Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][C:4]2[S:8]([C:11]3[CH:16]=[C:15](N)[CH:14]=[CH:13][C:12]=3[C:3]=2[CH:2]=1)(=O)=O.C1(C2C=CC=CC=2)C=CC=CC=1.[S].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH:2]1[C:3]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:8][C:4]=2[CH:5]=[CH:6][CH:1]=1
Reactant: Nc1ccc2c(c1)S(=O)(=O)c1cc(N)ccc1-2
Agent: [Al+3]
Agent: [Cl-]
Agent: [S]
Solvent: c1ccc(-c2ccccc2)cc1
Product: c1ccc2c(c1)sc1ccccc12

Procedure:
Benzidine sulfone used as the diamine component in the synthesis of the novel copolyamide is a known compound, and it can be prepared, for example, by a method comprising reacting biphenyl with sulfur in the presence of anhydrous aluminum chloride to form dibenzothiophene, oxidizing dibenzothiophene with hydrogen peroxide to form dibenzothiophene-5,5'-dioxide, nitrating the dioxide with concentrated nitric acid to form 3,7-dinitrodibenzothiophene-5,5'-dioxide and reducing the so formed dioxide with stannous chloride in the state acidified by hydrochloric acid to form benzidine sulfone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.Cl[CH2:23][CH:24]([OH:27])[CH2:25][OH:26].O>C1(C)C=CC=CC=1>[OH:27][CH:24]([CH2:25][OH:26])[CH2:23][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: O=C1Nc2ccc(O)cc2C1=Cc1c[nH]c2ncccc12
Reactant: OCC(O)CCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(OCC(O)CO)cc2C1=Cc1c[nH]c2ncccc12
Yield: 70 %

Procedure:
To a solution of 5-hydroxy-3-[(7-azaindol-3-yl)methylene]-2-oxindole (2.773 g, 10 mmol) in toluene (100 ml) was added portionwise under nitrogen NaH 80% (0.300 g, 10 mmol). After the salification was complete 3-chloro-1,2-propane-diol (1.547 g, 14 mmol) was added and the mixture heated to reflux for 5 h. After cooling water was added, the organic phase washed and evaporated to dryness. The residue was submitted to flash chromatography using CHCl3 --MeOH mixtures as eluant to give pure title compound in about 70% yield.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([Br:14])[N:7]=1>S(=O)(=O)(O)O>[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([Br:14])[N:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(Br)nc1Br
Agent: O=S(=O)(O)O
Product: COc1cc([N+](=O)[O-])c(Br)nc1Br
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To 150 ml of concentrated sulfuric acid were added at 0° C. 150 ml fuming nitric acid. 40.0 g of 2,6-dibromo-3-methoxypyridine (example E2) were added portionwise to this mixture at 0° C. The reaction mixture was stirred for 45 minutes at 0° C. and then heated to 65° C. for 2 h. The mixture was poured into 2 l of crushed ice and stored at 0° C. overnight. The resulting precipitate was filtered, washed with water and dried under vacuum to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28]>C(#N)C.ClCCl>[CH3:26][CH:27]([N:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1)[CH3:28]
Reactant: COc1cc(N2CCCNCC2)ccc1[N+](=O)[O-]
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(N2CCCN(C(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 60 h
Yield: 83.5 %

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (580 mg, 2.3 mmol) was dissolved in acetonitrile (10 mL). Potassium carbonate (952 mg, 6.9 mmol) and 1-iodopropane (0.344 mL, 3.45 mmol) were added. Reaction was stirred at it for 60 h. At this time the reaction mixture was diluted with dichloromethane and washed with a saturated sodium bicarbonate solution, water and a saturated sodium chloride solution, dried over Na2SO4 and filtered. Solvents were removed under reduced pressure and purified by SiO2 chromatography to afford 1-(1-methylethyl)-4-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (0.565 g, 1.92 mmol). ESIMS (M+H)+=295.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1.CC(C)=[O:23]>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:23])([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)=O
Reactant: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(O)(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3.55 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-bromobutyric acid, obtained by brominating 3-(2',4'-difluoro-4-biphenylyl)butyric acid, are dissolved in a mixture of 15 ml. of acetone and 15 ml. of water. One drop of sulfuric acid is added and the mixture is warmed to 45° for 4 hours and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid, m.p. 121°-123°.
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[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:28][C:29]([NH2:31])=[O:30].O>CN(C=O)C>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:28][C:29]([NH2:31])=[O:30])[N:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:19]=12
Reactant: NC(=O)CI
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Cn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and iodoacetamide (46 mg, 0.25 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 319.1, found 319.2.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:29]5[O:30][C:31]([CH:34]6OCC[O:35]6)=[CH:32][CH:33]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C1COCC1>[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:29]5[O:30][C:31]([CH:34]=[O:35])=[CH:32][CH:33]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(Cn2ncc3cc(Nc4ncnc5cc(-c6ccc(C7OCCO7)o6)ccc45)ccc32)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3c2)o1

