Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>CCOC(C)=O>[CH3:15][NH:14][C:10]1[N:9]=[C:8]([C:7]2[C:2]([O:39][C:36]3[CH:35]=[CH:34][C:33]([CH2:32][C:25]4[C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:22]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)=[N:23][N:24]=4)=[CH:38][CH:37]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Oc1ccc(Cc2nnc(-c3ccccc3)c3ccccc23)cc1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Cc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 130 °C

Procedure:
To a mixture of 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (0.0500 g, 0.23 mmol), 4-((4-phenylphthalazin-1-yl)methyl)phenol (0.071 g, 0.23 mmol) and cesium carbonate (0.15 g, 0.45 mmol) was added DMSO (0.5 mL). The resulting mixture was heated to 130° C. in a sealed tube for 15 hours, then diluted with EtOAc and extracted with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude concentrate was purified by Gilson reverse-phase HPLC (0.1% TFA in ACN/water; 15-95% ACN; 40 mL/min). Diluted product with DCM and extracted with saturated sodium bicarbonate. Dried organics over sodium sulfate, filtered and concentrated. Lyophilized concentrate to obtained N-methyl-4-(2-(4-((4-phenylphthalazin-1-yl)methyl)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=497 [M+H]+. Calc'd for C31H24N6O: 496.58.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1.[C:21]([C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[F:29])#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([S:30]([N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:5][C:4]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:3]=2[O:2][CH3:1])(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[F:29])#[N:22]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ccc(C#N)cn2)c(OC)c1
Product: COc1ccc(CN(c2ccc(C#N)cn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 18 using 6-((2,4-dimethoxybenzyl)amino)nicotinonitrile (Preparation 37) and 3-cyano-4-fluorobenzene-1-sulfonyl chloride. The residue was purified by reverse phase chromatography eluting with 0-100% MeCN in water/0.1% formic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:21]=[CH:20][C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[CH2:14][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[BH4-].[Na+]>O1CCOCC1.O>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:21]=[CH:20][C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[CH:13]([OH:15])[CH2:14][C:8]=2[CH:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)c1ccccc1S2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CC(O)c1ccccc1S2
Temperature: 40 °C
Reaction time: 4 h

Procedure:
14 g of 10,11-dihydro-2-dimethylsulphamoyl-dibenzo[b,f]-thiepin-10-one in 200 ml of dioxane are treated with 3.5 g of sodium borohydride in 15 ml of water and the mixture is stirred at 40° C for 4 hours. The mixture is evaporated under reduced pressure and the residue taken up in ethyl acetate and water. The organic phase is washed with water, dried and evaporated. 10,11-dihydro-2-dimethylsulphamoyl-dibenzo[b,f]-thiepin-10-ol is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]#[C:20][CH3:21]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1)[C:19]#[C:20][CH3:21]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
A mixture of 7.0 g (0.05 moles) of 5-hydroxy-benzo[1.3]dioxole, 6.91 g (0.05 moles) of anhydrous potassium carbonate in ml 25 of acetone was added with 6.65 g (0.05 moles) of 1-bromo-2-butyne. The mixture was heated to reflux for 6 hrs. The mixture was then cooled to room temperature, filtered and the filtrate evaporated u.v (20° C./21 mbar). The residue was then purified on silica gel column (eluant n-hexane: ethyl acetate 3:1 v/v). A liquid product (6.1 g, 95% purity) was obtained whose NMR and MS analyses correspond to those of the aforementioned compound.
Reaction SMILES: CC1CS[C@@H]2C(NC(=O)C(C3N=C(N[C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)SC=3)=NOC(C)(OC)C)C(=O)N2C=1C(OC(C)(C)C)=O.FC(F)(F)C(O)=[O:57]>C(O)=O>[C:34]1([C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[OH:57])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(O)C(F)(F)F
Solvent: O=CO
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2 g of the product of Step B were added with stirring at room temperature to 20 ml of trifluoroacetic acid held under nitrogen and after stirring for 10 minutes at room temperature, the mixture was concentrated under vacuum to a volume of 8 ml. The mixture was cooled in an ice water bath and 60 ml of isopropyl ether were slowly added thereto. The mixture was stirred for 10 minutes at room temperature and was vacuum filtered and the filter was rinsed with isopropyl ether. The filtrate was evaporated to dryness under reduced pressure to obtain 1.5 g of raw product. The latter was placed under an argon atmosphere and 7.5 ml of 50% aqueous formic acid were added thereto. The mixture was stirred at 40° C. for 15 minutes and was then vacuum filtered. The recovered product was rinsed twice with 1 ml of 50% aqueous formic acid and 3 times with 1 ml of distilled water to obtain 319 mg of triphenyl carbinol. The filtrate was distilled to dryness and ethanol was added. The mixture was triturated with 15 ml of ether and was vacuum filtered. The recovered product was rinsed with ether and dried to obtain 0.973 g of the syn isomer of 3-methyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3 -eme-4-carboxylic acid with an Rf=0.3 (acetone containing 10% water).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[CH:11]1([C:17]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([OH:23])[C:18](OCC)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[CH:11]1([C:17]([C:24]#[C:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([OH:23])[C:18]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCCC1
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)C(O)(C#Cc1ccccc1)C1CCCCC1
Yield: 27 %

