flavone-3-carboxylic acid was converted into the mixed anhydride with 5.5 g 4-dimethylaminopyridine and 2.2 ml methanesulfonyl chloride in 50 ml absolute dichloromethane under the conditions described in Example 1 (a), and the mixed anhydride was then reacted with 4.42 ml N-benzylpiperazine as described in Example 1 (b). The working up of the reaction mixture and the purification of the resulting crude title compound were carried out in the manner described in Example 1 (b). 9 g of 3-[(4-benzylpiperazin-1-yl)-carbonyl]flavone were obtained.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][C:14]([O:16]CC)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.Cl>[OH-].[K+]>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2
Reactant: CCOC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
22 G. of 5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid is stirred in 200 ml. of chloroform, 50 ml. of thionyl chloride and 1 ml. of dimethylformamide for 8 hours. The mixture is evaporated to dryness and the residue recrystallized from acetonitrile to yield 2-chloroformyl-5-oxo-5H-dibenzo[a,d]cycloheptene. This is dissolved in 200 ml. of chloroform and added to a 3-fold excess of ethereal diazomethane at 0° C. The mixture is left at 0° C for 12 hrs. then evaporated to dryness. The residue is recrystallized from acetonitrile to yield 2-diazoacetyl-5-oxo-5H-dibenzo[a,d]cycloheptene. The diazoketone is heated to reflux in 250 ml. of ethanol and a saturated triethylamine solution of 2 g. of silver benzoate is added slowly until gas evolution ceases. The solution is cooled, filtered and evaporated to yield ethyl (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetate. This ester is refluxed in 5% aqueous potassium hydroxide for 12 hrs. The solution is cooled, acidified with dilute hydrochloric acid and extracted with ether. The ether extract is dried and evaporated to yield (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid which can be recrystallized from acetone-hexane.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methane sulphonyl chloride (0.39 ml, 5.0 mmol) was added dropwise to a solution of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (0.51 g, 2.5 mmol) and 4-(dimethylamino)pyridine (0.61 g, 5.0 mmol) in dichloromethane (15 ml). The mixture was stirred at room temperature for 30 minutes and then concentrated to approximately half volume and purified by silica gel chromatography. Elution with a mixture of 3:1 to 1:1 iso-hexane:ethyl acetate yielded tert-butyl 3-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a mixture of 3.14 g (20 mmole) of 3-fluoro-4-nitro-phenol, 100 mL of acetonitrile and 8.3 g (60 mmole) of potassium carbonate was added 2.5 mL (21 mmole) of benzyl bromide. The mixture was heated to reflux for 1 hour, then cooled and concentrated under reduced pressure. The residue was stirred with 100 mL for 30 minutes. The solid was collected by filtration and air dried to give 4.76 g of 4-benzyloxy-2-fluoro-1-nitro-benzene as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[CH:2]1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>CN(C=O)C>[CH2:21]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[CH:2]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: c1cnc2[nH]cc(-c3c[nH]c4cnccc34)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: c1ccc(Cn2cc(-c3c[nH]c4cnccc34)c3cccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60 mg (0.16 mmol) of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrolo[2,3-c]-pyridine (“A18”) are added to a suspension, kept under argon, of 20 mg (0.5 mmol) of sodium hydride (60% in paraffin) in 1 ml of DMF. After stirring at room temperature for one hour, 25 μl (0.26 mmol) of benzyl bromide are added, and the mixture is stirred at room temperature for 19 hours. Methanol is added to the reaction mixture, which is subsequently evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: 3-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine as colourless solid;
Reaction SMILES: C(OCCCCO)(=O)C.O1CCCC1.[C:15]([O:18][CH2:19][CH:20]([CH3:23])[CH2:21][OH:22])(=[O:17])[CH3:16]>[W]=O.C(O)(=O)C>[C:15]([O:18][CH2:19][CH:20]([CH3:23])[CH:21]=[O:22])(=[O:17])[CH3:16].[CH3:23][CH:20]([CH2:21][OH:22])[CH2:19][OH:18]
Reactant: CC(=O)OCC(C)CO
Agent: O=[W]
Agent: CC(=O)OCCCCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OCC(C)C=O
Product: CC(CO)CO

