Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH2:9]1)=[O:7])(C)(C)C.F[C:22](F)(F)[C:23](O)=O.C(Cl)(=O)CC.C(N(CC)CC)C>C(Cl)Cl>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:10]2[CH2:9][N:8]([C:6](=[O:7])[CH2:22][CH3:23])[CH2:11]2)=[N:13][CH:14]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cn2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of 3-(5-nitro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (1.22 g, 4.36 mmol) in CH2Cl2 (100 ml) was treated with trifluoroacetic acid (TFA) (15 ml) and then stirred at room temperature for 2 h. After concentration, the raw mixture was digested in CH2Cl2 and washed with saturated aqueous NaHCO3. The aqueous phase was extracted with CH2Cl2 (×3), the combined organic layers dried over Na2SO4 and evaporated. The raw material was next dissolved in THF (80 ml) and the solution cooled to 0° C. Propionyl chloride (460 μl, 5.26 mmol) and triethylamine (735 μl, 5.28 mmol) were next added, the mixture allowed to reach 20° C. and stirred for a further 12 h. It was then diluted with CH2Cl2 and washed successively with 1N aqueous HCl, saturated aqueous NaHCO3 and water. The organic layer was dried (Na2SO4) and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 49:1) to afford the title compound (880 mg, 85% for two steps) as a brown oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][O:10][N:11]1[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]2[C:15]1=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccccn1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 46 %

Procedure:
2-Chloromethylpyridine hydrochloride (514 mg, 3.13 mmol), N-hydroxyphthalimide (515 mg, 3.18 mmol), and triethylamine (1.3 mL, 9.3 mmol) were mixed in acetonitrile (5 mL) and stirred at 80° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with 1N NaOH(aq), water, and brine. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was recrystallized from ethyl acetate and hexanes to provide N-(pyridine-2-ylmethoxy)phthalimide (364 mg, 1.44 mmol).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[C:10]([NH:11][C:12]([C:14]2([C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:16][CH2:15]2)=O)=[CH:9][CH:8]=[C:7]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:6]=1>C(O)C(C)C.CO>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2([C:12]3[NH:4][C:5]4=[N:6][C:7]([N:23]5[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]6[CH2:35][CH2:34][CH2:33][CH2:32]6)=[O:30])[CH2:24]5)=[CH:8][CH:9]=[C:10]4[N:11]=3)[CH2:16][CH2:15]2)[N:18]=1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnn2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)CO
Solvent: CO
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(c5cccnn5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 110 °C
Yield: 38.1 %