Procedure:
3-Quinuclidinol (2.5 g., 0.020 mole) was dissolved in 50 ml. of toluene and a small piece of sodium (~0.05 g.) was added. The toluene was refluxed for about 40 minutes until all the sodium had reacted. Ethyl α-cyclohexyl-α-phenylethynylglycolate (4.3 g., 0.015 mole) was subsequently added as a solution in 35 ml. of toluene, over an hour period, to the refluxing reaction mixture. The reaction mixture was refluxed for an additional 20 hours. During the last four hours about 40 ml. of solvent was distilled over. The reaction mixture was then worked-up as described previously. The basic chloroform extract yielded 4.0 g. of an oil, which partially crystallized upon the addition of anhydrous ether. A total of 1.6 g. (27%) of crude product was obtained. Recrystallization from hexane gave analytically pure material, m.p. 171°-172°.
Reaction SMILES: [CH:1]([O:3][C@H:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[C@@H:5]([CH:19]=[O:20])[CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:2].P([O-])(O)(O)=[O:38].[Na+].OO.Cl([O-])=O.[Na+]>C(#N)C.O>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:7][CH2:6][C@@H:5]([C@H:4]([O:3][CH:1]=[O:2])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[CH:27][CH:28]=1)[C:19]([OH:38])=[O:20]
Reactant: COc1ccc(-c2ccc(CC[C@@H](OC=O)[C@@H](C=O)CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2ccc(CC[C@@H](OC=O)[C@H](CCN3C(=O)c4ccccc4C3=O)C(=O)O)cc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 221.1 %

Procedure:
The compound obtained in step h (0.54 g) was taken in acetonitrile (6 mL) and water (1 mL). To this solution, sodium dihydrogen phosphate (0.054 g) was added. The reaction mixture was cooled to 0° C. and hydrogen peroxide (1 mL) and sodium chlorite (0.208 g) were added. After stirring the reaction mixture for an additional 1 hour, the solvents were evaporated on a rotary evaporator; the residue was taken into water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to get the title compound (0.5 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][C:5]([CH:7]([C:11]([OH:13])=[O:12])C(O)=O)=[O:6].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1.C(=O)([O-])O.[Na+]>O>[F:15][C:2]([F:1])([F:14])[CH2:3][CH2:4][C:5]([CH2:7][C:11]([O:13][CH2:16][CH3:17])=[O:12])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C(C(=O)O)C(=O)CCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)CCC(F)(F)F
Reaction time: 6 h
Yield: 24903.6 %

Procedure:
A mixture of 179 g of the 4,4,4-trifluorobutyrylmalonic acid ditheyl ester thus obtained, 260 ml of water and 322 mg of p-toluenesulfonic acid was refluxed with vigorous stirring for 6 hours. The reaction solution was then poured into saturated aqueous sodium hydrogencarbonate solution and extracted three times with diethyl ether. The ether layers were combined and the combined layer was washed with brine, dried over anhydrous magnesium sulfate. After the drying agent was removed, the solvent was removed under reduced pressure. The obtained residue was distilled inder reduced pressure to yield 98.8 g of the desired ethyl 4,4,4-trifluorobutyrylacetate in a yield of 74%.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:5]([C:8]#[N:9])[C:6]#[N:7]>C(O)C>[NH2:7][C:6]1[NH:2][N:1]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]=1[C:8]#[N:9]
Reactant: NN
Reactant: CC(C)(C)C(Cl)=C(C#N)C#N
Solvent: CCO
Product: CC(C)(C)c1n[nH]c(N)c1C#N

