Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]([C:28]([NH2:30])=[O:29])=[N:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=4)[CH:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:31][C:32]([F:39])([F:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl.N1C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]([C:28]([NH2:30])=[O:29])=[N:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][S:34]([CH2:33][C:32]([F:39])([F:38])[F:31])(=[O:36])=[O:35])[CH:22]=4)[CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Nc3cc(-c4cccc(N)c4)cnc3C(N)=O)cc2)CC1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3cc(-c4cccc(NS(=O)(=O)CC(F)(F)F)c4)cnc3C(N)=O)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of EXAMPLE 65A (18 mg, 0.045 mmol) in dichloromethane (0.4 mL) and pyridine (0.1 mL) was added to a cooled to 0° C. 2,2,2-trifluoroethanesulfonyl chloride (9 mg, 0.05 mmol). The reaction mixture was stirred slowly warming to ambient temperature over 18 hours and concentrated under reduced pressure. The crude material was purified by RP-HPLC (10 mM ammonium acetate/acetonitrile) to afford the title compound. 1H NMR (DMSO-d6) δ ppm 10.27 (s, 1H), 8.21 (d, J=3.0, 1H), 8.14 (d, J=1.9, 1H), 7.68-7.63 (m, 1H), 7.52-7.40 (m, 2H), 7.40-7.33 (m, 2H), 7.30-7.23 (m, 1H), 7.20-7.14 (m, 2H), 7.00-6.94 (m, 2H), 4.54 (q, J=9.8, 2H), 3.13 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H); MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:18][CH2:17]3)[C:14]3[C:19]([C:23]([O:25]C)=[O:24])=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:27]#[N:28].[I-].[Li+]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:17][CH2:18]3)[C:14]3[C:19]([C:23]([OH:25])=[O:24])=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:27]#[N:28]
Reactant: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(C3CC3)c12
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)O)c2n1C1CC1
Temperature: 100 °C

Procedure:
A solution of (S)-methyl 2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate (137 mg, 0.36 mmol) and lithium iodide (146 mg, 1.1 mmol) in pyridine (5 mL) was heated to reflux at 100° C. for 48 h. Another portion of lithium iodide (146 mg, 1.1 mmol) was added and the mixture was heated at 100° C. for another 48 h. The mixture was concentrated in vacuo, and subjected to the next reaction without further purification: LC-MS (ESI) m/z 364.1 [M+H]+.
Reaction SMILES: [C:1]([O:9][CH:10]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27]C(N)=S>CN(C)C=O>[C:2]1([C:1]2[O:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:27]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)C(OC(=O)c2ccccc2)c2ccc(C)cc2)cc1
Reactant: NC(N)=S
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(-c3ccccc3)oc2-c2ccc(C)cc2)cc1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
0.5 g of 2-oxo-1,2-di(p-tolyl)ethyl benzoate is dissolved in 10 ml of dimethylformamide in a reactor. 0.22 g of thiourea (2 eq.) is subsequently added and the reaction mixture is left to react at reflux (160° C.) for 5 hours. The solution is poured onto a water/ice mixture. The precipitated product is washed with water, filtered through a sintered glass filter under vacuum and placed overnight in a desiccator before being purified on a column of silica gel with dichloromethane as elutent.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH:12](Br)[CH3:13].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[O:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:3]([CH:4]=[O:5])[C:2]=2[O:1][CH2:13][CH2:12]1
Reactant: CC(Br)Br
Reactant: O=Cc1cccc(O)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: O=Cc1cccc2c1OCCO2
Yield: 69.6 %