Procedure:
Sodium methoxide (74.4 mg, 1.37 mmol) was added to a solution of (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridazin-3-yl)cyclopropanecarboxamide (100 mg, 0.22 mmol) in isobutanol (2 mL) and methanol (2 mL). The reaction mixture was heated to 110° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting crude was purified via preparative TLC to afford the title compound (35 mg). MS (ES+APCI) (M+H) 418.2; LCMS retention time: 3.439 min (Method W1).
Reaction SMILES: [CH2:1]([C:3]1([NH:26]C(=O)OC(C)(C)C)[CH2:8][CH2:7][CH:6]([O:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[C@@H:19]([CH2:22][C@@H:23]([OH:25])[CH3:24])[CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH3:2].[ClH:34]>ClCCl>[ClH:34].[NH2:26][C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH:6]([O:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[C@@H:19]([CH2:22][C@@H:23]([OH:25])[CH3:24])[CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](C)O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CCC1(N)CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](C)O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask containing a solution of tert-butyl N-(1-ethyl-4-[[(3R)-3-[(2S)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)carbamate (70 mg, 0.15 mmol, 1.00 equiv) in dichloromethane (3 mL) was added 12 M hydrochloric acid (0.3 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum to give 60 mg (crude) of (2S)-1-[(3R)-12-[(4-amino-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propan-2-ol hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:2]#[C:3][CH3:4].Cl.[CH3:21][O:22][NH2:23].Cl>N1C=CC=CC=1>[CH3:21][O:22][N:23]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]1[CH:7]=[C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])[N:11]=[CH:10][N:9]=1
Reactant: CON
Reactant: CC#CCOc1cc(C(=O)c2ccccc2)ncn1
Agent: Cl
Solvent: c1ccncc1
Product: CC#CCOc1cc(C(=NOC)c2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 3 ml of pyridine were added 0.3 g of 6-(2-butynyloxy)-4-benzoylpyrimidine and 0.15 g of O-methylhydroxylamine hydrochloride, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into 10% hydrochloric acid and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give two isomers of (6-(2-butynyloxy)-4-pyrimidyl)phenylketone O-methyloxime (referred to as isomers A and B).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22](O)=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:37].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][CH2:22][NH2:37])[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CCCN)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid (5.0 g) is reacted with ammonia following the procedure outlined in example 39 and reduced with lithium aluminium hydride (3.0 g) in THF at room temperature. Aqueous work-up and crystallisation from methanol gives 2.6 g of 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-24-amino-5α-chola-8,14-diene.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([N:23]=[CH:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([NH:23][CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 253A (0.025 g, 0.055 mmol) in tetrahydrofuran (1.2 mL) and methanol (0.005 mL, 0.110 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.044 mL, 0.088 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (5.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.18 (s, 2 H) 6.16 (t, J=6.62 Hz, 1 H) 7.01 (dd, J=5.15, 3.31 Hz, 1 H) 7.07 (d, J=7.72 Hz, 1 H) 7.12 (m, 1 H) 7.29 (t, J=7.54 Hz, 2 H) 7.53 (m, 3 H) 7.67 (d, J=7.72 Hz, 2 H) 8.08 (d, J=8.09 Hz, 1 H) 16.24 (s, 1 H). MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([NH:16][C@@H:17]([C:25]([N:27]([CH3:71])[C@H:28]([C:32]([NH:34][C@H:35]([C:60](NCC(OC(C)(C)C)=O)=[O:61])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:59])[NH:41][S:42]([C:45]1[C:57]([CH3:58])=[C:56]2[C:50]([O:51][C:52]([CH2:55]2)([CH3:54])[CH3:53])=[C:48]([CH3:49])[C:46]=1[CH3:47])(=[O:44])=[O:43])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)=[O:80]>>[NH2:1][C@H:2]([C:14]([NH:16][C@@H:17]([C:25]([N:27]([CH3:71])[C@H:28]([C:32]([NH:34][C@H:35]([C:60]([OH:61])=[O:80])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:59])[NH:41][S:42]([C:45]1[C:57]([CH3:58])=[C:56]2[C:50]([O:51][C:52]([CH2:55]2)([CH3:53])[CH3:54])=[C:48]([CH3:49])[C:46]=1[CH3:47])(=[O:43])=[O:44])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=CO
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC(C)(C)C)c(C)c2c1OC(C)(C)C2
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](N)CC(=O)OCc2ccccc2)C(=O)O)c(C)c2c1OC(C)(C)C2
Yield: 95 %

Procedure:
2.3 g of Boc-Asp(OBzl)-DPhe-NMeVal-Arg(Pbf)-Gly-OtBu are dissolved in 23 ml of 95% formic acid for the removal of the terminal protective groups and concentrated in vacuo after 30 min. The product is triturated with ether, filtered off and dried in vacuo. H-Asp(OBzl)-DPhe-NMeVal-Arg(Pbf)-Gay-OHxHCOOH is obtained in a yield of 95%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:14][CH2:15][CH3:16].[CH:21](OCC)=[O:22].C(O)(=O)C>O1CCCC1.ClCCl.O>[CH:21]([CH:14]([CH2:15][CH3:16])[C:13]([O:18][CH2:19][CH3:20])=[O:17])=[O:22]
Reactant: CCOC=O
Reactant: CCCC(=O)OCC
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C=O)CC
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (120.6 mL, 0.86 mol) (Aldrich) in tetrahyrofuran (370 mL) was cooled to −30° C. n-Butyllithium (2.5 M in hexanes, 344.2 mL, 0.86 mol) (Aldrich) was added drop wise at such a rate that the reaction mixture temperature was kept between −30 to 0° C. The reaction mixture was then cooled to −75° C. in a dry ice-acetone bath. A solution of ethyl butyrate (100 g, 0.86 mol) (Aldrich) in tetrahydrofuran (170 mL) was added drop wise over 28 minutes and keeping the reaction temperature between −75 to −70° C. The mixture was stirred at the same temperature for an additional 30 minutes. Ethyl formate (125 mL, 1.55 mol) (Aldrich) was then added to this mixture over 25 minutes and maintaining the temperature between −75 to −70° C. The resultant mixture was allowed to warm to room temperature and stirred at room temperature for 3 hours. With external cooling in a cold water bath to keep the reaction temperature below 30° C. acetic acid (98.55 mL, 1.72 mol) was added, followed by water (430 mL) and dichloromethane (200 mL). After separating the layers, the organic layer was washed with water (300 mL). The combined water layer was extracted with dichloromethane (200 mL). The combined organic layer was washed with aqueous sodium bicarbonate solution (200 mL). The basic aqueous solution was extracted with dichloromethane (100 mL). All organic layers were then combined, dried over sodium sulfate over night, filtered and distilled to remove solvent leaving about 180 mL. (Some of the product was distilled over with tetrahydrofuran.) The residue was distilled at 65–81° C. (23 mm Hg). The fraction distilling over at 70–81° C. (23 mm Hg) gave ethyl 2-formylbutyrate. (Yield 68.35 g, 55.1%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13]C(C)(C)C)=[O:12])[C:6]1=[O:22].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][N:7]([C@@H:10]([C:18]([CH3:20])([CH3:21])[CH3:19])[C:11]([OH:13])=[O:12])[C:6]1=[O:22]
Reactant: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2F)C1=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2F)C1=O
Yield: 72.7 %