Procedure:
Hydrazine (40 g) was dissolved in ethanol (100 ml) and was placed in a flask equipped with a condenser, a dropping funnel, a thermometer and a magnetic stirrer. A solution of the above pentenenitrile intermediate (b) (80 g) in ethanol (300 ml) was added with stirring at a rate that the temperature did not rise above 35° C. The reaction mixture was then gently refluxed for 90 minutes, the solvent was partially removed and the residue was treated with water. The product was filtered off and dried.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([O:18][CH2:19][CH2:20][OH:21])([C:16]#[N:17])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:22][OH:23]>C(O)C>[Si:1]([O:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13]([O:18][CH2:19][CH2:20][OH:21])([C:16](=[NH:17])[NH:22][OH:23])[CH2:14][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(C#N)(OCCO)CC1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC1CCC(OCCO)(C(=N)NO)CC1
Temperature: 80 °C
Yield: 86.8 %

Procedure:
A mixture of 4-((tert-butyldimethylsilyloxy)methyl)-1-(2-hydroxyethoxy)cyclohexane carbonitrile (3.44 g, 10.97 mmol) and 50% aq. hydroxylamine (0.725 g, 10.97 mmol) in ethanol (17 mL) was heated at 80° C. (oil bath temp) for 6 h. The mixture was concentrated to dryness in vacuo and the residual solid triturated with ethanol to obtain the title compound, 4-((tert-butyldimethylsilyloxy)methyl)-N-hydroxy-1-(2-hydroxyethoxy)cyclohexanecarboximidamide (3.30 g, 9.52 mmol, 87% yield) as a tan crystalline powder: HPLC: retention time=1.96 min (area percent=91%); LCMS: m/z 347 (M+H), 369 (M+Na); 1H NMR (500 MHz, CDCl3) δ ppm 0.02 (6H, s), 0.87 (9H, s),1.23 (1H, t, J=7.0 Hz), 1.25-1.34 (2H, m), 1.49-1.58 (2H, m), 1.57-1.63 (1H, m), 1.67-1.77 (2H, m), 2.05-2.16 (2H, m), 3.41-3.46 (4H, m), 3.69-3.72 (2H, m), 4.78 (2H, s), 7.95 (1H, brs); 13C NMR (126 MHz, CDCl3) δ ppm-5.22, 18.5, 25.0, 26.1, 32.0, 38.6, 62.1, 64.1, 66.9, 77.9, 154.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[F:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([CH:31]=[O:32])[CH:29]=4)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:34]=[CH:33][C:13]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([CH:31]([OH:32])[C:8]5[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=5)[CH:29]=4)[CH2:24][CH2:23]3)[CH2:20][CH2:21]2)=[CH:12][CH:11]=1
Reactant: COc1ccccn1
Reactant: O=Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Product: COc1ncccc1C(O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 75.2 %

Procedure:
2-Methoxypyridine (0.3 ml) and 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-formylindoline (0.5 g) were treated in accordance with the method described in J. Org. Chem., 1367 (1988). to give the title compound (0.493 g) as a pale yellow oil (yield: 75.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2c(/C=C/c3ccccc3)cccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1CNc1ccc2c(CCc3ccccc3)cccc2n1

Procedure:
(2-Methoxy-benzyl)-[5-((E)-styryl)-quinolin-2-yl]-amine (example 2, 102 mg, 0.279 mmol) was dissolved in 20 mL ethanol. Palladium on charcoal (10%, 30 mg, 0.028 mmol) was added and the reaction mixture war hydrogenated with a hydrogen balloon overnight. The palladium was filtered off and the solvent was evaporated. The title compound was obtained as a light brown oil (97 mg, 95%), MS: m/e=369.0 (M+H+).
Reaction SMILES: C(S[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH3:15])[C:7](=[O:16])[CH2:6][N:5]=1)C.[CH:17]([NH:19][NH2:20])=O>C(O)CCC>[CH3:15][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4]2=[N:20][N:19]=[CH:17][N:5]2[CH2:6][C:7]1=[O:16]
Reactant: CCSC1=NCC(=O)N(C)c2ccccc21
Reactant: NNC=O
Solvent: CCCCO
Product: CN1C(=O)Cn2cnnc2-c2ccccc21
Reaction time: 16 h

Procedure:
A mixture of 1,3-dihydro-5-(ethylthio)-1-methyl-2H-1,4-benzodiazepin-2-one (1 eq.) and formic hydrazide (5.8 eq. Aldrich) in n-butanol (0.1 M in benzodiazepine) was stirred at reflux under N2 for 24 hours. An additional 1.67 eq. of formic hydrazide was added and refluxing continued an additional 16 hours. The yellow solution was evaporated in vacuo and the residue was purified via flash chromatography eluting with a gradient from 98:2® 96:4 CH2Cl2/MeOH. The product was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)Cc1cccc(Br)n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Br)n1
Temperature: 25 °C

