Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(OCC)(=[O:24])C>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:13](=[O:24])[CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Into a round-bottom flask, was placed a solution of tert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.4, 515 mg, 1.80 mmol, 1.00 equiv) in ethyl acetate (5 mL). A solution of NaIO4 (963 mg, 4.50 mmol, 2.50 equiv) in water (5 mL) and RuCl3 (74.7 mg, 0.36 mmol, 0.20 equiv) was carefully added. The resulting mixture was stirred overnight at room temperature. The solids were removed by filtration and the filtrate was washed with 2×20 mL of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 432 mg (80%) of the title compound as a light yellow oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.C([O:23][C:24]1[C:25](=[O:35])[C:26](=O)[C:27]=1[NH:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])CCC>O1CCCC1>[CH3:2][C:3]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:4]=1[CH2:5][NH:6][C:26]1[C:25](=[O:35])[C:24](=[O:23])[C:27]=1[NH:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH3:31]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: Cc1ccc(C)c(CN)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cc(C)ccc2C)c(=O)c1=O
Yield: 87.2 %

Procedure:
Tetrahydrofuran (10 mL), 2,5-dimethylbenzylamine hydrochloride (0.858 g, 5.0 mmol, Example 94, Step 2), triethylamine (0.51 g, 5.0 mmol), and 3-butoxy-4-(1,1-dimethylpropylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5.0 mmol, Example 3) were stirred together at room temperature for approximately 18 hours. After removal of solvent the residue was triturated with water, with diethyl ether, and dried to give 1.31 g of a light yellow solid. Three recrystallizations of the crude product from acetonitrile provided 0.812 g of the title compound as a fluffy, white solid: mp 199°-200° C. (softens 195° C.). MS (m/z) 301 ([M+H]+). HPLC indicates a major component (>99%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46]I>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:21][CH:20]2[CH2:44][O:45][CH3:46])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Product: COCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(COCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with methyl iodide there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 643 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9](Cl)(=[O:11])[CH3:10].O>N1C=CC=CC=1>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)(=[O:11])[CH3:10]
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(Br)cn1
Yield: 85 %

Procedure:
In 29 ml of pyridine was dissolved 1 g of 2-amino-5-bromopyridine which was then acetylated through reaction with 0.61 ml of acetyl chloride at room temperature for 15 hours with stirring. Following the addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer thus obtained was washed with brine. Dehydration, filtration and concentration under vacuum of the organic layer provided a solid which was then recrystallized in ethanol and hexane to obtain the title compound. 1.06 g. Yield 85%.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].[C:9]1(=[O:27])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH2:20]Br)=O)[C:12](=[O:22])[C:11]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:10]12>C(O)C>[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:20]=[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:12](=[O:22])[C:11]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:10]3[C:9]2=[O:27])[N:8]=1)[CH3:4]
Reactant: CN(C)CC(N)=S
Reactant: O=C(CBr)CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1nc(CCCCN2C(=O)c3ccccc3C2=O)cs1