Procedure:
Prepared according to Procedure C from (1-benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinazolin-4-yl]-amine hydrochloride (0.27 g) stirred in THF:2N HCl (2:1, 15 ml) at 20° C. for 1 hour. Filtration gave 5-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde, which was not further characterised.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:31]([NH:33][C@H:34]([C:37]([NH:39][C@H:40]([C:49]([NH:51][CH2:52][C:53]([NH:55][C@H:56]([C:61]([NH:63][C@H:64]([C:98]([N:100]1[CH2:111][CH2:110][CH2:109][C@H:101]1[C:102]([NH:104][CH2:105][C:106]([NH2:108])=[O:107])=[O:103])=[O:99])[CH2:65][CH2:66][CH2:67][N:68](C(OC12CC3CC(CC(C3)C1)C2)=O)[C:69](=[NH:84])[NH:70]C(OC12CC3CC(CC(C3)C1)C2)=O)=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)=[O:38])[CH2:35][OH:36])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8].C(OCC)C>FC(F)(F)C(O)=O>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:31]([NH:33][C@H:34]([C:37]([NH:39][C@H:40]([C:49]([NH:51][CH2:52][C:53]([NH:55][C@H:56]([C:61]([NH:63][C@H:64]([C:98]([N:100]1[CH2:111][CH2:110][CH2:109][C@H:101]1[C:102]([NH:104][CH2:105][C:106]([NH2:108])=[O:107])=[O:103])=[O:99])[CH2:65][CH2:66][CH2:67][NH:68][C:69](=[NH:70])[NH2:84])=[O:62])[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])=[O:50])[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=1)=[O:38])[CH2:35][OH:36])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCN(C(=N)NC(=O)OC12CC3CC(CC(C3)C1)C2)C(=O)OC12CC3CC(CC(C3)C1)C2)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reaction time: 0.25 h

Procedure:
A solution of L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosylglycyl-L-leucyl-Nδ,Nω-bisadamantyloxycarbonyl-L-arginyl-L-prolylglycinamide (XXI) (1.54 g) in trifluoroacetic acid (TFA) (5 ml) is allowed to stand at room temperature for 15 minutes. Absolute ethyl ether (25 ml) is then added to the reaction mixture and the precipitate is collected by filtration and washed thoroughly with absolute ethyl ether. The precipitate is dried in vacuo to give L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosylglycyl-L-leucyl-L-arginyl-L-prolylglycinamide XXII.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[N:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[CH:16][CH:15]=1
Reactant: CSc1ccc(B(O)O)c(F)c1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)c(F)c1
Yield: 54.6 %

Procedure:
1-Methylethyl 4-[({6-[2-fluoro-4-(methylthio)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.16 g, 55%) was prepared as a light yellow solid from [2-fluoro-4-(methylthio)phenyl]boronic acid (prepared as in Example 161, Alternative synthesis, Step 2, 0.26 g, 1.4 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 0.25 g, 0.7 mmol), Na2CO3 (0.148 g, 1.4 mmol), Pd(PPh3)2Cl2 (49 mg, 0.07 mmol), water (1 mL) and DME (2 mL) in a manner similar to Example 21, Step 3. LRMS (APCI), m/z 419 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[CH:6][C:7]=1[NH:8][NH2:9].[CH:21]1[C:26]([CH:27]([CH:30]=O)[CH:28]=O)=[CH:25][CH:24]=[N:23][CH:22]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:30]=[C:27]([C:26]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:28]=[N:9]1
Reactant: O=CC(C=O)c1ccncc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NN)c(F)c2)C(=O)O1
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cc(-c4ccncc4)cn3)c(F)c2)C(=O)O1
Yield: 66.3 %