Procedure:
To a solution of (6-bromo-pyridin-2-yl)-acetic acid (34.0 g, 158.14 mmol) in ethanol (300 ml) was added conc. H2SO4 (5.0 ml) and heated to reflux for 12 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to dryness. Water was added to the residue and the product was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhy. Na2SO4 and concentrated under reduced pressure to furnish the crude product. Column chromatography purification furnished the title compound as a brown liquid. Yield=31.2 g (82%). TLC (20% ethyl acetate in hexane) Rf=0.51; LCMS: RtH7=0.996, [M+1]+=244.0 and 246.0; HPLC: RtH9=3.87 min (97.2%); 1H NMR (400 MHz, CDCl3): δ 7.53 (t, 1H), 7.39 (d, 1H), 7.28 (d, 1H), 4.19 (q, 2H), 3.83 (s, 2H), 1.25 (t, 3H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.CCN=C=NCCCN(C)C.[NH2:35][C:36]1[N:37]=[C:38]([C:42]([O:44][CH3:45])=[O:43])[N:39]([CH3:41])[CH:40]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([C:21]([NH:35][C:36]3[N:37]=[C:38]([C:42]([O:44][CH3:45])=[O:43])[N:39]([CH3:41])[CH:40]=3)=[O:23])[N:18]([CH3:20])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: Cn1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1C(=O)O
Reactant: COC(=O)c1nc(N)cn1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(NC(=O)c2cc(-c3ccc(N)cc3)cn2C)cn1C
Reaction time: 6 h

Procedure:
0.3 gm of boc protected 6 (0.94 mmol, 1.2 eq) was dissolved in DMF (5 mL) to which 2.0 eq of EDCI and 2.5 eq of DMAP were added. The mixture was allowed to stir for 30 minutes after which commercially available methyl 4-amino-1-methyl-1H-imidazole-2-carboxylate (0.121 g, 0.79 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for a further 6 hour at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed saturated aqueous NaHCO3 (50 mL), water (50 mL), brine (50 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product (0.48 gm) was used for the boc deprotection step to afford 11. For boc deprotection, the crude intermediate was dissolved in a small volume of MeOH and 4M HCl in dioxane (5 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 2 hours at which point TLC showed completion of reaction. Excess solvent was evaporated under vacuum to obtain a brown coloured solid (11). The solid product was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give pure 11. Yield 0.35 gm, 81% over two steps.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:31](C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH2:31][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cccc2c1C(=O)NC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 257.9 %

Procedure:
A mixture of 4 g (21 mmol) of the preceeding diamine, 4.6 g (21 mmol) of di-tert-butyl dicarbonate, and 100 mL of dry CH2Cl2 was stirred for 12 hours at room temperature. Solvent and volatile by-products were removed by evaporation under reduced pressure, leaving 6 g (100% yield) of 6-(tert-butyloxycarbonylamino)-1-diethylamino-2-hydroxyhexane as an oil which was not further purified. It was dissolved in 100 mL of dry tetrahydrofuran (THF) along with 3.27 g (22 mmol) of phthalimide, 5.77 g (22 mmol) of triphenylphosphine, and 3.83 g (22 mmol) of diethyl azodicarboxylate (DEAD). The solution was stirred at room temperature for 12 hours at which point, to complete the reaction, an additional 1.64 g (11 mmol) of phthalimide and 1.92 g (11 mmol) of DEAD were added and stirring continued for 1 hour. Solvent was removed and the residual oil partitioned between ether and 1% hydrochloric acid. The aqueous phase was separated, made basic with NaOH solution, and extracted with ether. The ether extract was dried over anhydrous MgSO4, filtered evaporated. A pale yellow oil resulted which was dried under high vacuum to afford 9.2 g of the protected amino-phthalimide as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].[H][H]>CCOC(C)=O.CO.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C=CC(=O)O)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)O)ccc1O
Yield: 89.1 %

Procedure:
To a solution of 3-(4-Hydroxy-3-methoxy-phenyl)-acrylic acid (20 g, 103 mmol) in EtOAc (100 ml) and MeOH (100 ml) was added carefully 10% Pd/C (2.0 g), the reaction mixture was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen, then the solution was passed through a celite pad and the catalyst was washed with methanol, the filtrate was concentrated and dried at 50° C. under reduced pressure to give product (18 g, 89.16%). LC-MS: m/e 195 (M−1).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17](O)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CCCCCC(=O)O
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CCCCCC(O)=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and hexanoic acid
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(N2CCC(S(=O)(=O)c3ccc4ccccc4c3)CC2)nc1
Yield: 31.1 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (Example 11, Step 3, 130 mg, 0.51 mmol) was reacted with 2-chloro-5-nitropyridine (158 mg, 1.0 mmol) to afford the title compound (63 mg), a yellow solid, in 31% yield.