Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24](=[O:35])[CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl.O.C1(C)C=CC=CC=1>[NH2:27][CH2:26][CH2:25][C:24]([C:21]1[N:22]=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C@@H:8]([OH:7])[C@H:9]([NH:5][C:3](=[O:4])[CH:2]([F:38])[F:1])[CH2:10][F:11])=[CH:17][CH:16]=2)=[CH:19][CH:20]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCCC(=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: NCCC(=O)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A solution of the product of step 3, Example 28 (554 mg, 1 mmol) in methylene chloride (20 ml) at 0° C. is treated with trifluoroacetic acid (10 ml) and allowed to warm to room temperature. After 30 minutes, water (3 drops) is added. The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is then diluted with toluene and evaporated. The material is purified by HPLC (Gemini NX C18MP A=0.1% trifluoroacetic acid in water MP B=0.1% trifluoroacetic acod in acetonitrile, Gradient 10% B to 50% in 10 min) to give title compound (248 mg): MS (ESI+) m/z 396.0 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(I)cc1
Yield: 67.7 %

Procedure:
0.75 g (0.00394 mol) of 1-benzyl-4-hydroxy-piperidine and 0.546 ml (0.00394 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 1.0 g (0.00375 mol) of 4-iodobenzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.07 g (68%) of 1-benzyl-piperidin-4-yl 4-iodo-benzoate were obtained as yellow crystals; m.p. 77°-78°.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:34][CH2:33][CH2:31][OH:32])=[O:16])[CH2:6][CH2:5]2
Reactant: NCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCO)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (5.00 g 19.98 mmol) in 150 mL THF was treated with 3.65 g CDI (22.5 mmol) and the exothermic reaction let stir for 1 h at room temperature. Ethanolamine (1.35 g, 22.10 mmol) in 50 mL THF was added over 1 h and the solution stirred overnight. The reaction was concentrated, dissolved into 375 mL CH2Cl2 and washed with 250 mL 0.1 M HCl, 250 mL 0.5 M NaHCO3, 2×100 mL saturated NaCl and dried over Na2SO4. The acidic aqueous phase was extracted 3×100 mL CH2Cl2 and washed with 50 mL saturated NaCl and dried over Na2SO4. The combined organics were concentrated and purified by flash chromatography yielding 2.88 g of 6-hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as an off white impure solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(O)COCc1ccccc1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Ethyl 4-benzyloxyacetoacetate (42.1 g) synthesized according to the method describe in U.S. Pat. No. 5,399,722 was dissolved in methanol (300 mL) and sodium borohydride (3.03 g) was added at a temperature of from 5° C. to 10° C. The mixture was stirred for 1 hr and water (300 mL) was added. The solvent was mostly evaporated, and the organic layer extracted twice with MTBE (300 mL) was washed twice with 2% sodium hydrogen carbonate (100 mL) and washed twice with saturated brine (150 mL), dried over anhydrous magnesium sulfate and filtrated. MTBE was evaporated to give ethyl (±)-4-benzyloxy-3-hydroxybutanoate (38.8 g). To a solution of lithium diisopropylamide 1.5 M cyclohexane solution (190 mL) in THF (200 mL) was added a solution of ethyl (±)-4-benzyloxy-3-hydroxybutanoate (29.4 g) in THF (50 mL) at a temperature of from −78° C. to −60° C. and the temperature was raised to −20° C. Separately, 2-iodoethanol (34.4 g) and ethyl vinyl ether (23.1 g) were mixed in the presence of p-toluenesulfonic acid monohydrate (20 mg) to give 2-(1-ethoxyethoxy)ethyl iodide (47.9 g) and 39.3 g thereof was added dropwise at a temperature near −20° C. to 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was poured into a 1N aqueous hydrochloric acid (450 mL), and the mixture was extracted twice with MTBE (200 mL) and washed with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated and methanol (300 mL) and p-toluenesulfonic acid monohydrate (5.3 g) were added to the residue. The mixture was stirred at room temperature for 6 hr. Triethylamine (2.0 g) was added to the reaction mixture and the solvent was mostly evaporated. The residue was extracted with ethyl acetate (300 mL). The organic layer was washed with water (150 mL) and saturated aqueous sodium hydrogen carbonate solution (150 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated. Diisopropyl ether (120 mL) was added to the residue and the mixture was recrystallized to give the title compound (5.65 g) (yellow fine crystals). The peak of syn-form (1′R*,2R*-body) was not detected in NMR and HPLC under the following conditions.
Reaction SMILES: F[C:2]1[C:3]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=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>[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:3]([C@H:8]3[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: O[C@H]1CCC[C@@H](c2nccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2nccnc2[C@H]2CCC[C@@H](O)C2)cc1)c1nc2ccccc2[nH]1
Temperature: 180 °C