Procedure:
100 mg (0.354 mmol) of (S)—N-{[3-(3-fluoro-4-hydrazinophenyl)-2-oxooxazolidin-5-yl]methyl}-acetamide and 52.8 mg (0.354 mmol) of 2-(4-pyridyl)malondialdehyde were combined with 5 mL ethanol as a solvent. Then, the resultant mixture was slowly heated to reflux, thereby the solid was substantially dissolved. TLC monitoring was performed to determine completion of the reaction. Then, the resultant mixture was cooled to room temperature and vacuum filtered to afford the product (13a) as a light yellow solid, with a yield of 66.3%, melting point: 203.8-205.0° C., HPLC: 99.97%.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[CH:8][C:7]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CN1CCNCC1
Reactant: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(COS(C)(=O)=O)c1=O
Product: CC(C)Cn1nc(-c2ccc(S(C)(=O)=O)cc2)cc(CN2CCN(C)CC2)c1=O
Yield: 88.5 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 88.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([C:20]([NH:22][O:23]C4CCCCO4)=[O:21])=[CH:15][CH:16]=3)[CH2:11]2)=[O:9])[CH:2]=1.[ClH:30]>CO>[ClH:30].[OH:23][NH:22][C:20]([C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:19][N:10]([C:8](=[O:9])[CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:11]2)=[CH:16][CH:15]=1)=[O:21]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)Cc1cccnc1)CC2
Agent: Cl
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CN(C(=O)Cc1cccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 140 mg 2-(pyridin-3-ylacetyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide in 6 ml methanol and 6 ml 0.1 N aqueous hydrochloric acid is stirred overnight at ambient temperature. Subsequently, the reaction mixture is evaporated. The residue is dissolved in a mixture of water and acetonitrile and lyophilized. 113 mg of the title compound are obtained as colorless solid. MH+=312.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[CH:6]=[CH:7]/[C:8]1[NH:16][C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH3:19])[C:12](=[O:20])[N:11]([CH2:21][CH3:22])[C:10]=2[N:9]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:28])[C:15]2[C:14](=[O:17])[N:13]([CH2:18][CH3:19])[C:12](=[O:20])[N:11]([CH2:21][CH3:22])[C:10]=2[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CC)c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CC)c1=O
Yield: 67.4 %

Procedure:
Compound 64 (1.20 g, 3.24 mmol) obtained in Example 7 was dissolved in 25 ml of dimethylformamide. To the solution were added 1.12 g (8.10 mmol) of potassium carbonate and subsequently 0.40 ml (6.49 mmol) of methyl iodide, and the resultant mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble matters were filtered off, and 100 ml of water was added to the filtrate. The mixture was extracted three times with 50 ml of chloroform. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (eluent: 40% ethyl acetate/hexane), followed by recrystallization from isopropanol to give 840 mg (yield 68%) of Compound 65 as pale yellow needles.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([N+:22]([O-:24])=[O:23])([CH2:20]O)[CH2:18][OH:19].N1C=CC=CC=1.C(Cl)Cl.C(OCC)(=O)C>CCOCC>[S:9]([O:8][CH2:20][C:17]([F:16])([N+:22]([O-:24])=[O:23])[CH2:18][OH:19])([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])C(F)(CO)CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])C(F)(CO)COS(=O)(=O)C(F)(F)F
Reaction time: 16 h
Yield: 46.1 %

Procedure:
A solution of 10.9 ml (0.65 mol) of triflic anhydride in 210 ml of ether was added dropwise over 25 minutes to a solution of 17.4 g (0.124 mol) of 2-fluoro-2-nitro-1,3-propanediol and 6.0 ml (0.074 mol) of pyridine in 210 ml of ether, at a temperature just below 26° C. After 16 hours, the resulting precipitate was filtered and washed with ether. The filtrate was stripped of solvent and the residue was partitioned between 300 ml of methylene chloride and 60 ml of water. The methylene chloride layer was washed with 30 ml of water, dried over sodium sulfate and chromatographed on a 125 g silica gel column. Elution with 500 ml of methylene chloride and with 1100 ml of 9:1 methylene chloride-ethyl acetate gave 15.5 g (88% yield) of 2-fluoro-2-nitro-1,3-propanediol monotriflate, which was recrystallized from methylene chloride. Skelly F: mp 29°-30°; proton NMR (CDCl3) δ2.65 (broad s, 1H,OH), 4.10 (d,J=14 Hz, 2H, CH2OH), 5.07 (m, J=14 Hz, 2 H CH2OSO2CF3); fluorine NMR (CDCl3) φ72.0 (s, 3F, CF3), 139.4 (quint, J=14 Hz, 1F, O2NCF): IR (CH2Cl2) 3625 (OH), 1580, 1350 (NO2), 1420, 1220, 1140, 900 (OSO2CF2), 1000 cm-1 (CF).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH2:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40])[CH2:11][O:12][Si:13]([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:14])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N)COCc1ccccc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)Nc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 48 h
Yield: 73.7 %

