Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(C2/C(=C/C=C3/N(CCCS([O-])(=O)=O)C4C(C/3(C)C)=CC(S([O-])(=O)=O)=CC=4)/CCCC=2C=CC2C(C)(C)C3C(N=2)=[N+](CCCS([O-])(=O)=O)C=CC=3)=CC=1)(O)=O.[Na+:60].[Na+].Cl[C:63]1=[C:64]([CH:90]=[CH:91][C:92]2[C:100]([CH3:102])([CH3:101])[C:99]3[C:94](=[CH:95][CH:96]=[C:97]([S:103]([O-:106])(=[O:105])=[O:104])[CH:98]=3)[N+:93]=2[CH2:107][CH2:108][CH2:109][CH2:110][S:111]([O-:114])(=[O:113])=[O:112])[CH2:65][CH2:66]/[C:67]/1=[CH:68]\[CH:69]=[C:70]1/[C:71]([CH3:89])([CH3:88])[C:72]2[C:73](=[N:87]/1)[N:74]([CH2:79][CH2:80][CH2:81][CH2:82][S:83]([O-:86])(=[O:85])=[O:84])[CH:75]=[C:76]([Cl:78])[CH:77]=2.[Na+].[Na+].B([C:120]1[CH:121]=[C:122]([CH:126]=[CH:127][CH:128]=1)[C:123]([OH:125])=[O:124])(O)O>>[C:123]([C:122]1[CH:121]=[C:120]([C:63]2=[C:64]([CH:90]=[CH:91][C:92]3[C:100]([CH3:102])([CH3:101])[C:99]4[C:94](=[CH:95][CH:96]=[C:97]([S:103]([O-:106])(=[O:105])=[O:104])[CH:98]=4)[N+:93]=3[CH2:107][CH2:108][CH2:109][CH2:110][S:111]([O-:114])(=[O:113])=[O:112])[CH2:65][CH2:66]/[C:67]/2=[CH:68]\[CH:69]=[C:70]2/[C:71]([CH3:88])([CH3:89])[C:72]3[C:73](=[N:87]/2)[N:74]([CH2:79][CH2:80][CH2:81][CH2:82][S:83]([O-:86])(=[O:85])=[O:84])[CH:75]=[C:76]([Cl:78])[CH:77]=3)[CH:128]=[CH:127][CH:126]=1)([OH:125])=[O:124].[Na+:60].[Na+:60]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(C=CC2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1Cl
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: CC1(C)C(/C=C/C2=C(c3ccc(C(=O)O)cc3)/C(=C/C=C3/N(CCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=Nc2c1ccc[n+]2CCCS(=O)(=O)[O-]
Agent: CC1(C)C(C=CC2=C(c3ccc(C(=O)O)cc3)/C(=C/C=C3/N(CCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=Nc2c1ccc[n+]2CCCS(=O)(=O)[O-]
Agent: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(/C=C/C2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1Cl
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(C=CC2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1c1cccc(C(=O)O)c1

Procedure:
Compound 40 is prepared analogously to compound 17 (Example 17), except with compound 39 and 3-boronobenzoic acid as starting materials.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][NH2:18]>C(O)C>[Br:1][C:2]1[C:7]([NH:18][CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: CCO
Product: CNc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and methylamine in ethanol. ES-MS m/e (°/o): 271 (M{81Br}+H+, 95), 269 (M{79Br}+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]([CH3:13])[C:9]2=[O:12])=[CH:5][C:4]=1[N+:14]([O-])=O.O.O.Cl[Sn]Cl.C(Cl)Cl.[OH-].[Na+]>C(O)C.O>[NH2:14][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:3]=1[O:2][CH3:1])[C:9](=[O:12])[N:8]([CH3:13])[CH2:7]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C)C2=O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COc1cc2c(cc1N)CN(C)C2=O
Temperature: 65 °C
Yield: 70.8 %

Procedure:
To 6-methoxy-2-methyl-5-nitroisoindolin-1-one (111 mg, 0.5 mmol) in ethanol (6 mL) and water (0.6 mL) was added SnCl2.2H2O (451 mg, 2 mmol) and the mixture was heated to 65° C. for 5 h. DCM (20 mL) and 2M NaOH(aq) (10 mL) were added and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give 5-amino-6-methoxy-2-methylisoindolin-1-one (68 mg, 71%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=193 at 2.32 min. 1H NMR (400 MHz, DMSO): δ 7.01 (s, 1H), 6.74 (s, 1H), 5.44 (br s, 2H), 4.24 (s, 2H), 3.85 (s, 3H), 3.02 (s, 3H).