Procedure:
2,3-Dihydroxybenzaldehyde (58 g, 420 mmol) was added to a refluxing mixture of dibromoethane (107.4 g, 570 mmol), sodium hydroxide (35.7 g, 890 mmol) and tetrabutyl ammonium bromide (3 g) in water (50 mL). After heating at reflux for 4 h, the mixture was cooled and the organic layer separated, washed with base, dried over sodium sulfate and concentrated in vacuo. The residue was Kugelrohr distilled at 135° to give the product (48 g, 70%) which solidified on standing (mp 61°-62° C.). Anal. Calc'd: C, 65.85; H, 4.91; Found: C, 65.73; H, 4.86.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>CN(C=O)C.O>[CH2:13]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH:6]=[CH:7]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2ccn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A solution of 6-bromoindole (5.0 g, 26 mmol) in dry DMF (45 mL) was cooled in an ice bath. Sodium hydride (2.2 g of 60% dispersion in oil, 55 mmol) was added. After stirring for 30 minutes under nitrogen at room temperature, the reaction mixture was cooled in an ice bath, and benzyl bromide (6.1 mL, 51 mmol) was added. After stirring for one hour at room temperature, the reaction mixture was poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was then washed with water and brine, then dried over anhydrous magnesium sulfate and evaporated to dryness. Purification of the residue by flash chromatography using hexane as an eluant and drying for 30 minutes at 60° C. yielded 1-benzyl-6-bromo-1H-indole (5.83 g, 80%) as a waxy solid, mp: 85-88° C. Mass spectrum (+ESI, [M+H]+) m/z 286; 1HNMR (500 MHz, DMSO-d6): δ 7.7 (d, 1H, J=0.61 Hz), 7.50-7.55 (m, 2H), 7.30 (t, 2H, J=7.3 Hz), 7.2-7.25 (m, 1H), 7.2 (d, 2H, J=8.4 Hz), 7.15 (dd, 1H, J=8.4 Hz and 1.7 Hz), 6.5 (dd, 1H, J=3.1 Hz and 0.77 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].ClS(C1C=CC=CC=1C(O)=O)(=O)=[O:16].C1(C)C(C)=CC=CC=1>O>[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:16])(=[O:4])=[O:3]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cl
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(O)c1cccc(S(=O)(=O)O)c1
Yield: 95.6 %

Procedure:
250 g of 3-(chlorosulfonyl)benzoic acid containing 35.9% of water (corresponding to 160.2 g (0.73 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 86 g of water and 500 g of xylene and heated in a water separator. A total of 171 ml of water are expelled. The reaction mixture is cooled and the precipitated product filtered off with suction. After drying at 100° C./100 torr (13.16 kPa) 144.3 g of 3-sulfobenzoic acid are obtained, the purity determined by titration being 97.5%; this corresponds to a yield of 95.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]=O)[CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1cccnc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3cccnc3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 3-pyridinecarboxaldehyde to provide 47 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:31])=[CH:5]2.O=[C:33]([C:39]1C2C(C3C=CC=CC=3C=1OS(C(F)(F)F)(=O)=O)=CC=CC=2)[C:34](OCC)=O>>[C:27]([O:26][C@@H:20]([C:7]1[C:6]2[C:5]([C:4]3[CH:3]=[CH:2][CH:11]=[CH:10][C:9]=3[C:8]=1[O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[CH:39][CH:33]=[CH:34][CH:31]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:29])([CH3:28])[CH3:30]
Reactant: CCOC(=O)C(=O)c1c(OS(=O)(=O)C(F)(F)F)c2ccccc2c2ccccc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(OS(=O)(=O)C(F)(F)F)c2ccccc2c2ccccc12

