Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH3:51])[C:24](=[O:50])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)=[O:33])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[OH:21][C:18]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:11][C:2]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32](=[O:33])[NH:31][C:28]4[CH:27]=[CH:26][C:25]([C:24]([N:23]([CH3:51])[CH3:22])=[O:50])=[CH:30][CH:29]=4)=[CH:40][CH:39]=3)=[N:3]2)=[CH:8][CH:7]=1)([CH3:20])[CH3:19]
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: CC(C)(O)c1ccc2c(N3CCOCC3)nc(Cl)nc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(C(C)(C)O)cc4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 4.9 %

Procedure:
To a 50 mL round bottom flask, 2-(2-chloro-4-morpholino-quinazolin-7-yl) propan-2-ol (0.08 g, 0.00026 mol), N,N-dimethyl-4-[3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]ureido}-benzamide (0.128 g, 0.000312 mol), cesium carbonate (0.169 g, 0.00052 mol), DMF (3 mL) and water (1 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.009 g, 0.000013 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 5 h. To the cooled reaction mixture, water was added and extracted with ethyl acetate. The organic layer was separated, washed with water, brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 10% MeOH in chloroform. The compound was further purified by prep TLC using 10% MeOH in chloroform to obtain the title compound [0.007 g, 5%]. 1H NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.97 (s, 1H), 8.44 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.97 (d, J=8.8 Hz, 3H), 7.54 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 5.30 (s, 1H), 3.83 (brs, 4H), 3.81 (brs, 4H), 2.96 (s, 6H), 1.52 (s, 6H). LC-MS (ESI): Calculated mass: 554.2; Observed mass: 555.1 (RT: 0.17 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[O:5])[CH3:2].C(OC(NC(C(O)C1C=CC=CC=1)C(OC)=O)=O)C>>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(c1ccccc1)C(O)C(=O)OC
Agent: CCOC(=O)NC(C(=O)OC)C(O)c1ccccc1
Product: CCOC(=O)N[C@H](c1ccccc1)[C@H](O)C(=O)OC

Procedure:
(±)-(2RS,3SR)-Methyl 3-(ethoxycarbonylamino)-2-hydroxy-3-phenylpropanoate ((±)-21a) and (±)-(2RS,3SR)-Methyl 2-(ethoxycarbonylamino)-3-hydroxy-3-phenylpropanoate ((±)-21 b).
Reaction SMILES: CO[C:3](OC)(OC)[CH2:4][CH2:5][CH2:6][CH3:7].Cl.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:29]=1[NH:30][CH2:31][C:32]1([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:27][CH:26]=[CH:25][CH:24]=2>C1(C)C=CC=CC=1>[CH2:4]([C:3]1[N:30]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:19]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1
Temperature: 25 °C

Procedure:
Trimethylorthovalerate (1.8 mL, 10.4 mmol) and pyridine hydrochloride (92 mg, 0.8 mmol) were added to a suspension of 4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (8.0 mmol) in toluene (40 mL). The reaction mixture was heated at reflux for 2.5 hours and then cooled to ambient temperature. A precipitate was isolated by filtration and dried to provide 4-[(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a white solid, mp 180-181° C. MS (ESI) m/z 340 (M+H)+; Anal. calcd for C20H25N3O2: C, 70.77; H, 7.42; N, 12.38. Found: C, 70.58; H, 7.53; N, 12.40.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9](=[O:18])[C:8]=2[CH:19]=1>O.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH:9]([OH:18])[C:8]=2[CH:19]=1
Reactant: O=c1c2ccccc2ccc2ccc(Cl)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1c2ccccc2C=Cc2ccc(Cl)cc21