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:12]2[C:17]([CH:18]=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:25][C:18]1[C:19]2[C:24]([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:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: c1ccc2cc(-c3c4ccccc4cc4ccccc34)ccc2c1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12

Procedure:
5.6 g (18.0 mmol) of 9-(2-naphthyl)anthracene and 90 mL of carbon tetrachloride were put into a 500-mL three-neck flask and stirred. A solution in which 3.2 g (20 mmol) of bromine was dissolved in 10 mL of carbon tetrachloride was dropped into the above solution through a dropping funnel. After that, the solution was stirred at the room temperature for 1 hour, and a sodium thiosulfate aqueous solution was added to the reaction solution to complete the reaction. A water layer of the reaction mixture was extracted by chloroform, and the extracted solution and an organic layer were together washed with a saturated sodium hydrogen carbonate solution and saturated saline. The organic layer was dried with magnesium sulfate, and the mixture was filtrated naturally to remove the magnesium sulfate. Then, the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with ethanol, whereby 5.5 g of a yellow powdery solid, which was a target matter, was obtained with the yield of 79%.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=2)[O:5][C:4](=[O:30])[CH:3]=1.[C:31]([C:35]1[CH:40]=[C:39]([O:41][CH2:42][CH2:43][O:44][Si](C(C)(C)C)(C)C)[C:38]([CH3:52])=[CH:37][C:36]=1[S:53]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+].NC1C=CC(CCC(=O)CCC2C=CC(N)=CC=2)=CC=1>CN(C=O)C>[C:31]([C:35]1[CH:40]=[C:39]([O:41][CH2:42][CH2:43][OH:44])[C:38]([CH3:52])=[CH:37][C:36]=1[S:53][C:3]1[C:4](=[O:30])[O:5][C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=2)([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=2)[CH2:7][C:2]=1[OH:1])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Reactant: COc1cc(CCC2(CCc3ccc(O)c(OC)c3)CC(O)=CC(=O)O2)ccc1O
Agent: Nc1ccc(CCC(=O)CCc2ccc(N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CCC2(CCc3ccc(O)c(OC)c3)CC(O)=C(Sc3cc(C)c(OCCO)cc3C(C)(C)C)C(=O)O2)ccc1O
Reaction time: 0.17 h

Procedure:
The compound was prepared using General Method 9 and the following quantities: 100 mg (0.24 mmol) of 4-hydroxy-6,6-bis-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example QQ), 123 mg (0.24 mol) of toluene-4-thiosulfonic acid S-{2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-phenyl} ester (prepared in Example PPP), 133 mg (0.96 mmol) of K2CO3, and 10 mL of DMF. The reaction was worked up by addition of 10 mL 1. ON HCl and stirring for 10 minutes, followed by extraction with EtOAc. The organic layer was dried (Na2SO4), concentrated, and chromatographed on silica gel, eluting with (1:1 CH2Cl2 :EtOAc+2% MeOH), to give the title compound, m.p. 76-82° C. 1H NMR (DMSO-d6) δ 1.5 (s, 9 H), 1.75 (s, 3 H), 2.05 (m, 4 H), 2.6 (m, 4 H), 2.95 (s, 2 H), 3.7 (m, 8 H), 3.95 (t, 2 H), 4.8 (br s, 1 H), 6.65 (m, 7 H), 7.0 (s, 1 H), 8.75 (s, 2 H).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[NH4+:15].[OH-]>O1CCCC1>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([NH2:15])(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc2cnccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Isoquinoline-5-sulfonyl chloride (528 mg) was dissolved in tetrahydrofuran (8 mL), cooled to 0° C., then concentrated NH4OH (0.7 mL) was added and the reaction was allowed to come to room temperature overnight. The product was filtered off, washed with water, and dried under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][S:14][CH3:15])=[C:11]([C:16]([OH:18])=O)[N:10]=[N:9]1.[CH2:19]([NH:23][C@@H:24]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][C@H:26]([C:37]([O:39][CH3:40])=[O:38])[CH2:25]1)[CH:20]([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>ClCCCl.C(=O)([O-])O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][S:14][CH3:15])=[C:11]([C:16]([N:23]([CH2:19][CH:20]([CH3:22])[CH3:21])[C@@H:24]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][C@H:26]([C:37]([O:39][CH3:40])=[O:38])[CH2:25]2)=[O:18])[N:10]=[N:9]1