Procedure:
Prepared by the similar method to make (S)-ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate in Example 20, using ethyl 2-oxo-2-(10-(trifluoromethylsulfonyloxy)phenanthren-9-yl)acetate instead of ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate. 1H-NMR: 400 MHz, (CDCl3) δ: 8.74-8.69 (m, 2H), 8.41 (d, J=4.4 Hz, 1H), 8.19 (d, J=4.2 Hz, 1H), 7.79-7.61 (m, 4H), 6.00 (s, 1H), 4.189-4.14 (m, 1H), 4.05-4.00 (m, 1H), 1.25 (s, 9H), 1.03 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([N:5]([C:14](=[O:19])[CH2:15][N:16]([CH3:18])[CH3:17])[NH:6][C:7](=[O:13])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:2]([CH3:4])[CH3:3].[OH2:20].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>CO>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[OH:20][NH:6][C:7]([C@H:8]([C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]([NH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:14](=[O:19])[CH2:15][N:16]([CH3:17])[CH3:18])=[O:13])[CH2:9]/[CH:10]=[CH:31]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:13]
Reactant: CC(C)CCC(=O)NN(CC(C)C)C(=O)CN(C)C
Reactant: O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CN(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.590 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(dimethylamino)acetyl]valerohydrazide in 10 ml of methanol was treated with 0.210 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.478 g of (E)-2(R)-[1(S)-(hydroxy-carbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(dimethylamino)acetyl]valerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1([C:55]2[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=2)[NH2:58])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>CN(C=O)C>[N:49]1([C:55]2[CH:56]=[C:57]([NH:58][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(N2CCOCC2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 43 %

Procedure:
DIEA (0.028 mL, 0.160 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.030 g, 0.146 mmol) and HATU (0.061 g, 0.160 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-morpholin-4-ylaniline (0.026 g, 0.146 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 43% yield: LCMS (ESI) m/z 367 (MH+).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:9]([C:11]([CH2:16][CH3:17])([CH2:14]O)[CH2:12][OH:13])[CH3:10].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([C:11]1([CH2:16][CH3:17])[CH2:12][O:13][C:4]2([CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]2)[O:7][CH2:14]1)[CH3:10]
Reactant: CCC(CC)(CO)CO
Reactant: O=C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(CC)COC2(CCC(=O)CC2)OC1
Temperature: 25 °C
Yield: 16365.5 %

Procedure:
30 g (0.27 mmol) of cyclohexane-1,4-dione, 35.4 g (0.27 mol) of 2,2-diethylpropane-1,3-diol and 360 mg of para-toluenesulfonic acid were heated in 200 ml of toluene on a water separator. After the mixture had been cooled to room temperature and the water of reaction separated off, the organic phase was washed with a semisaturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After the solvent had been evaporated, 65 g of crude product were obtained which was purified by flash chromatography (ethyl acetate/petroleum ether=1:4). The first fraction contained the 1,4-diketal which was formed as secondary product (10 g). The main fraction contained 28.5 g (47%) of a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=2)=[N:5][CH:4]=1.C([O-])(=[O:17])C.[K+].[OH-].[Na+].Cl>C(O)(=O)C.C(Cl)(Cl)Cl>[OH:17][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=2)=[N:5][CH:4]=1
Reactant: BrCc1cnc(-c2cccc(I)c2)o1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: OCc1cnc(-c2cccc(I)c2)o1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 99.6 %

Procedure:
5-Bromomethyl-2-(3-iodophenyl)-1,3-oxazole (300 mg, 0.824 mmol) obtained in Step 1 was dissolved in acetic acid (8 mL), and the mixture was stirred at 80° C. for 4.5 hours after adding potassium acetate (162 mg, 1.65 mmol). The mixture was cooled to room temperature, diluted with chloroform, and washed with water and a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in ethanol (3 mL) and THF (3 mL), and the mixture was stirred at room temperature for 2 hours after adding a 1 mol/L aqueous sodium hydroxide solution (4.12 mL, 4.12 mmol). The mixture was neutralized with 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give 5-hydroxymethyl-2-(3-iodophenyl)-1,3-oxazole (247 mg, quantitative).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5](N)[C:4]=2[N:3]=1.[CH2:17]([C@H:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([CH:24]1[NH:25][CH2:26][CH2:27][N:28]([N:9]2[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[CH:5][C:4]3[N:3]=[C:2]([CH3:1])[S:11][C:10]2=3)[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Product: Cc1nc2c(s1)N(N1CCNC(Cc3ccccc3)C1)c1ccccc1N=C2
Yield: 35.1 %