Procedure:
A solution of Example 135B (199 mg, 0.54 mmol) in dichloromethane (1.5 mL) was treated with trifluoroacetic acid (1.5 mL) at 25° C. for 16 h. The solvents were evaporated, and the crude residue was purified using reverse phase chromatography using 95% water (0.1% trifluoroacetic acid)/5% acetonitrile-100% acetonitrile to give the title compound (0.121 g, 73%).
Reaction SMILES: C1(S([C:10]([F:21])([F:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)=O)C=CC=CC=1.CC([O-])(C)C.[K+]>C1COCC1.CN(C=O)C>[F:20][C:10]([F:21])=[CH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)C(F)(F)CCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: FC(F)=CCCc1ccccc1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Typical Procedures for the Preparation of 1,1-Difluoro-1-alkenes (10) from Alkyl-substitued Difluoromethyl Sulfones (4): Under an argon atmosphere, into a Schlenk flask containing 1,1-difluoro-4-phenylbutyl phenyl sulfone (4g) (100 mg, 0.32 mmol) in THF (4 mL) at −20° C., was added dropwise via a syringe t-BuOK (224 mg, 2 mmol) in DMF (4 mL). The reaction mixture was stirred at −20° C.˜rt for 1 h, and the completion of the reaction was monitored by 19F NMR [δ −89.6 (d, J=46.6 Hz, 1F); −91.6 (dd, J=46.6 Hz, 24.8 Hz, 1F)]. The reaction was then quenched by adding aqueous NaCl solution (10 mL), followed by extraction with Et2O (15 mL×3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was removed. The crude product was purified by a flash chromatography to give 1,1-difluoro-4-phenyl-1-butene (10a) (46 mg, 85% yield) as a colorless liquid. The characterization data is consistent with that early reported.8h
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[CH3:2].[C:11]([NH:15][CH2:16][CH2:17][CH2:18][NH2:19])([CH3:14])([CH3:13])[CH3:12]>C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C@@H:6]([C:7]([OH:9])=[O:8])[NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:2]
Reactant: CC(C)(C)NCCCN
Reactant: CCOC(=O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NCCCNC(C)(C)C)C(=O)O
Yield: 77.2 %

Procedure:
In a manner analogous to that of Example 1, 400 ml of triethylamine are added to 317 g (2.2 mols) of maleic acidmonoethyl ester, and the mixture is subsequently reacted with 260 g (2.0 mols) of 3-tert-butylaminopropylamine. The reaction mixture is further processed as in Example 1 to yield 423.4 g (77.2% of theory) of a white crystalline aspartic acid derivative, which melts at 174°-175° C. after recrystallisation in a mixture of ethanol/acetone (1:3).
Reaction SMILES: C[O-].[Na+].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([O:22]C(=O)CCC)[CH2:14]2)=[CH:5]1.[NH4+].[Cl-].O>CO>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([OH:22])[CH2:14]2)=[CH:5]1
Reactant: CCCC(=O)O[C@@H]1C[C@H](c2c[nH]c3ccccc23)c2ccccc21
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: O[C@@H]1C[C@H](c2c[nH]c3ccccc23)c2ccccc21
Yield: 89.7 %