Procedure:
A mixture of (rac)-cis-3-(3-fluoropyrazin-2-yl)cyclohexanol (140 mg, 0.713 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (340 mg, 1.427 mmol), and cesium carbonate (465 mg, 1.427 mmol) in NMP (1.8 ml) was heated in a Biotage™ microwave reactor at 180° C. for 45 min. The mixture was partitioned between H2O (10 ml) and CH2Cl2 (20 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-cis-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone as a brown foam. MS (ESI, pos. ion) m/z: 415.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[C:2]1[CH:14]=[CH:13][CH:12]=[C:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH:3]=1.[I:21]I>C1COCC1>[I:21][C:12]1[CH:13]=[CH:14][C:2]([C:1]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:3][C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: II
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(I)c(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Yield: 94 %

Procedure:
A dry and nitrogen-flushed 10-ml-Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with a solution of the di-tert-butyl isophthalate (278 mg, 1 mmol) in dry THF (1 ml). After cooling to 0° C., a freshly prepared (TMP)2Mg.2LiCl solution (0.6 mol/l in THF, 1.83 ml, 1.1 mmol) was added dropwise and the reaction mixture was stirred at the same temperature. The completion of the metalation (2 h) was checked by GC-analysis of reaction aliquots quenched with a solution of I2 in dry ether. Iodine (508 mg, 2 mmol) dissolved in dry THF (2 ml) was then added at 0° C. and the resulting mixture warmed to room temperature. After stirring for 1 hour, the reaction mixture was quenched with sat. aq. Na2S2O3, extracted with ether (3×20 ml) and dried over Na2SO4. After filtration the solvent was removed in vacuo. Purification by flash-chromatography (n-pentane/diethyl ether, 10:1) furnished compound 51a (380 mg, 94%) as a yellow oil.
Reaction SMILES: C([O:4][C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:9])[CH2:6][CH2:7][OH:8])(=O)C.[OH-].[K+].CO.O>C(Cl)(Cl)Cl>[C:11]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:5]([OH:4])([CH3:9])[CH2:6][CH2:7][OH:8]
Reactant: CC(=O)OC(C)(CCO)c1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CC(O)(CCO)c1ccccc1-c1ccccc1

Procedure:
2.84 g. of 3-acetoxy-3-p-biphenylyl-1-butanol are boiled for 2 hours with 2 g. of KOH in 50 ml. of methanol, water and chloroform are added and the mixture is worked up to give 3-p-biphenylyl-1,3-butanediol, m.p. 115°-117°.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: c1ccccc1
Product: CC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
Benzene was alkylated with isobutylene in batch-type reactor. The reactor was loaded with 1.25 g of Beta Zeolite CP 814E (Zeolyst International) and 55.5 mL (48.75 g) of benzene, sealed into the reactor, and the reactor was then purged with nitrogen. 11.4 g of isobutylene were then loaded into the reactor and the reactor was pressurized with N2 to 500 psi. The reaction was carried out at 180° C. for 2 hours. The reactor was then cooled to room temperature, depressurized and the liquid product was analyzed by GC. t-Butylbenzene was produced in 38% yield.
Reaction SMILES: [C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[C:18](=[O:24])=[N:19]S(Cl)(=O)=O>C(#N)C>[C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[N:10]([C:18]([NH2:19])=[O:24])[C:9]2=[O:17])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2cnccc2C1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2ccncc21

Procedure:
The title compound was prepared from 3-(2-thenoyl)-6-azaoxindole (Example 38) according to the procedure of Example 2C, using 3-(2-thenoyl)-6-azaoxindole (3.09 g, 12.6 mmol), N-chlorosulfonyl isocyanate (1.2 mL, 13.8 mmol) and acetonitrile (60 mL). Reaction time: 31/2 hours.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25](O)=[O:26])[CH:21]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:25]([C:22]3[CH:21]=[C:20]([CH3:19])[O:24][N:23]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1cc(C(=O)O)no1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1cc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (240 mg, 0.921 mmol) and 5-methylisoxazole-3-carboxylic acid (140 mg, 1.105 mmol). The product was purified with flash-chromatography. Yield 46 mg (13%). 1H-NMR (400 MHz; d6-DMSO): δ 1.15 (d, 3H), 4.28-4.35 (m, 2H), 4.40-4.50 (m, 1H), 6.45 (d, 1H), 6.93 (d, 1H), 7.81 (d, 1H), 7.91-7.93 (m, 1H), 7.98 (d, 1H), 8.07 (d, 1H), 8.71 (d, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH2:16])[C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:6]=1.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(O)C.C(NCC)C>[NH:16]([C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C@H:8]([C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Solvent: O
Solvent: CCNCC
Solvent: CC(C)O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 64.6 %