Procedure:
By a similar method to Example 460, using 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(0.703 g, 3.0 mmol) and (S)-2-benzyl-piperazine (0.538 g, 3.0 mmol) give 0.410 g of the title compound as a yellow solid: mp 250–252° C.; mass spectrum (ion spray): m/z=390 (M+1); Analysis for C22H23N5S(0.6 H2O): calcd: C, 66.01; H, 6.09; N, 17.49; found: C, 65.94; H, 5.66; N, 17.8 1.
Reaction SMILES: COC(C12CC3(O)CC(CC(F)(C3)C1)C2)=O.CCN(S(F)(F)F)CC.[F:26][C:27]12[CH2:37][CH:31]3[CH2:32][C:33]([F:36])([CH2:35][C:29]([C:38]([O:40]C)=[O:39])([CH2:30]3)[CH2:28]1)[CH2:34]2.[OH-].[Na+]>O.C1COCC1.CO.C(Cl)(Cl)Cl>[F:26][C:27]12[CH2:37][CH:31]3[CH2:32][C:33]([F:36])([CH2:35][C:29]([C:38]([OH:40])=[O:39])([CH2:30]3)[CH2:28]1)[CH2:34]2
Reactant: COC(=O)C12CC3CC(F)(CC(F)(C3)C1)C2
Agent: CCN(CC)S(F)(F)F
Agent: COC(=O)C12CC3CC(O)(CC(F)(C3)C1)C2
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C12CC3CC(F)(CC(F)(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Under a N2 atmosphere was added 22.8 g (100 mmol) of methyl-3-fluoro-5-hydroxyadamantane-1-carboxylate to 400 ml of dry chloroform and the resultant solution was cooled to -50° C. To this solution was added drop-wise 13.1 ml (100 mmol) of DAST. The suspension was allowed to warm to ambient temperature and then heated to reflux for 1.5 hours. The resultant solution was cooled and treated with water (400 ml). The organic layer was separated, and the aqueous layer was washed again with chloroform (50 ml). The organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 23.2 g of crude product. Under a N2 atmosphere was added to 75 ml of methanol, 50 ml of THF, 250 ml of water, 22.0 g (95.6 mmol) of methyl 3,5-difluoroadamantane-1-carboxylate generated in this step, followed by 8.0 g (200 mmol) of NaOH pellets. The solution was allowed to stir overnight. The aqueous solution was extracted with ethyl acetate. The aqueous layer was acidified to a pH of 1.0 with 1N HCl and the resultant solution was extracted with ethyl acetate (200 ml), and this organic extract was washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 19.8 g (96%) of 3,5-difluoroadamantane-1-carboxylic acid. An analytical sample of this compound was obtained following an EtOAc/Hexane recrystallization: mp 162-164° C.; 1H NMR (CDCl3) 3C NMR (DMSO) 30.16, 35.67, 39.55, 42.09, 44.92, 46.92, 93.29. Crystals from the recrystallization were suitable for X-ray analysis. Anal. Calc'd for C11H14O2F2 : C, 61.10; H, 6.53; F, 17.57; Found: C, 61.00; H, 6.57; F, 17.32.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([OH:14])=[O:13]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)CCl
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A solution of 4-aminobenzonitrile (12 g, 101.6 mmol) and chloroacetic acid (20 g, 211.6 mmol) in water (250 mL) was refluxed until the product began to separate out. After cooled down to the room temperature, the solids were collected by filtration, washed with ether, and dried in vacuo to afford 10.35 g (58%) of the title compound which was pure enough for the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.46 (dd, 2H), 6.93 (t, 1H), 6.65 (dd, 2H), 3.91 (d, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[CH3:49][C:50]1([C:65]([O:67][CH2:68][CH3:69])=[O:66])[O:55][CH2:54][C:53](B2OC(C)(C)C(C)(C)O2)=[CH:52][O:51]1>>[O:42]=[S:38]1(=[O:41])[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C@:16]23[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]2[C@@H:18]2[C@@:13]([CH3:43])([CH2:14][CH2:15]3)[C@@:12]3([CH3:44])[C@@H:21]([C@:22]4([CH3:25])[C@@H:9]([CH2:10][CH2:11]3)[C:8]([CH3:45])([CH3:46])[C:7]([C:53]3[CH2:54][O:55][C:50]([CH3:49])([C:65]([O:67][CH2:68][CH3:69])=[O:66])[O:51][CH:52]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:36][CH2:37]1
Reactant: CCOC(=O)C1(C)OC=C(B2OC(C)(C)C(C)(C)O2)CO1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=COC(C)(C(=O)OCC)OC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 13.3 %