Procedure:
Following the procedure of Example 1, a stirred solution containing 3.2 g. of dimethylaminothioacetamide hydrochloride, and 6.48 g of bromomethyl 4-phthalimidobutyl ketone [prepared by the procedure of Chem. Listy., 49, 1385 (1955); C.A., 50, 5573c (1956)]; in 50 ml. of ethanol was heated at refluxing temperature for about 5 hours and was then cooled. Volatile constituents were removed by evaporation in vacuo leaving 2-(dimethylaminomethyl)-4-(phthalimido-1-butyl)thiazole as a semi-solid residue. The compound was utilized without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncn1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyrimidin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.23 (s, 9H), 7.40 (d, 2H, J=8.4 Hz), 7.51 (dd, 1H, J=8.8 Hz, 2 Hz), 7.71-7.80 (m, 6H), 9.03 (d, 1H, J=4.8 Hz), 9.33 (d, 1.2 Hz), 10.91 (b, 1H). MS:m/z 434.0 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:21]=[C:22]=[O:23])[CH:19]=[CH2:20]>>[CH2:18]([NH:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23])[CH:19]=[CH2:20]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: C=CCN=C=O
Product: C=CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 95.8 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol) allyl isocyanate, 19.6 mg (96%) of the title compound were recovered.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9](O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]1([CH2:33][O:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN1CCOCC1.N1C2C(=NC=CC=2)N(O)N=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[C@H:18]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([NH:35][O:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)N1CCOCC1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)N1CCOCC1)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.9 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-[5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxobutanoic acid (212 mg, 0.58 mmol) in dichloromethane (DCM) (10 ml) was added O-(phenylmethyl)hydroxylamine (93 mg, 0.75 mmol), 4-methylmorpholine (0.17 ml, 1.5 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (79 mg, 0.58 mmol), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (133 mg, 0.70 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 5 hours. The reaction mixture was then washed with water (15 mL) and NaHCO3 solution (15 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (3R)-3-(cyclopentyl methyl)-4-[(5S)-5-(4-morpholinylcarbonyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-oxo-N-[(phenylmethyl)oxy]butanamide (57 mg, 21% yield). MS: 472 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[O:33][CH3:34]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][C:25]([CH3:32])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:19][C:18]=2[O:33][CH3:34])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COC(=O)c1nc(-c2ccc(N)c(OC)c2)oc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)c(C)o3)cc2OC)nc1Cl
Yield: 70.4 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.135 g, 0.78 mmol), thionyl chloride (4 mL), methyl 2-(4-amino-3-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (105d) (0.3 g, 1.03 mmol) and pyridine (5 mL), to obtain 0.23 g of the title compound as a colorless solid (71%).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2O1.[Cl:64]C1C=CC(B(O)O)=CC=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][C:32]([Cl:64])=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Agent: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Product: Clc1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and 4-chlorophenylboronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-chlorophenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.99 (bs, 1H), 8.05 (bs, 1H), 7.85 (s, 1H), 7.50-7.42 (m, 4H), 7.23 (bs, 1H), 7.10 (dd, 1H, J=2.4 and 8.7 Hz), 7.06 (t, 1H, J=2.4 Hz), 7.00-6.94 (m, 1H), 6.73 (d, 1H, J=8.7 Hz), 6.63 (d, 1H, J=8.7 Hz); LCMS: ret. time: 16.12 min.; purity: 86%; MS (m/e): 490 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH2:13].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:9][C:10]1[CH:11]=[C:12]([NH:13][C:6]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)=[O:8])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: O=C(O)c1ncc[nH]1
Reactant: Nc1cc(F)cc(F)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cc(F)cc(F)c1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (2.50 g, 22.3 mmol) in DMF (30 mL) were added 3,5-difluoroaniline (2.23 mL, 22.3 mmol), EDCHCl (6.41 g, 33.46 mmol) and HOBt (4.52 g, 33.46 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuum and the crude was dissolved in dichloromethane. The solution was washed with a diluted aqueous solution of potassium carbonate, dried over sodium sulphate, filtered and concentrated. 2.75 g (55% yield) of the title compound were obtained as a solid.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C1CCC(c2cccnc2F)CC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
4-(2-Fluoropyridin-3-yl)cyclohexanone (0.05 g, 0.26 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.19 g, 0.78 mmol), and cesium carbonate (0.25 g, 0.78 mmol) were mixed in NMP (1 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 140° C. for 48 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was partially purified by silica gel chromatography. The impure product was then dissolved in a minimal amount of DCM, and hexanes were added until a precipitate formed. The resulting suspension was partially concentrated and filtered to give 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 412.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:20][S:21]([O:1][CH2:2][C@H:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1COc2ccccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1COc2ccccc2O1
Reaction time: 0.5 h

Procedure:
To a solution of 0.410 g (2.467 mM) of (R)-2-hydroxymethyl-1,4-benzodioxane and 0.52 ml (3.70 mM) of triethylamine in 30 ml of diethyl ether was added 0.21 ml (2.71 mM) of methanesulfonyl chloride dropwise with ice-cooling and the mixture was stirred for 0.5 hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was passed through a short silica gel column (hexane-ethyl acetate=3/1 to 2/1) to provide crude (S)-2-methanesulfonyloxymethyl-1,4-benzodioxane.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.[C:19]([O:27][CH2:28][C@H:29]1[O:37][C@@:32]([O:35][CH3:36])([CH2:33][OH:34])[C@@H:31]([OH:38])[CH2:30]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC[C@H]1O[C@](OC)(CO)[C@@H](O)C1)(=O)C1C=CC=CC=1>CO>[C:19]([O:27][CH2:28][C@H:29]1[O:37][C:32]([O:35][CH3:36])([CH2:33][OH:34])[C@@H:31]([OH:38])[CH2:30]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CO[C@@]1(CO)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Agent: CO[C@]1(CO)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC1(CO)O[C@H](COC(=O)c2ccccc2)C[C@@H]1O