Procedure:
A solution of 0.30 gram (0.0078 mole) of sodium borohydride in 5 milliliters of water was added to a solution of 0.75 gram (3.2 millimoles) of 3-chloro-5H-dibenzo[a,d]cyclohepten-5-one in 50 milliliters of methanol and the resulting mixture heated for 15 minutes at reflux temperature to obtain 3-chloro-5H-dibenzo[a,d]cyclohepten-5-ol intermediate in the reaction mixture. The solvent was evaporated and the residue intermediate slurried with water, filtered, washed and dried at 65° C. in vacuum oven for three hours.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2)[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[O:23]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:18][CH:17]=3)[CH2:12][CH2:13][CH2:14]2)=[O:23])=[CH:26][CH:27]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CCN(CC)CCCCOc1ccc2c(c1)CCCN2
Product: CCN(CC)CCCCOc1ccc2c(c1)CCCN2C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to example 3.9, Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine and 4-chlorophenyl chloroformate were converted to yield 6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless oil, MS: 431 (MH+, 1Cl).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].[CH3:21]I>C1COCC1>[CH3:21][O:1][CH2:2][CH2:3][C@@H:4]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
(R)-tert-Butyl 3-hydroxy-1-phenylpropylcarbamate (Intermediate 60, 258 mg, 1.03 mmol) was dissolved in THF under nitrogen at 0° C. NaH was added and the reaction mixture was stirred at 0° C. for 10 min. MeI was added and the reaction mixture was stirred at room temperature for 30 min. then quenched with sat. aq. Na2SO4 and extracted with Et2O. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified via column chromatography using a biotage SP1 25+M column with a gradient 50% EtOAc in heptane calculated from TLC. Product fractions were combined and concentrated to give the title compound as a white solid (78 mg, 29%). LCMS=[M+H]=266
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][O:41][CH3:42])=[CH:35][C:3]=1[CH2:4][N:5]([CH:32]1[CH2:34][CH2:33]1)[C:6](=[O:31])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[Cl:30])=[CH:14][CH:13]=1)[CH:8]([OH:10])[CH3:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:1][C:2]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][O:41][CH3:42])=[CH:35][C:3]=1[CH2:4][N:5]([CH:32]1[CH2:34][CH2:33]1)[C:6](=[O:31])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[Cl:30])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9]
Reactant: COCCc1ccc(Cl)c(CN(C(=O)C(Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C(C)O)C2CC2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCCc1ccc(Cl)c(CN(C(=O)C(Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C(C)=O)C2CC2)c1
Temperature: 25 °C

Procedure:
N-[2-Chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-hydroxybutanamide from the previous step (1 eq.) in dichloromethane (0.05 M) was added at 0° C. Dess-Martin periodinane (1.2 eq.). The resulting solution was allowed to warm to RT over 2 h before the reaction was quenched with methanol and diluted with ether. This was then washed sequentially with sat. aq. NaHCO3, water and brine. Drying of the organic layer over MgSO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a colorless oil. Further purification by way of flash chromatography (SiO2, Hex→10:1 (v/v) Hex:EtOAc) afforded the title compound as a viscous oil.
Reaction SMILES: [Na].[C:2]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O)([O:4]CC)=O.[F:14][C:15]([F:20])([F:19])[C:16]([NH2:18])=[NH:17]>C(O)C>[F:14][C:15]([F:20])([F:19])[C:16]1[NH:18][C:2](=[O:4])[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:17]=1
Reactant: N=C(N)C(F)(F)F
Reactant: CCOC(=O)C1CCCCC1=O
Agent: [Na]
Solvent: CCO
Product: O=c1[nH]c(C(F)(F)F)nc2c1CCCC2
Temperature: 25 °C