Procedure:
Alternatively, at least a portion of the 4-acetoxybutyraldehyde reaction product may be preferably converted to produce tetrahydrofuran (THF). Preferably, the 4-acetoxybutyraldehyde is hydrogenated to produce 4-acetoxybutanol, which then is dehydroacetoxylated to produce THF. The hydrogenation to produce 4-acetoxybutanol is preferably conducted according to the conditions described above. The 4-acetoxybutanol can then undergo a dehydroacetoxylation reaction to produce THF and acetic acid. The dehydroacetoxylation step is preferably performed at temperatures in the range of from 20 to 300° C. in the presence of a dehydroacetoxylation catalyst, such as silica, silica-alumina, and/or tungsten oxide. A final hydrolysis step may be performed to convert any 3-acetoxy-2-methylpropanol, formed by the hydrogenation of 3-acetoxy-2-methylpropionaldehyde, to 2-methyl-1,3-propanediol (MPD)
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[CH:12].[CH3:13][NH:14][CH3:15].C1COCC1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CCOC(C)=O>[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH2:3][CH2:2][N:14]([CH3:15])[CH3:13])#[CH:12]
Reactant: CNC
Reactant: C#Cc1ccccc1NCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C#Cc1ccccc1NCCN(C)C
Temperature: 80 °C
Yield: 50 %

Procedure:
N-(2-Chloroethyl)-2-ethynylaniline (0.5 g, 2.79 mmol) in ACN (16 mL) was treated with 2M dimethylamine in THF (4.2 mL, 8.37 mmol), sodium iodide (1.25 g, 8.37 mmol), sodium carbonate (887 mg, 8.37 mmol) and heated in a sealed tube at 80° C. (oil bath temperature) for 15 h, with stirring. EtOAc was added (100 mL) and the organic phase was washed first with water (100 mL) and then with brine. Removal of the volatiles by evaporation, after drying over sodium sulfate and purification of the crude over silica gel (DCM/7N NH3 in MeOH 9/1) afforded the title compound (265 mg, 50%).
Reaction SMILES: O1C=CC[CH:2]1C(O)=O.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[C:19]([OH:21])=[O:20].CC(C)([O-])C.[K+].C[Si](C)(C)[N-][Si](C)(C)C.[K+]>O1CCCC1>[CH3:2][C:10]1([C:19]([OH:21])=[O:20])[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: O=C(O)C1CC=CO1
Agent: CC(C)(C)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCc2ccccc2C1

Procedure:
The title compound was prepared following the procedures described for Reference Example 5 substituting 2,3-dihydrofuran-2-carboxylic acid with 1,2,3,4-tetrahydro-2-naphthoic acid at Step A and potassium tert-butoxide in tetrahydrofuran with potassium hexamethyldisilazide (0.5 M in toluene) at Step B. 1H NMR (500 MHz, CD3OD): δ 7.12-7.0 (m, 4H), 3.71 (d, 1H), 3.22 (d, 1H), 2.84 (t, 1H), 2.65 (d, 1H), 2.17 (m, 1H), 1.77 (m, 1H), 1.28 (s, 3H).
Reaction SMILES: [OH-].[Na+].C(O[C:7](=[O:9])[CH3:8])(=O)C.[CH:10]1[C:23]([NH2:24])=[CH:22][C:13]2[CH:14]=[CH:15][C:16]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:17][C:12]=2[CH:11]=1>>[NH:24]([C:23]1[CH:10]=[CH:11][C:12]2[C:13](=[CH:14][CH:15]=[C:16]([S:18]([OH:21])(=[O:19])=[O:20])[CH:17]=2)[CH:22]=1)[C:7]([CH3:8])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2cc(S(=O)(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc2cc(S(=O)(=O)O)ccc2c1

Procedure:
The suspension thus obtained [1.20 moles of 2-amino- naphthalene-6(8)-sulfonic acid, pH 0.8] is brought at 70° C. with 245 parts of 33% strength sodium hydroxide solution to pH 7.0 and has added to it 155 parts of acetic anhydride (1.5 moles) in the course of 15 minutes, during which the pH decreases to 3.0 and the Bronner acid goes into solution. The acetylation is quantitative. Salting out gives 289 parts of 2-acetaminonaphthalene-6-sulfonic acid calculated at 100% (1.09 moles which corresponds to 73% of theory based on 2hydroxynaphthalene) having a purity of about 70% (diazotization value after hydrolysis, molecular weight 265.3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH:18]=[CH2:17]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
5-hydroxyindole (1.00 g, 7.29 mmol) and potassium carbonate (1.38 g, 9.94 mmol) were taken up in 20 mL of dimethylformamide (DMF) and stirred at 60° C. for 0.5 hours. Allyl bromide (0.57 mL, 6.62 mmol) was added and the reaction was stirred for an additional 18 hours then cooled and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by flash chromatography on silica gel (10% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:5](=[O:7])[CH3:6])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (2.32 g, 24.6 mmol) was added dropwise to a cold (0° C.) solution of (4-fluorophenyl)(piperidin-4-yl)methanone (5.00 g, 20.5 mmol) in DCM (33 mL) and triethylamine (10.0 mL, 71.8 mmol). The resulting mixture was removed from the ice bath after 5 minutes and stirred at room temperature for 2 hours. The reaction was then added to a mixture of 1 M aqueous K3PO4 (100 mL), H2O, and DCM was added. The layers were separated and the aqueous layer again extracted with DCM. The combined organic layers was dried (Na2SO4), filtered, concentrated under reduced pressure and chromatographed (CH2Cl2/EtOAc) to provide the title compound as a clear oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[N:28](COCC3C=CC=CC=3)[C:26]2=[O:27])[C@H:22]([O:43][CH2:44][CH2:45][O:46][CH3:47])[C@@H:21]1[OH:48])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:43][CH2:44][CH2:45][O:46][CH3:47])[C@@H:21]1[OH:48])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)n(COCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Reaction time: 16 h

