Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]1([C:7]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1c[nH]nc1-c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c[nH]nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a solution of 3-phenyl-1H-pyrazole-4-carboxylic acid (1.0 g, 5.31 mmol) in dichloromethane (14.2 mL) and methanol (3.5 mL) was added trimethylsilyldiazomethane (2.66 mL, 5.31 mmol). The mixture was stirred at ambient temperature. After 30 min, additional trimethylsilyldiazomethane (0.80 mL, 1.59 mmol) was added. After 10 min, the mixture was concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (0.9 g). MS 203.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O>CO.[Pd]>[C:11]1([NH:10][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH2:1])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnccc1Nc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cnccc1Nc1ccccc1
Reaction time: 10 h
Yield: 99.8 %

Procedure:
To a solution of 3-nitro-N-phenylpyridin-4-amine (20 g, 93 mmol) in MeOH (500 mL) was added 10% Pd/C. The reaction was stirred under a hydrogen atmosphere for 10 h. The reaction was filtered and the filtrate was concentrated to afford the product (17.2 g, 100%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:15](=[O:28])[C:14]([C:29]#[N:30])=[C:13]2[N:31]1[CH2:36][CH2:35][N:34]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:33][CH2:32]1
Reactant: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)ccc2n(Cc2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 72 (397 mg, 1 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethylacetate to yield 212 mg (43%) of white solids. M.P. 253° C. 1H NMR (DMSO-d6): δ 3.69 (m, 4H), 3.96 (m, 4H), 5.45 (s, 2H), 6.66 (m, 1H), 7.08 (d, J=3.6 Hz, 1H), 7.20 (m, 2H), 7.27 (m, 2H), 7.46 (d, J=9.0 Hz, 1H), 7.69 (dd, J=2.4, 9.0 Hz), 7.89 (s, 1H). EIMS m/z 514 (M+23). Anal. (C26H20ClFN4O3) C, H, N.
Reaction SMILES: I.[CH3:2][NH+:3]1[C:19]2[C:11]([N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:10][C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2>C([O-])([O-])=O.[Na+].[Na+]>[CH3:2][N:3]1[C:19]2[C:11]([N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:10][C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: C[NH+]1C2=c3ccccc3=NC2=Cc2ccccc21
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1c2c3ccccc3nc-2cc2ccccc21
Yield: 51.3 %

Procedure:
5-Methylquindolinium hydroiodide (1.5 g, 4.2 mmol) from Example 3 was shaken with a 5% solution of Na2CO3 (100 mL) and extracted with chloroform (2×200 mL). The extract of the free base was purified on a basic alumina column using chloroform to elute the quindoline impurity; elution with 1-2% methanol in chloroform gave 0.5 g of the title compound as a purple solid, mp 178°-180° C. [lit 166°-169° C. (Gellert, E.; Raymond-Hamet; Schlittler, E. Helv. Chim. Acta 1951, 34, 642-651)]; 1H NMR (DMSO-d6) δ 8.92 (s, H11), 8.50 (d, J=9.2, 1H, H4), 8.47 (d, J=8.4, 1H, H6), 8.38 (d, J=8.4, 1H, H1), 7,89 (t, J=7.6, 1H, H3), 7.69-7.64 (m, 2H, H2 and H9), 7.52 (t, J=8.4, 1H, H8), 7.02 (t, J=8.4, 1H, H7), 4.90 (s, 3H, NCH3); 13C NMR (DMSO-d6) δ 160.46, 144.76, 138.96, 132.56, 130.13, 129.47, 128.66, 126.15, 124.97, 124.26, 123.60, 119.30, 116.36, 116.23, 113.64, 38.73.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([C:14]([OH:16])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.[CH3:17]O>ClCCl>[CH:5]1([C:14]([O:16][CH3:17])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CO
Reactant: O=C(O)C1CCc2ccccc21
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 100 %

Procedure:
Thionyl Chloride (0.95 mL, 13.0 mmol) was added to a room temperature solution of indane-1-carboxylic acid dissolved in 20 mL of dichloromethane. The reaction mixture was stirred at room temperature for 35 minutes after which time the volume was reduced by approximately 50% via a rotovap. Then 20 mL of methanol was added and the reaction was stirred at room temperature for 3 hours. Evaporation of the solvent and column chromatography (9/1 hexanes/EtOAc) afforded of methyl indane-1-carboxylate (2.2 g, 100%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.Cl[C:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][N:25]=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:17]2[CH2:18][CH2:19][N:20]([C:24]3[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:21][CH:22]=2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccc(-c2[nH]c(C3=CCNCC3)nc2Cl)cc1
Reactant: FC(F)(F)c1cccnc1Cl
Product: FC(F)(F)c1ccc(-c2[nH]c(C3=CCN(c4ncccc4C(F)(F)F)CC3)nc2Cl)cc1