Reactant: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Reactant: CSCc1c(C(=O)O)nnn1-c1ccccc1F
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3F)c2CSC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
1-(2-Fluorophenyl)-5-[(methylsulfanyl)methyl]-1H-1,2,3-triazole-4-carboxylic acid (960 mg), 1-tert-butyl 3-methyl (3R,5S)-5-(isobutylamino)piperidine-1,3-dicarboxylate (1.15 g) and N,N-diisopropylethylamine (1.6 μl) were dissolved in 1,2-dichloroethane (10 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (1.50 g) was added and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (1.60 g).
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:19]([NH:27][NH2:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:28]/[NH:27][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3): 0.91 (t, 3H), 1.36 to 1.39 (m, 4H), 1.69-1.75 (m, 2H), 3.73 (t, 2H), 3.87 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 13.98 (br, s 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(O)(=O)CC.[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([C:7]=1[OH:13])=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:12]=2)([O-:23])=[O:22]
Reactant: Oc1ccnc2cc(C(F)(F)F)ccc12
Reactant: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: O=[N+]([O-])c1cnc2cc(C(F)(F)F)ccc2c1O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(trifluoromethyl)-4-quinolinol (22.7 g, 0.106 mol) and propionic acid (106 mL) was heated to 120° C. Nitric acid (10 mL of 70%) was added dropwise and heating was continued for an additional 2 hours. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration then washed with water and diethyl ether to provide 13.3 g of 3-nitro-7-(trifluoromethyl)-4-quinolinol as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[CH3:36][O:37][CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[CH3:36][O:37][CH:38]1[CH2:42][CH2:41][N:40]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:39]1
Reactant: COC1CCNC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: Cl
Product: COC1CCN(C(=O)C(C)n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 3-methoxypyrrolidine hydrochloride (Matrix and Cat. No. 023344). LCMS (M+H)+: m/z=557.2.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C(Cl)Cl>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:17]([CH3:16])(=[O:19])=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
To a suspension of 1-(4-fluorophenyl)piperazine dihydrochloride (2.53 g; 10.0 mmol; 1.0 eq.) in anhydrous DCM (50 mL) was added TEA (3.33 g; 33.0 mmol; 3.3 eq.) and the resulting mixture was chilled at 0° C. A 1N solution of methanesulfonyl chloride (1.26 g; 11.0 mmol; 1.1 eq.) in DCM (11 mL) was added dropwise. After 20 min at 0° C., the reaction mixture was stirred at rt for 3 h. Water was added and the mixture extracted with DCM. The combined organic layers were washed with an aqueous saturated solution of NaHCO3, water, brine then dried over MgSO4, filtered and evaporated to give a white powder. Crystallization from EtOAc gave a white solid (1.98 g, 76% yield). HPLC, Rt: 2.3 min (purity: 100%). 1H NMR (CDCl3) δ: 7.08-6.83 (m, 4H), 3.41 (m, 4H), 3.22 (m, 4H), 2.85 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][C:24]([CH3:30])([C:26](OC)=[O:27])[CH3:25])[CH:19]=2)[CH:14]=1)(OC)=[O:8].[NH4+].[Cl-].Cl>O1CCCC1.C(OCC)(=O)C>[OH:8][CH2:7][C:11]([CH3:32])([CH3:31])[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][C:24]([CH3:30])([CH3:25])[CH2:26][OH:27])[CH:19]=2)[CH:14]=1