Procedure:
(2S)-1-(Benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}propan-2-amine (1.55 g, 5.25 mmol) was dissolved in 60 mL of dry CH2Cl2. Triethylamine (1.46 mL, 10.5 mmol) and 4-chloro-3-nitroquinoline (1.09 g, 5.25 mmol) were then added and the reaction was stirred under N2 for 2 days. The reaction mixture was then concentrated and the resulting material was partitioned between 50 mL of CH2Cl2 and 50 mL of saturated NaHCO3 solution. The layers were separated and the organic portion was washed with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 0-10% ethyl acetate/CH2Cl2) gave 1.81 g of N-[(1S)-2-(benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: OCc1ccc(Cl)cc1CCc1ccc(F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2CCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-[2-(4-fluorophenyl)ethyl]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.86-2.95 (4H, m), 5.03 (2H, s), 5.70 (1H, d, J=2.0 Hz), 6.91-7.01 (4H, m), 7.21-7.24 (2H, m), 7.33-7.36 (2H, m), 7.58 (1H, d, J=1.6 Hz), 7.96 (1H, s), 8.57 (1H, dd, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C24H18ClFN4O, 433. Found, 433.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[C@@H:26]([OH:30])[CH:27]([CH3:29])[CH3:28])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[CH3:32]I>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[C@@H:26]([O:30][CH3:32])[CH:27]([CH3:29])[CH3:28])[CH2:22][CH2:23]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: CC(C)[C@H](O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CI
Product: CO[C@H](C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C(C)C

Procedure:
The title compound, white solid (5.7 mg, 69%), MS (ISP) m/z=446.4 [(M+H)+], was prepared in accordance with the general method of example 62 from (S)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide (8 mg, 18.5 mmol) and methyl iodide.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][CH3:12])[C:5]=1[OH:13])(=[O:3])[CH3:2].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].Cl>C(O)C.CO>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][CH3:12])[C:5]=1[OH:13])(=[O:3])[CH:2]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CC=Cc1cccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CC=Cc1cccc(C(=O)C=Cc2ccccc2)c1O
Reaction time: 8 h

Procedure:
3.5 g (20 mmol) of 2-acetyl-6-(1-propenyl)phenol and 2.1 g (20 mmol) of benzaldehyde are dissolved in 20 ml of ethanol, 4 ml of concentrated NaOH are added, the mixture is stirred overnight, the red crystal slurry is diluted with methanol and acidified with concentrated HCl and, after cooling, the product is filtered off with suction. Orange-red crystals of melting point 95°-98° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][CH3:17])=[N:4][CH:5]=[C:6]([N+:13]([O-])=O)[C:7]=1/[CH:8]=[CH:9]/N(C)C.Cl.[OH-].[Na+]>[Fe].CCO>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[N:4][CH:5]=[C:6]2[NH:13][CH:9]=[CH:8][C:7]=12
Reactant: COc1ncc([N+](=O)[O-])c(/C=C/N(C)C)c1Br
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ncc2[nH]ccc2c1Br
Temperature: 90 °C
Yield: 77.8 %

Procedure:
In A suspension of Iron powder (1.62 g, 28.9 mmol, 5.5 eq), [(E)-2-(3-Bromo-2-methoxy-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine (1.59 g, 5.27 mmol), and EtOH (0.05M) were stirred while heating to 90° C. To the suspension was added dropwise concentrated HCl (1.6 mL) and the suspension refluxed (100° C.) for 2 hr. The reaction was cooled and neutralized by pouring reaction mixture into 200 mL of 1N NaOH and stirring. The resulting mixture was extracted with EtOAc (3×100 mL), the combined organics washed with brine and concentrated to a beige powder. The crude solid was further purified using chromatography eluting with EtOAc/Heptane giving 4-Bromo-5-methoxy-1H-pyrrolo[2,3-c]pyridine as a beige solid (0.980 g, 4.10 mmol, 78%). MS ESI m/z 229.2 (M+2H)+. 1NMR (400 MHz, CDCl3) δ 8.55 (br s, 1H), 8.36 (s, 1H), 7.47 (m, 1H), 6.60 (m, 1H), 4.12 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1>>[F:32][C:31]1[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:15]([CH3:18])(=[O:16])=[O:17])=[N:27][C:28]([NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)=[N:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Reactant: NCCc1ccc(O)cc1
Product: CS(=O)(=O)N(Cc1cccc(-c2nc(NCCc3ccc(O)cc3)ncc2F)c1)C1CCNCC1

Procedure:
Intermediate 77 was coupled with tyramine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 500. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.23 (d, 1H), 8.16 (s, 1H), 7.96 (d, 1H), 7.48 (m, 2H), 7.05 (d, 2H), 6.69 (d, 2H), 4.54 (s, 2H), 3.90 (m, 1H), 3.56 (t, 2H), 3.34 (m, 2H), 3.00 (s, 3H), 2.91 (m, 2H), 2.80 (t, 2H), 1.84 (m, 4H).