Procedure:
4-[4-Chloro-5-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-1,2,3,6-tetrahydropyridine from step (b) above reacted with 2-chloro-3-trifluoromethyl-pyridine (251 mg, 1.39 mmol, TCI America) under the conditions of Example 22(d) to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 473 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH2:17])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:18][CH2:19][C:20]([CH2:22]Cl)=O>>[Cl:18][CH2:19][C:20]1[N:17]=[C:15]([CH:14]=[C:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[O:16][CH:22]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=C1c2ccccc2-c2ccccc21
Product: ClCc1coc(C=C2c3ccccc3-c3ccccc32)n1
Yield: 36 %

Procedure:
In substantially the same manner as in Reference Example 47, 9-fluorenylideneacetamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(9-fluorenylidene)methyloxazole. The yield was 36%. Recrystallization from ethyl acetate-hexane gave yellow prisms, mp 175-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:6]
Reactant: O=C(O)c1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccncc1)c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
A mixture of 2,4,6-trichlorobenzoic acid (224 mg, 10 mmol), 4-aminopyridine (141 mg, 1.5 mmol), HATU (1140 mg, 3 mmol), and DIPEA (646 mg, 5 mmol) in 5 mL anhydrous DMF was stirred under nitrogen at room temperature overnight. The reaction mixture was poured into ice-water (20 mL) and extracted EtOAc (2×50 mL). The combined organics were evaporated to dryness in vacuum and the residue was purified by silica gel column chromatography (EtOAc) to afford the desired product (72 mg, yield: 24%). 1HNMR: (CD3OD-d4, 400 MHz): δ 8.38 (d, J=6.0 Hz, 2H), 7.65 (d, J=6.0 Hz, 2H), 7.52 (s, 2H). LCMS (ESI) m/z: 301.1 [M+H+].
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][C:11]#[N:12].[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[N:13][OH:14])[C:11]#[N:12]
Reactant: N#CCc1nc2ccccc2[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(=NO)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To an ice-cooled stirred solution of 10 g of 2-benzimidazolylacetonitrile (63.6 mmol, 1 eq) in 50 ml of glacial acetic acid is added dropwise a solution of 4.83 g of sodium nitrite (70 mmol, 1.1 eq) dissolved in a minimum amount of water (10 mL). When the addition is completed, the reaction mixture is allowed to stir at room temperature for 1 h. The precipitate formed in the course of the reaction is filtered and washed with 2×20 ml of cold water and 2×30 ml of diethylether to provide 11.8 g of the product as light yellow solid.
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1.[CH2:24]([S:28](Cl)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[CH2:24]([S:28]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCS(=O)(=O)Cl
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pyridine (18 μl, 0.22 mmol) and 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 50 mg, 0.22 mmol) in CH2Cl2 (4 ml) was treated with butane-1-sulfonyl chloride (56 μl, 0.43 mmol). The reaction was stirred at rt for 18 h then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase was separated, dried (MgSO4) and evaporated. The residue was dissolved in EtOAc (5 ml) and extracted into 2M HCl (10 ml). The aqueous phase was then basified using 2M NaOH to pH=8 and extracted with CH2Cl2 (2×10 ml). The combined organic phases were dried (MgSO4) and evaporated to afford the title compound: RT=3.29 min, m/z (ES+)=351.2 [+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:44]=[CH:43][C:18]([C:19]([NH:21][C:22]2[C:26](/[CH:27]=[CH:28]/[P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:25][N:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:23]=2)=[O:20])=[CH:17][CH:16]=1.[H-].[Na+].[CH3:47]N(C)C=O.CI>O>[CH3:47][N:21]([C:19](=[O:20])[C:18]1[CH:43]=[CH:44][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)[C:22]1[C:26](/[CH:27]=[CH:28]/[P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:25][N:24]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:23]=1
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)C(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Yield: 83 %