Reactant: COC(=O)C(C)(C)Cc1ccc2cc(CC(C)(C)C(=O)OC)ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CO)Cc1ccc2cc(CC(C)(C)CO)ccc2c1
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of 6.0 g of lithium aluminum hydride in 1 liter of dry tetrahydrofuran, 40 g of 2,6-bis(2-carbomethoxy-2-methylpropyl)naphthalene was added slowly. The reaction mixture thickened on stirring overnight. Then there was added 150 ml of ethyl acetate, 60 ml of saturated aqueous NH4Cl and 150 ml of concentrated HCl. After thorough mixing the solid and liquid were separated by filtration. The filtrate was evaporated to dryness and the residue was recrystallized from benzene to obtain about 20 g of 2,6-bis(3-hydroxy-2,2-dimethylpropyl)naphthalene. The solid from the above filtration was slurried with 50 ml of H2O, 10 ml of concentrated HCl and 50 ml of benzene and the mixture was heated at reflux for 1 hr. The benzene layer was separated, dried with MgSO4 at 80° C, filtered hot and then cooled to precipitate about 10 g of 2,6-bis(3-hydroxy-2,2-dimethylpropyl)naphthalene, m.p. 162°-165° C.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]1[O:22][C:21]2[CH:20]=[C:19]3[C:15]([CH:16]=[CH:17][NH:18]3)=[CH:14][C:13]=2[O:12]1.[OH-].[Na+]>C(OCC)C.O>[CH2:11]1[O:22][C:21]2[CH:20]=[C:19]3[C:15]([C:16]([CH:4]=[O:5])=[CH:17][NH:18]3)=[CH:14][C:13]=2[O:12]1
Reactant: CN(C)C=O
Reactant: c1cc2cc3c(cc2[nH]1)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cc3c(cc12)OCO3
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69 %

Procedure:
To an ice cold solution of DMF (50 mL, excess) was added POCl3 (8 mL, 85.7 mmol) in a drop wise fashion. After addition the mixture was stirred at 0° C. for 5 min and at room temperature for 45 min. The mixture was cooled to 0° C. and 5,6-methylenedioxy-indole (10 g, 62.1 mmol) was added in portion. After complete addition, the mixture was stirred at 0° C. for 10 min and at room temperature for 20 min and finally at 60° C. for 6 h. The mixture was cooled to room temperature and then to 0° C. followed by the addition of 1N NaOH solution (150 mL). The mixture was stirred at room temperature for 30 min as result a homogenous solution was obtained. To the mixture was added 100 mL of water and stirring was continued at room temperature overnight. The product, 5,6-methylenedioxy-indole-3-carboxaldehyde separated as a solid, which was filtered, washed (water followed by hexane) and dried. The filtrate also provided additional product upon extraction from ethyl acetate (3 times). The combined organic extractions were washed successively with water and brine. After drying over MgSO4, solvent was evaporated. A solid was obtained which was suspended in 100 mL of diethyl ether, sonicated for few minutes and was filtered. The solid was further washed with diethyl ether and was dried. A combined crude yield of 8.08 g (69%) of the 5,6-methylenedioxy-indole-3-carboxaldehyde was obtained which was subjected to N-methylation without further purifications. To a cold (0° C.) solution of 5,6-methylenedioxy-indole-3-carboxaldehyde (see above) (8 g, 42.32 mmol) in dry DMF (40 mL) was added NaH (60% dispersion in mineral oil, 2.1 g, 52.5 mmol). The resulting mixture was stirred at 0° C. for 30 min. Iodomethane (5 mL, 80.3 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0° C. for 15 min and at room temperature for 2 h. The mixture was cooled to 0° C. and was quenched with water. The mixture was further diluted with water (˜700 mL). The product, 5,6-methylenedioxy-1-methyl-indole-3-carboxaldehyde separated as a solid which was filtered, washed (water followed by hexane) and dried to provide 6.2 g (72% yield) of the desired product. MS: 204 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.C(OC(OCC)OCC)C.[Cl-].[NH4+]>C(O)C>[CH3:14][CH2:13][O:12][C:5]([C:6]([CH2:1][C:2]([CH3:4])=[O:3])=[O:8])=[O:11]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)C(=O)CC(C)=O