Procedure:
5′-O-t-Butyldiphenylsilyl-3-benzyloxymethyl-2′-O-(methoxyethyl)-5-methyluridine is dissolved in anhydrous MeOH and is added to a pressure bottle containing 10% Pd on carbon under an argon atmosphere. The vessel is pressurized with hydrogen gas to 30 psi and shaken for 16 hours. The mixture is filtered through a celite pad and the solvent is evaporated in vacuo. The residue is dissolved in 1M NEt3 in anhydrous MeOH and the solution is heated at reflux temperature for 2 hours. The solvent is evaporated in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1CCON=1.[CH2:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH3:8].C(=O)[C:15]1[CH:20]=[CH:19]C=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:7]([N:9]1[CH2:12][CH2:13][CH2:2][CH2:11][CH2:10]1)[C:8]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CCN(CC)CC
Reactant: BrC1=NOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCCCC2)cc1
Reaction time: 16 h

Procedure:
3-Bromo-4,5-dihydroisoxazole III-14 is dissolved in methylene chloride (0.06 M with respect to isxozaole) after which triethylamine (2.5 equiv) and benzaldehyde (1.25 equiv) are added followed by sodium triacetoxyborohydride (1.5 equiv). The reaction is allowed to stir for 16 h after which point is diluted with ethyl acetate and washed with dilute NaOH and then brine. The organic layer is then dried over sodium sulfate and concentrated under vacuum to provide crude material which was purified using flash silica gel chromatography (ethyl acetate/hexanes) to provide N-benzylpiperidine III-19 as a white solid. [M−H]−=308.1 m/z. Activity: A.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])=O)C.O.[NH3:20]>C(O)C>[C:4]([CH2:6][N:7]1[C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])(=[O:3])[NH2:20]
Reactant: CCOC(=O)CN1C(=O)COc2cc(F)ccc21
Reactant: N
Solvent: CCO
Solvent: O
Product: NC(=O)CN1C(=O)COc2cc(F)ccc21
Yield: 40 %

Procedure:
A mixture of 4-ethoxycarbonylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (1.27 g), ethanol (20 ml) and 28% ammonia water (10 g) was mixed at room temperature for 2 hours, and refluxed for 3 hours. After the solvent was concentrated, it was mixed with water, and filtered. Resulting product was washed with water and ethanol in that order, and recrystallized from methylisobutyl ketone to give the desired 4-carbamoylmethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (0.45 g). mp. 216.5°-219° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)([O-:9])=[O:8].C1(=O)[NH:23]C(=O)C2=CC=CC=C12>CCOCC>[NH2:23][C:1](=[O:5])[C:2]([C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=2)[NH:15][CH:14]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: CCOCC
Product: NC(=O)C(=O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 24 °C
Reaction time: 48 h

Procedure:
Oxalyl chloride (19.2 mmol) is added dropwise to a suspension of 5-nitroindole (6.2 mmol) and phthalimide (0.4 g) in ether (30 mL) and the mixture stirred 48 h at 24° C. The reaction vessel is then equipped with a Dewar condenser, chilled to 0° C., and anhydrous ammonia bubbled through the mixture during 1.5 h. The gas and solvent are removed in vacuo. The resulting yellow solid is triturated with water, filtered, and the retentate washed with toluene. The solid is dried, affording 2-amino-1-(5-nitro-1H-indol-3-yl)-ethane-1,2-dione. A portion of this compound (0.59 mmol) is taken into THF (15 mL) and treated with borane-THF (2.4 mL of 1 M solution) 16 h at 28° C. The reaction is neutralized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract is dried in vacuo, redissolved in ethanol (10 mL) and refluxed in the presence of cesium fluoride (360 mg) and sodium carbonate (312 mg). The mixture is filtered through Celite, evaporated and the residue chromatographed on silica gel using chloroform-methanol-ammonia (8:2:0.2) as eluent affording the title compound (20 mg).