Procedure:
To a mixture of diethyl (E)-2-[3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate (50 mg), sodium hydride (60% in oil, 3.9 mg) and N,N-dimethylformamide (2 mL) was added methyl iodide (14 mg) with stirring, and the mixture was further stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by reverse phase partition-high performance liquid chromatography (elution with distilled water containing 0.1% trifluoroacetic acid/acetonitrile) to give a colorless oil. To remove remaining trifluoroacetic acid, water was added to the oil, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-[3-(methyl{4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as a colorless oil (42.5 mg, yield 83%)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][C:10]=1[CH3:20])=[O:8].[N+](=[CH2:23])=[N-]>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH3:23])=[O:18])[C:12]2=[CH:11][C:10]=1[CH3:20])=[O:8]
Reactant: C=[N+]=[N-]
Reactant: Cc1cc2n(c1C(=O)c1cccn1C)CCC2C(=O)O
Solvent: ClCCl
Product: COC(=O)C1CCn2c1cc(C)c2C(=O)c1cccn1C
Temperature: 25 °C

Procedure:
A solution of 200 mg. of 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of methylene chloride is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([CH2:34][C:35]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][CH:36]=3)[C:20]([NH:22][C@@H:23]([CH2:27][S:28][S:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([OH:26])=[O:25])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[NH2:18][C@@H:19]([CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)[C:20]([NH:22][C@@H:23]([CH2:27][S:28][S:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:24]([OH:26])=[O:25])=[O:21]
Reactant: CC(C)(C)SSC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)SSC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of the prepared (R)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Fmoc-Trp-Cys(StBu)-OH) (Compound SP602) (500 mg, 0.809 mmol) in N,N-dimethylformamide (1.6 mL) was mixed with 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (134 μL, 0.890 mmol) with stirring at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (R)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (H-Trp-Cys(StBu)-OH) (Compound SP639) (290 mg, 0.733 mmol, 91%).
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[S:4]([NH2:7])(=[O:6])=[O:5].[C:22](OC)(OC)(OC)[O:23][CH3:24].C(O)(=O)C>O1CCOCC1>[CH3:22][O:23][C:24]1[O:1][C:2]([CH3:21])([CH3:20])[CH:3]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:12][CH:13]=2)[S:4](=[O:5])(=[O:6])[N:7]=1
Reactant: COC(OC)(OC)OC
Reactant: CC(C)(O)C(c1ccc(N2CCOCC2)cc1)S(N)(=O)=O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC1=NS(=O)(=O)C(c2ccc(N3CCOCC3)cc2)C(C)(C)O1