Procedure:
To 10 mL of absolute ethanol under a nitrogen atmosphere was added 0.15 g of sodium metal. After all the sodium had reacted, 1.00 g of 2-carboethoxycyclohexanone was added followed by 0.78 g of 85% trifluoroacetamidine. The reaction was refluxed gently overnight. The reaction was cooled to room temperature and all solvents were removed by evaporation. The pH of the residue was adjusted to 6 with dilute hydrochloric acid and refluxed briefly and allowed to cool. The resulting solid was collected. (0.73 g, 57%): 1H NMR (DMSO-d6, 300 MHz) δ 13.0 (s, 1H), 2.78 (m, 2H), 2.45 (m, 2H), 1.78 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH:31]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:32][C:33]([O:35]C)=[O:34].O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[CH:31]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:32][C:33]([OH:35])=[O:34]
Reactant: COC(=O)CC(c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC(c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 3-(4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-3-phenylpropanoate (0.22 g, 0.39 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.033 g, 0.78 mmol) in water (1 mL). After stirring at room temperature for 24 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.080 g, 37%); 1H NMR (DMSO-d6): δ 1.45 (d, 1H, J=13.2 Hz), 1.55 (d, 1H, J=13.2 Hz), 1.81 (t, 2H, J=6.8 Hz), 2.33 (t, 2H, J=6.8 Hz), 2.48-2.50 (m, 2H), 2.57-2.68 (m, 4H), 3.07-3.10 (m, 2H), 3.84 (t, 2H, J=6.8 Hz), 4.37 (d, 1H, J=5.2 Hz), 4.70 (d, 1H, J=5.2 Hz), 5.52 (t, 1H, J=7.2 Hz), 6.75 (t, 1H, J=7.2 Hz), 6.86 (d, 2H, J=8.4 Hz), 6.96 (d, 3H, J=3.2 Hz), 7.16-7.24 (m, 3H), 7.29-7.32 (m, 1H), 7.37 (d, 4H, J=4 Hz), 10.80 (s, 1H), 11.50 (br, 1H); MS for C32H35N5O4 m/z 554.05 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28](O)=[O:29])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:56][CH2:57][CH2:58][NH2:59].C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:56][CH2:57][CH2:58][NH:59][C:28]([C:14]1[N:15]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:23]=2)[CH:16]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:31])=[O:10])[N:13]=1)=[O:29]
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)O)n1
Reactant: NCCCl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCCl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
90.6 mg (0.2 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylic acid (Example 20A) are dissolved in 500 μl of DMF, and 36.65 mg (0.3 mmol) of DMAP and 114 mg (0.3 mmol) of HATU are added. After stirring at RT for 5 minutes, a solution of 46.4 mg (0.4 mmol) of 1-chloro-2-aminoethane and 25.8 mg (0.2 mmol) of N,N-diisopropylethylamine in 500 μl of DMF is added dropwise. The reaction mixture is stirred at RT for 6 h, then filtered and purified by preparative HPLC (method 9). The product-containing fractions are evaporated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17](O)=O)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:20][C:21]1[CH:22]=[C:23]([NH2:28])[C:24]([NH2:27])=[CH:25][CH:26]=1>C(O)CO>[F:20][C:21]1[CH:26]=[CH:25][C:24]2[N:27]=[C:17](/[CH:16]=[CH:15]/[C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:28][C:23]=2[CH:22]=1
Reactant: Nc1ccc(F)cc1N
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Solvent: OCCO
Product: COc1cc(/C=C/c2nc3ccc(F)cc3[nH]2)ccc1-n1cnc(C)c1
Temperature: 100 °C

Procedure:
(E)-3-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-acrylic acid (100 mg, 0.39 mmol) and 4-fluorobenzene-1,2-diamine (49 mg, 0.39 mmol) were placed in a 4-mL vial. Ethylene glycol (1 ml) was added and the reaction mixture heated to 100° C. for 16 h and then to 165° C. overnight.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.COCCOC.[F:16][C:17]([F:22])([F:21])[C:18](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:18][C:17]([F:22])([F:21])[F:16])=[C:4]([Cl:9])[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(Br)cc1Cl
Solvent: COCCOC
Product: FC(F)(F)CNc1ccc(Br)cc1Cl
Temperature: 110 °C