Procedure:
Ethyl acetopyruvate was prepared from acetone and diethyl oxalate as described in Org. Synthesis, Coll. Vol. 1, 238 (1958). Further reaction with triethylorthoformate and ammonium chloride in ethanol afforded the known enol ether 1. See L. Claisen, Chem. Ber., 40, 3903 (1907).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:23])=[N+:20]([O-])[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:23][OH:3])=[N:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Product: OCc1ccc(OCc2ccccc2)cn1
Temperature: 120 °C
Reaction time: 1.33 h
Yield: 54 %

Procedure:
To a methylene chloride (100 mL) solution of 5-benzyloxy-2-methyl-pyridine (5.99 g, 30.1 mmol) described in Manufacturing Example 127-1-1 was added m-chloroperbenzoic acid (8.79 g, 33.1 mmol, purity: 65%) at 0° C., which was stirred for 2 hours at room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture at 0° C., which was extracted with methylene chloride. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain 5-benzyloxy-2-methyl-pyridine-1-oxide (7.71 g). Acetic anhydride (77 mL) was added to 5-benzyloxy-2-methyl-pyridine-1-oxide (7.71 g) thus obtained, which was stirred for 80 minutes at 120° C. This mixture was cooled to room temperature and then concentrated under a reduced pressure. To an ethanol (50 mL) solution of this residue was added a 5 N sodium hydroxide aqueous solution (7 mL), which was stirred for 50 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. The residue was partitioned into saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (4.17 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9](=[CH:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)[C:10](O)=[O:11].[CH:23]1([N:29]=[C:30]=NC2CCCCC2)CCCCC1.CNC>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9](=[CH:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)[C:10]([N:29]([CH3:30])[CH3:23])=[O:11]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C(=CNc1ccc(I)cc1)C(=O)c1ccccc1Cl
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)C(=CNc1ccc(I)cc1)C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a suspension of 2-chloro-α-[[(4-iodophenyl)amino]methylene]-β-oxobenzenepropanoic acid (43 mg, 0.10 mmol) in 1 mL of CH2Cl2 was added N,N′-dicyclohexylcarbodiimide (21 mg, 0.10 mmol). The mixture was cooled in an ice bath and 50 μL (0.10 mmol) of a 2M solution of dimethylamine in THF was added. The reaction mixture was stirred at rt for 16 h. The formed DCU was removed by filtration. The filtrate was washed with water and evaporated to dryness. The title compound (22 mg, 50%) was isolated by column chromatography (5% MeOH in CH2Cl2); MS 410 (M−45), 455(M+1), 477(M+Na+).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:52])[OH:51])=[O:46])[CH2:40][CH2:41][C:42](=[O:44])[OH:43])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N1CCCCC1.C(O)(=O)C>CS(C)=O>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:45]([NH:47][C@H:48]([C:53]([OH:55])=[O:54])[CH2:49][C:50](=[O:51])[OH:52])=[O:46])[CH2:40][CH2:41][C:42](=[O:43])[OH:44])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
Fmoc-D-Trp-L-Leu-Gly-L-Arg-L-Glu-L-Asp-OH (50 mg), was dissolved in 0.5 ml of dimethylsulfoxide and 0.5 ml of piperidine was added to the solution. After reacting for an hour, the reaction mixture was neutralized with acetic acid under cooling.