Procedure:
1.1 g (5 mmol) of Phe-Gly (manufactured and sold by PEPTIDE INSTITUTE INC., Japan) was dissolved in a mixture of 2 ml of water, 2 ml of 2-propanol and 1.5 ml of diethylamine to obtain a solution. To the obtained solution was gradually added 1.8 g (6.5 mmol) of trityl chloride, followed by stirring for one hour. To the resultant reaction mixture was added water, to thereby generate a precipitate. The generated precipitate was collected, washed with water and then dissolved in 5 ml of acetic acid, to thereby obtain an acidic solution. The solvents were distilled off from the obtained acidic solution under reduced pressure, to thereby obtain 1.5 g of Trt-Phe-Gly. 604 mg (1.3 mmol) of the obtained Trt-Phe-Gly, 158 mg (1.3 mmol) of DMAP and 853 mg (1.0 mmol) of paclitaxel were dissolved in 20 ml of methylene chloride to obtain a solution. To the obtained solution was added 164 mg (1.3 mmol) of DIPC and stirred overnight at room temperature to effect a reaction. After completion of the reaction, the solvents were distilled off from the resultant reaction mixture under reduced pressure. The resultant residue was purified by silica gel column chromatography (silica gel: Art No. 9385, Silica gel 60, 200-400 mesh, manufactured and sold by Merck KGaA, Germany; column: 4.0×30 cm; eluent: methylene chloride/acetonitrile ratio=80/20), to thereby obtain 980 mg of 2′-Trt-Phe-Gly-paclitaxel. 800 mg of the obtained 2′-Trt-Phe-Gly-paclitaxel was treated with 10 ml of 90% acetic acid to effect a reaction for removing an N-trityl group. The resultant product was purified by silica gel column chromatography (silica gel Art No. 9385, Silica gel 60, 200-400 mesh, manufactured and sold by Merck KGaA, Germany; column 4.0×30 cm; eluent: methylene chloride/methanol/acetonitrile ratio=95/5/5), and subsequently converted from an acetate to a corresponding hydrochloride with an ion exchange resin, to thereby obtain 450 mg of 2′-Phe-Gly-paclitaxel hydrochloride (186).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:45]=[CH:44][C:17]([C:18]([N:20]([CH3:43])[C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=4[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[O:35])=[O:19])=[CH:16][C:15]=3[O:46][CH3:47])=[O:12])[C:4]=2[N:3]=1.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>N1C=CC=CC=1>[CH3:48][S:49]([NH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([NH:13][C:14]3[CH:45]=[CH:44][C:17]([C:18]([N:20]([CH3:43])[C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=4[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)=[O:35])=[O:19])=[CH:16][C:15]=3[O:46][CH3:47])=[O:12])[C:4]=2[N:3]=1)(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(N)nc12
Solvent: c1ccncc1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(NS(C)(=O)=O)nc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.9 %