Procedure:
2-Hydroxy-2-methyl-1-(4-morpholin-4-ylphenyl)propane-1-sulfonamide (41 mg) was stirred with tetramethyl orthocarbonate (0.2 ml), glacial acetic acid (0.01 ml) and dioxane (0.1 ml) at 90° C. for 4 hours. The solvents were removed under reduced pressure and the residue was used further without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.[Li+].CC([N-]C(C)C)C.[I:19]I>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([I:19])[O:8][C:7]=12
Reactant: Clc1nccc2ccoc12
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1nccc2cc(I)oc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
7-Chlorofuro[2,3-c]pyridine (7.60 g, 49.7 mmol) was placed in a three-necked flask fitted with a thermometer and nitrogen inlet and then anhydrous tetrahydrofuran (150 mL) was added. The solution was cooled to −78° C. To this cold solution was added gradually 2 M LDA solution (32.3 mL, 64.6 mmol) by syringe and the resulting mixture was stirred for 2 h at −78° C. Then a solution of iodine (15.1 g, 59.5 mmol) in dry THF (100 mL) was added at −78° C. and the resulting mixture was allowed to warm to RT overnight. The reaction was quenched with aqueous sodium thiosulfate (75 mL) and diluted with ethyl acetate (150 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×75 mL). All organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to give 13.7 g (99%) of the title compound as a brown solid. 1H NMR (300 MHz, CDCl3): δ 7.06 (s, 1H), 7.40 (d, J=6.0 Hz, 1 H), 8.17 (d, J=6.0 Hz, 1H).
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH2:16][O:17]CC1OC1)([CH2:10][O:11]CC1OC1)[CH2:4][O:5]CC1OC1>CO>[CH2:4]([C:3]([CH2:16][OH:17])([CH2:10][OH:11])[CH2:2][CH3:1])[OH:5]
Reactant: CCC(COCC1CO1)(COCC1CO1)COCC1CO1
Solvent: CO
Product: CCC(CO)(CO)CO
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A 0.15 liter autoclave was charged with 23.2 g of MMA (0.75 moles). The temperature was maintained at 50° C. With agitation, 41.8 g of a 50% solution trimethylolpropane triglycidyl ether (0.05 moles; 0.15 eq) in methanol was added slowly at 0.7 g/min. No temperature increase was observed during the addition. After addition was complete, the reaction mixture was agitated for 30 minutes. The reaction was complete when the IR bands for the epoxy group at 914, 840 and 755 cm-1 were no longer present. The unreacted MMA was then removed from the reaction mixture by venting to a collection vessel. Residual MMA and methanol were removed from the product by reduced pressure distillation. 24.3 g of the MMA adduct of the triglycidyl ether of trimethylolpropane was obtained (95% of theory). The product had a total amine value of 291.3 mg KOH/g, an N--H equivalent weight of 254.2. This product will be identified as TMPTGEMMA-2 in following examples.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][S:12][CH2:13][CH2:14][OH:15])=[CH:4][N:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:16]([O:15][CH2:14][CH2:13][S:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][CH:4]=2)(=[O:18])[CH3:17]
Reactant: Nc1ncc2ncn(CSCCO)c2n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCCSCn1cnc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 100 ml flask equipped with a magnetic stirring bar and a CaCl2 drying tube was charged with 1.0 g (4.4 mM) 2-amino-9-(2-hydroxyethylthiomethyl)-9H-purine, 0.054 g (0.44 mM) 4-dimethylaminopyridine, 0.9 ml (8.8 mM) acetic anhydride, and 200 ml of dry DMF. The solution was stirred for 24 hrs at room temperature and then quenched with 5 ml of MeOH. The solution was evaporated in vacuo (bath temp 40° C.) and the brown oil so obtained chromatographed using the "flash" method. Elution of the column with 1.5% methanol in ethyl acetate provided a yellow oil which crystallized on standing. The light yellow crystals were dissolved in a solution of 2% MeOH in toluene and treated with 0.05 g Darco G-60. The methanol was evaporated from the toluene solution resulting in the precipitation of light yellow crystals. The product was dried for 16 hrs at 78° C. to yield the title compound, mpt. 119°-120.5° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]([NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: NS(=O)(=O)c1cc2ccccc2o1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1cc2ccccc2o1
Yield: 82 %

Procedure:
2-Benzofuransulfonamide (7.6 mmol), prepared as described in Example 1, was reacted with 3,4-dichlorophenylisocyanate (7.6 mmol) as described in Method A to obtain 2.4 g of the title product as a solid. 1H NMR (CD3SOCD3): δ9.43 (s, 1 H), 7.88 (d, J =8 Hz, 1 H), 7.85 (s, 1 H), 7.80 (m, 1 H), 7.76 (m, 1 H), 7.59 (dd, J =6, 8 Hz, 1 H), 7.52 (d, J =8 Hz, 1 H), 7.45 (dd, J =6, 8 Hz, 1 H), 7.35 (dd, J =3, 6 Hz, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:19]=1[CH2:20][N:21]([CH:42]([CH3:44])[CH3:43])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:18]([F:17])[C:19]=1[CH2:20][N:21]([CH:42]([CH3:44])[CH3:43])[C:22](=[O:23])[NH:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:34]2[CH2:35][CH2:36][CH:37]([CH2:40][NH:1][CH2:2][C@@H:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH2:38][CH2:39]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CC(C)N(Cc1c(F)cccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N(Cc1c(F)cccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.159 g, 0.65 mmol), 1-(2,6-difluoro-benzyl)-3-[4-(4-formyl-piperidine-1-sulfonyl}-phenyl]-1-isopropyl-urea (0.6 mol),and glacial acetic acid (0.037 g, 0.65 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.041 g, 0.65 mmol) was added and the mixture stirred over night at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1) to give 0.12 g of product as an off white solid.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[CH:25]1([NH:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([N:31]2[C:2]3[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=3)[C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NNC1CCCCC1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(C3CCCCC3)c3cc(O)ccc23)c(O)c1
Yield: 24.7 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2 mmol) and cyclohexylhydrazine hydrochloride (0.150 g, 1.0 mmol) to give 0.040 g of product as a white solid