Procedure:
4-Bromo-2-chloroaniline (5000 mg, 24.22 mmol) was dissolved in trifluoroacetic acid (40 ml) and 1,2-dimethoxyethane (50 ml) then cooled under argon to 0° C. To the mixture was added 2-picoline borane complex (12951.34 mg, 121.08 mmol) and then the reaction mixture was heated 110° C. for 90 minutes. Solvents were removed under reduced pressure and crude material was taken up in 1N HCl and stirred at 110° C. 30 minutes. Crude mixture was then diluted with EtOAc and water and extracted EtOAc (3 times). Organics were washed with water then brine, dried over sodium sulfate and evaporated to dryness under reduced pressure. Crude material was purified by silica gel chromatography using EtOAc/Hexanes as the eluent to afford 4-bromo-2-chloro-N-(2,2,2-trifluoroethyl)aniline.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].C([Br:31])CO.C(OCC)(=O)C>ClCCl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@H:5]1[O:4][CH2:1][CH2:2][Br:31])(=[O:10])[CH3:9]
Reactant: OCCBr
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OCCBr)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 9.46 g (24.3 mmol) of penta-O-acetyl-β-D-glucopyranose and 3.04 g (24.3 mmol) of ethylene bromohydrin in 100 mL of dichloromethane was put in a 200 mL round bottom flask in an argon atmosphere. Subsequently, 10 mL of boron trifluoride diethyl ether complex was slowly added dropwise to this solution with stirring. The resulting mixture was continuously stirred with ice cooling for another one hour and then stirred at room temperature overnight while protecting it from light. After the stirring, the color of the reaction solution turned orange. An adequate amount of ethyl acetate was added to the reaction solution, and the organic phase was washed with water, a saturated aqueous sodium hydrogen carbonate and a saturated saline successively. After the organic solution was dried over anhydrous sodium sulfate, the organic phase was filtered, and the solvent was evaporated under reduced pressure to give 2-bromoethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in the form of an oil (yield 11.0 g; 100%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[N:5]=[C:4]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[C:3]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38]>C(O)CO>[OH:30][CH2:31][CH2:32][O:37][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[N:5]=[C:4]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[C:3]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38]
Reactant: COc1cccc(Cc2nc(Cl)c(Oc3ccccc3OC)c(NS(=O)(=O)c3ccc(C(C)C)cn3)n2)c1
Solvent: OCCO
Product: COc1cccc(Cc2nc(NS(=O)(=O)c3ccc(C(C)C)cn3)c(Oc3ccccc3OC)c(OCCO)n2)c1

Procedure:
In analogy to Example 45, by reacting 5-isopropyl-pyridine-2-sulphonic acid [6-chloro-2-(3-methoxy-benzyl)-5-(2-methoxy- phenoxy)-pyrimidin-4-yl]-amide with Na in ethylene glycol there was obtained 5-isopropyl-pyridine-2-sulphonic acid [6-(2-hydroxy-ethoxy)-2-(3-methoxy-benzyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as a white foam. MS: 579.3 (M-H)
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O>[CH2:11]([C:17]1[S:18][C:19]([CH:3]=[O:4])=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCc1cccs1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCc1ccc(C=O)s1
Temperature: 5 °C
Yield: 85 %

Procedure:
In a 3 liter-four-necked flask, 173.7 (2.38 mol) of N,N-dimethylformamide was placed and cooled to 5° C., followed by addition of 201.4 g (1.31 mol) of POCl3 in 15 min. below 10° C. under stirring. After stirring for 30 min. below 10° C., 200 g (1.19 mol) of 2-hexylthiophene was added dropwise to the mixture in 10 min. at room temperature, followed by stirring for 1.5 hours and further stirring for 2 hours at 60° C. After the reaction, the reaction mixture was poured into 5 liter of iced water, subjected to 3 times of extraction with 2 liter of chloroform and washed 6 times with 2 liter of water. The organic layer was dried with CaCl2, followed by distilling-off of the solvent and reduced-pressure distillation in an atmosphere of nitrogen to obtain 199.2 g of a product (yield: 85.0%).
Reaction SMILES: [CH:1]1([S:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:25])[CH3:24]>CC(C)=O>[CH:1]1([S:7][CH2:8][S:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:23](=[O:25])[CH3:24])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc(SCSC2CCCCC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(SCSC2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
In 300 g of acetone was dissolved 26 g of the cyclohexylthio(4-hydroxyphenylthio)methane crude product in Synthesis Example 10. To this were added 21 g (0.15 mol) of potassium carbonate and 8.7 g (0.11 mol) of acetyl chloride. While heating in an oil bath at 70° C., the solution was ripened for 4 hours. At the end of ripening, the inorganic salt was filtered and washed with 50 g of acetone. The filtrate and wash liquid combined was concentrated, and the residue was dissolved in 300 g of dichloromethane and washed with 50 g of water. The organic layer was concentrated in vacuum again, obtaining 30 g of an oily product, which was used in the subsequent reaction without further purification.
Reaction SMILES: C(OC1C=CC(Cl)=C[C:7]=1[C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=1)=[O:9])CCC.N1CCOCC1.[S]>>[C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)(=[O:9])[CH3:7]
Reactant: CCCCOc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(=O)OCC)cc1
Agent: [S]
Solvent: C1COCCN1
Product: CC(=O)NCCc1ccc(CC(=O)O)cc1