Procedure:
The title compound was prepared following the method described in step 1 for the preparation of Example 1, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and ethyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-1,3-dioxine-2-carboxylate as the reactants. The product was isolated as a mixture of diasteromers in 13.3% yield. MS: m/e 741.55 (M+H)+, 2.72 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 6.35-6.30 (m, 1H), 5.36 (d, J=5.5 Hz, 1H), 4.73 (s, 1H), 4.60 (s, 1H), 4.42 (ddd, J=15.4, 7.6, 1.4 Hz, 1H), 4.33-4.21 (m, 2H), 4.20-4.12 (m, 1H), 3.14-3.00 (m, 11H), 2.80-2.47 (m, 2H), 2.12-1.73 (m, 2H), 1.69 (s, 3H), 1.62 (s, 3H), 1.55-1.19 (m, 11H), 1.10-1.02 (m, 12H), 1.00-0.94 (m, 6H), 0.92-0.87 (m, 3H), 0.86-0.78 (m, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:10]([C:27]([O:29][CH3:30])=[O:28])[CH2:9]1)=O)(C)(C)C.[ClH:31].C(OCC)(=O)C>>[ClH:31].[ClH:31].[CH3:26][O:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[O:23][CH3:24])[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(OC)c(OC)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1CNCCN1Cc1cc(OC)c(OC)c(OC)c1
Reaction time: 5 h

Procedure:
In 4.5N HCl-ethyl acetate solution (20 ml) is dissolved methyl 4-tert-butoxycarbonyl-1-(3,4,5-trimethoxybenzyl)piperazine-2-carboxylate (5.0 g) obtained in Reference Example 19, and the solution is left standing at room temperature for 5 hours. The reaction mixture is concentrated under reduced pressure to give crystalline methyl 1-(3,4,5-trimethoxybenzyl)-piperazine-2-carboxylate dihydrochloride (4.3 g). This product is recrystallized from ethanol to afford colorless needles, m.p. 170-175° C.
Reaction SMILES: [C:1]1(B2OC(C)(C)C(C)(C)O2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.I[C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[OH-].[K+]>O1CCOCC1.O>[C:1]1([C:17]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc(C2=CCCCC2)c(C(=O)O)c1

Procedure:
In analogy to a procedure described by Masuda et al. [M. Murata, T. Oyama, S. Watanabe, Y. Masuda, Synthesis 2000, 778] a stirred mixture of 1 eq. 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, 0.8 eq. 2-iodo-5-methanesulfonyl-benzoic acid, 2 eq. aqueous 3M KOH solution and 0.03 eq PdCl2 (dppf)2-CHCl3 in dioxane (0.2 ml per mmol) were heated to 80° C. for 5 h. Then the reaction mixture is diluted with water, extracted with AcOEt, the aqueous phase acidified with 2N H2SO4, extracted with AcOEt and the pooled organic extracts dried over Na2SO4, filtered and evaporated. The crude product is purified by flash-chromatography on silica gel with heptane/AcOEt as eluent to yield the title compound; MS (ISN): 279.8 M−H−.