Procedure:
A solution of the product of Step 5 (5.6 g) in anhydrous methanol (140 mL) containing p-toluenesulfonic acid (374 mg) was refluxed for 30 min. The reaction mixture was cooled and neutralized with triethylamine. The solution was evaporated to dryness and applied on a column of silica gel equilibrated and eluted with etylacetate-ethanolhexane (10:1:10). Two fractions were obtained, methyl 6-O-benzoyl-4-deoxy-α-D-fructofuranoside and methyl 6-O-benzoyl-4-deoxy-β-D-fructofuranoside; methyl 6 -O-benzoyl-4-deoxy-β-D-fructofuranoside was the more polar of the two. The yield of methyl 6-O-benzoyl-4-deoxy-α-D-fructofuranoside was 2.45 g (syrup). The yield of methyl 6-O-benzoyl-4-deoxy-β-D-fructofuranoside was 1.47 g. The structures of methyl 6-O-benzoyl-4-deoxy-α-D-fructofuranoside and methyl 6-O-benzoyl-4-deoxy-β-D-fructofuranoside were established by 1H and 13C nmr.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][C@H:21]([C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])[CH3:22])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:84])[C@H:39]([CH2:80][CH:81]([CH3:83])[CH3:82])[NH:40][C:41](=[O:79])[C@H:42]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[NH:43]C(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CC1C=CC(O)=CC=1)NC(OC(C)(C)C)=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:84])[C@H:39]([CH2:80][CH:81]([CH3:82])[CH3:83])[NH:40][C:41](=[O:79])[C@H:42]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[NH:43][C:27](=[O:28])[CH2:26][NH:25][C:23](=[O:24])[C@H:21]([CH3:22])[NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonyl-L-tyrosyl-L-alanylglycine is substituted for the N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine of Example 12 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tyrosyl-L-alanylglycyl-L-phenylalanyl-L-leucine benzyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH:29]=O>>[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:29]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: O=CCc1ccccc1Br
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Oc1cccc(-c2c(-c3ccccc3Br)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2-Bromo-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 441.8; HRMS: calcd for C22H13BrF3NO+H+, 444.02053; found (ESI, [M+H]+), 444.0191.
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:9][C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)=[N:7][CH:6]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH3:15][C:10]1([C:8]2[S:9][C:5]([CH2:4][NH2:1])=[CH:6][N:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2ncc(CN=[N+]=[N-])s2)OCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2ncc(CN)s2)OCCO1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of the crude azide (113 mg, 0.50 mmol) in THF (6 mL) were added polymer supported Ph3P (262 mg, 1.00 mmol) and water (2 mL). The reaction mixture was stirred at 60° C. for 1 h, cooled down to rt, filtered and concentrated under reduced pressure. The residue was redissolved in CH2Cl2/MeOH 9:1, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 02: tR=0.48 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h
Yield: 89.6 %

Procedure:
A solution of 21 g of indole-4-carboxylic-acid-methylester in 100 ml of methylene-chloride, 24.9 ml of triethylamine and 7.34 g of 4-dimethyl-aminopyridine is proportionately mixed at 0° C. with 34.2 g of p-toluene-sulfonic-acid-chloride. After 16 h at 0° C., the mixture is diluted with methylene chloride, washed neutral with saturated sodium bicarbonate solution and NaCl solution, and the solvent is distilled off in vacuum. 35.37 g of 1-tosylindole-4-carboxylic-acid-methylester with a m.p. of 145°-147° C. (diisopropylether) is obtained.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=CC=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2C3C=CC(C(O)=O)=CC=3C3C2=CC=CC=3)=[CH:3][CH:2]=1.O[C:31]1[N:35]=[C:34]([NH-:36])[S:33][N:32]=1>>[CH:3]1[C:2]2[C:1](=[CH:24][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]=1[C:7]1[S:33][CH:34]([NH:35][C:31]#[N:32])[NH:36][N:8]=1
Reactant: O=C(O)c1ccc2c(c1)c1ccccc1n2Cc1ccc(-c2ccccc2)cc1
Reactant: [NH-]c1nc(O)ns1
Product: N#CNC1NN=C(c2ccc3ccccc3c2)S1

Procedure:
9-Biphenyl-4-ylmethyl-9H-carbazol-3-carboxylic acid (3-hydroxy-(1,2,4-thiadiazol-5-yl) amide;
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:20]1[CH2:48][O:47][C:22]2([CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Sn](CCCC)(CCCC)CCCC)=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[O:21]1>C1(C)C(C)=CC=CC=1>[CH2:20]1[CH2:48][O:47][C:22]2([CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([C:2]4[N:3]=[C:4]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]5)[C:5]5[C:10]([CH:11]=4)=[CH:9][CH:8]=[CH:7][CH:6]=5)=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[O:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(N4CCC5(CC4)OCCO5)cc3)cc3ccccc23)CC1
Yield: 51.6 %

Procedure:
3-Bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.72 g) and 4-(4,4-ethylenedioxypiperidin-1-yl)phenyltributylstannum (3.12 g) were reacted in the presence of tetrakistriphenylphosphine dichioride (0.5 g) in xylene (50 ml) at 140° C. for 5 hr. The reaction solution was concentrated, and ethyl acetate and an aqueous saturated solution of sodium bicarbonate were added to the resulting residue, for partitioning. The resulting organic layer was washed with water and brine, dried over magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 1.27 g of the title compound as a white powder.