Procedure:
To a solution of 4-(2-amino-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (90 mg) in pyridine (1 ml) was added methanesulfonyl chloride (18 mg) in ice water bath under nitrogen and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution, water and brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-methanesulfonylamino-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (15 mg) as a powder.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:11][C:12](=[O:23])[C@@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[Li+].[BH4-]>C1COCC1>[C:19]([O:18][C:16](=[O:17])[NH:15][C@H:13]([C:12](=[O:23])[NH:11][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:3][OH:2])[CH3:14])([CH3:20])([CH3:21])[CH3:22]
Reactant: COC(=O)C(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1ccccn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC(CO)c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a suspension of ((S)-2-tert-Butoxycarbonylamino-propionylamino)-pyridin-2-yl-acetic acid methyl ester (1.12 g, 3.32 mmol) in 15 mL of THF was added LiBH4 (2 M in THF, 1.66 mL, 3.32 mmol) drop wise and the reaction was stirred at room temperature for 16 h. The reaction was carefully quenched by water, neutralized with 0.1 N HCl aq., extracted with EtOAc, washed with aq. NaHCO3 and Brine. Dried over Na2SO4, filtered and concentrated in vacuo to afford [(S)-1-(2-Hydroxy-1-pyridin-2-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (770 mg, 77%) as a white foam, m/z 310.60 [M+1]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:40]=[CH:39][C:35]([CH:36]=[N:37][OH:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:38]/[N:37]=[CH:36]/[C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:41])=[CH:40][CH:39]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Yield: 77.6 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 4-(3-bromo-propoxy)-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (0.46 g, 0.97 mmol), 4-trifluoromethyl-benzaldehyde oxime (0.19 g, 1.01 mmol) and cesium carbonate (1.26 g, 3.86 mmol) in acetone (35 mL). The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 10/90) to give 2-{[4-(trifluoromethoxy)benzoyl]amino}-4-{3-[({(1E)-[4-(trifluoromethyl)phenyl]methylidene}amino)oxy]propoxy}benzoic acid methyl ester (0.44 g, 78%) as a white solid. 1H NMR (500 MHz, DMSO-d6); δ 11.92 (s, 1H), 8.38 (s, 1H), 8.32 (d, 1H), 8.05 (d, 2H), 7.97 (d, 1H), 7.80-7.21 (AA′BB′, 4H), 7.60 (d, 2H), 6.82 (dd, 1H), 4.34 (t, 2H), 4.21 (t, 2H), 3.87 (s, 3H), 2.18 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]2SCCS2)[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2].O.S(Cl)(Cl)(=O)=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]=[O:33])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C5SCCS5)c(c34)C[C@H]2N(C)C1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
2.05 g (5 mmol) of 1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]urea is dissolved under argon in 46 ml of chloroform. Then 3.5 g of silica gel and, under vigorous agitation, dropwise 3.5 ml of water are added. During a time period of 30 minutes, a solution of 1.18 ml of sulfuryl chloride in 30 ml of chloroform is added drop by drop. After stirring for 3 hours at room temperature, 7.5 g of potassium carbonate is added and the mixture is vigorously stirred for 20 minutes. The precipitate is filtered off and washed with chloroform. The precipitate is moistened with ethanol and introduced into 300 ml of saturated sodium chloride solution which is then repeatedly extracted with chloroform. The chloroform extracts and the chloroform filtrate are jointly dried over magnesium sulfate and evaporated. The subsequent crystallization is performed from ethyl acetate, thus isolating 0.93 g of 1,1-diethyl-3-(6-methyl-2-formyl-8α-ergolinyl)urea (54% yield).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][NH:13][C:14]1[C:19]([Cl:20])=[C:18]([CH3:21])[N:17]=[C:16]([CH3:22])[N:15]=1)C1C=CC=CC=1.Cl>C(O)C>[Cl:20][C:19]1[C:14]([NH:13][CH2:12][C:11]2[CH:10]=[C:9]([OH:8])[CH:25]=[CH:24][CH:23]=2)=[N:15][C:16]([CH3:22])=[N:17][C:18]=1[CH3:21]
Reactant: Cc1nc(C)c(Cl)c(NCc2cccc(OCc3ccccc3)c2)n1
Agent: Cl
Solvent: CCO
Product: Cc1nc(C)c(Cl)c(NCc2cccc(O)c2)n1
Yield: 51.9 %

Procedure:
In analogy to the method described in example B1, 23.5 g (66 mmol) of (3-benzyloxybenzyl)(5-chloro-2,6-dimethylpyrimidin-4-yl)amine (from example A2) are reacted with 240 ml of 12.5N hydrochloric acid in 240 ml of ethanol. Extraction with ethyl acetate at a pH of 8 gives, after concentration, a solid residue which is extracted by stirring with water and dried. 9.03 g (52%) of the title compound are isolated as a beige crystallizate. m.p.: 194-197° C.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[Br:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[F:21]>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[F:21])[O:22][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(F)c(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
Add TBSCl (3.37 g, 22.37 mmol) and imidazole (1.9 g, 27.96 mmol) to a solution of 3-bromo-4-fluoro-phenol (3.56 g 18.64 mmol) in CH2Cl2 (60 ml). Stir the solution at ambient temperature for 3 hours. Quench the reaction with water (30 mL). Extract the aqueous layer with CH2Cl2 (30 mL×3). The combined organic layers are washed with brine, dried over Na2SO4, concentrated under vacuum. The residue is purified by silica gel chromatography (petroleum ether) to give (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane as colorless oil (5.81 g, 99%), MS (m/z): 303 (M−1).