Procedure:
The ethyl 4-(2-aminoethyl)-phenylacetate hydrochloride used as starting material is prepared in the following manner: 4-(2-acetamidoethyl)-acetophenone is reacted with morpholine and sulfur to give the thiomorpholide of 4-(2-acetamidoethyl)-phenylacetic acid (m.p. 117°-118° C.). Subsequent alkaline saponification, followed by esterification with ethanolic hydrochloric acid, gives ethyl 4-(2-aminoethyl)-phenylacetate hydrochloride; m.p. 177°-178° C., after recrystallization from ethanol.
Reaction SMILES: C(OC(N1C[C@H:10](O)[CH2:9][C@H:8]1[CH2:13]O[Si](C(C)(C)C)(C)C)=O)C=C.C(OC1C=C(OC)C(C(N2CC(=C)CC2CO[Si](C(C)(C)C)(C)C)=O)=CC=1[N+]([O-])=O)CCOC1C=C(OC)C(C(N2CC(=C)CC2CO[Si](C(C)(C)C)(C)C)=O)=CC=1[N+]([O-])=O.[CH2:83]([O:86][C:87]([N:89]1[CH2:93][C@H:92]([OH:94])[CH2:91][C@H:90]1[C:95]([OH:97])=[O:96])=[O:88])[CH:84]=[CH2:85].C(OC(N1C[C@H](O)C[C@H]1CO)=O)C=C.NC1C=CC(I)=CC=1C(N1CC(=C)C[C@H]1CO)=O>CO>[CH2:83]([O:86][C:87]([N:89]1[CH2:93][C@H:92]([OH:94])[CH2:91][C@H:90]1[C:95]([OH:97])=[O:96])=[O:88])[C:84]1[CH:10]=[CH:9][CH:8]=[CH:13][CH:85]=1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: C=C1CC(CO[Si](C)(C)C(C)(C)C)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)CC4CO[Si](C)(C)C(C)(C)C)cc3[N+](=O)[O-])cc2OC)C1
Agent: C=C1C[C@@H](CO)N(C(=O)c2cc(I)ccc2N)C1
Agent: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Solvent: CO
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
A solution of benzyl chloroformate (12.5 mL, 87.7 mL) in toluene (40 mL) was added to a solution of trans-4-hydroxy-L-proline 1 (10 g, 76.3 mmol) and NaHCO3 (16 g, 190 mmol) in H2O (165 mL) over a period of 15 minutes. After stirring at room temperature for 12 hours the two phases were allowed to separate. The aqueous phase was washed with diethyl ether (4×50 mL), cooled in an ice bath, and then acidified to pH 2 with conc. HCl. The resultant product was extracted with ethyl acetate (5×50 mL) and the combined organic extracts were dried (MgSO4) and the excess solvent evaporated in vacuo to afford a colourless viscous oil (20.30 g, 100%). [α]27D=−565° (c=0.1, MeOH). 1H NMR (CDCl3): δ 2.07-2.31 (m, 3H, H1), 3.52-3.59 (m, 2H, H3), 4.43-4.53 (m, 2H, H2,H11a), 5.8 and 5.11 (s, 2H, minor and major rotamers of H6, 1:2), 6.0 (bs, 2H, OH), 7.26-7.29 and 7.32-7.34 (m, 5H, minor and major rotamers of H arom, 1:2). IR (thin film): v=3414 (OH), 2940 (OH), 1682 (C═O), 1495, 1429, 1359 (CO2-), 1314, 1269, 1205, 1180, 1174, 1127, 1082, 1051, 993, 914, 866, 826, 769, 741, 697 cm−1. MS (EI): m/e (relative intensity): 266 (M+, 1), 265 (6), 220 (5), 176 (15), 130 (34), 108 (2), 91 (100), 86 (4), 68 (11). HRMS calcd. for C13H15NO5=265.0950 found 265.0976.