Procedure:
3 mL 30% NaOMe in methanol was added to 13.49 g butyric acid (1R,3S)-3-(1H-indol-3-yl)-indan-1-yl ester in 100 mL methanol. TLC showed full conversion after 1.5 hours. 1.5 g solid NH4Cl and 50 mL water were added. Methanol was removed in vacuo and after aqueous work up, (1R,3S)-3-(1H-indol-3-yl)-indan-1-ol (37.9 mmol ) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].C1(C)C(S(O[CH2:30][CH:31]2[CH2:35][CH:34]=[CH:33][CH2:32]2)(=O)=O)=CC=CC=1>>[CH:31]1([CH2:30][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])[CH2:35][CH:34]=[CH:33][CH2:32]1
Reactant: Cc1ccccc1S(=O)(=O)OCC1CC=CC1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2CC=CC2)c(=O)[nH]c1=O
Yield: 49.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and (cyclopent-3-en-1-yl)methyl toluenesulfonate were reacted by the same method with the example 1 to obtain the titled compound (68 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=1)[CH2:9][OH:10])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[NH2:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[CH:12]=1)[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(Br)c1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: NC(CO)c1cccc(-c2cccnc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of [1-(3-bromo-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (160 mg, 0.51 mmol) in ethyleneglycoldimethylether (10 mL) in a sealed tube were added pyridine-3-boronic acid (82 mg, 0.66 mmol), cesium carbonate (500 mg, 1.53 mmol) and water (2 mL). Argon was bubbled through the solution for 10 min, and Pd(PPh3)4 (30 mg, 0.025 mmol) was added. The reaction mixture was heated at 100° C. for 6 h. The reaction mixture was cooled down to room temperature, and ethyl acetate (20 mL) was added. The reaction mixture was washed with saturated NH4Cl (2×10 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated in vacuo, and the crude product was diluted in CH2Cl2 (8 mL) and trifluoroacetic acid (2 mL). The reaction mixture was agitated for 1 h and concentrated in vacuo. The residue was purified by solid phase extraction (SCX cartridge, silca gel benzene sulfonic acid linked) to give the title product (110 mg, 100% yield) as brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10]CC)=[O:9])[CH2:3]1.[OH-].[Na+]>>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1
Reactant: CCOC(=O)C1CN(C)CCN1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCNC(C(=O)O)C1
Yield: 99.4 %

Procedure:
Ethyl 4-methylpiperazine-2-carboxylate (1.03 g, 6 mmol) was reacted with NaOH (0.48 g, 12 mmol) according to the procedure as described in Example 21, Step A to give the title compound as colorless oil (0.86 g, 100%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH:15]=[CH:16][N:17](C)C)=[C:10]([Cl:21])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:24]N>C(O)C.C(OCC)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][NH:17][N:24]=2)=[C:10]([Cl:21])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1Cl
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc[nH]n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of [3-chloro-4-(3-dimethylamino-acryloyl)-phenyl]-carbamic acid tert-butyl ester (250 mg) in ethanol (1.25 ml) is treated with hydrazine hydrate (0.25 ml) and the mixture is stirred at room temperature for 3 hours. The mixture is then diluted with 30 mL of diethyl ether, washed three times with water, once with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure and the resulting residue is chromatographed over silica gel (67% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an oil.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:19][CH2:18]3)[C:14]([C:32](=[O:34])[NH2:33])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][N:45]([C:48](=[O:50])[CH3:49])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:48]([N:45]1[CH2:44][CH2:43][N:42]([C:39]2[CH:40]=[CH:41][C:36]([NH:35][C:11]3[N:16]=[C:15]([N:17]4[CH2:18][CH2:19][CH:20]([CH2:23][NH2:24])[CH2:21][CH2:22]4)[C:14]([C:32]([NH2:33])=[O:34])=[CH:13][N:12]=3)=[CH:37][CH:38]=2)[CH2:47][CH2:46]1)(=[O:50])[CH3:49]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(On3nnc4ccccc43)ncc2C(N)=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(N4CCC(CN)CC4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
A mixture of tert-butyl (1-(2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-5-carbamoylpyrimidin-4-yl)piperidin-4-yl)methylcarbamate (138 mg, 0.294 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (84 mg, 0.38 mmol) and p-toluenesulfonic acid (56 mg, 0.294 mmol) in dioxane (4 mL) was stirred at 100° C. for 3 h. dioxane was removed in vacuo. The residue was dissolved in CH2Cl2 (5 mL) and TFA (5 mL). The solution was stirred at room temperature for 30 min. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (15 mg). MS 453.6 (M+H); UV 222.8, 263.8 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[S-:12][C:13]#[N:14].[NH4+]>CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:12][C:13]#[N:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(SC#N)c[nH]c2c1
Yield: 28.8 %

Procedure:
Using the procedure described in Tetrahedron Letters 40 (1999), 1195-1196, 6-methoxy-1H-indole (1.0 g, 6.8 mmole) and ammonium thiocyanate (0.621 g, 8.1 mmole) were dissolved in methanol (35 ml) and treated with ceric ammonium nitrate (8.56 g, 15.6 mmole)in methanol (175 ml) at room temperature. The reaction mixture was stirred for 15 m and then diluted with water (700 ml) and extracted with methylene chloride (4×125 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography (silica gel) using ethyl acetate:hexane (1:9) as the eluting solvent to afford 6-methoxy-3-thiocyanato-1H-indole (0.40 g 29% yield).