Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.[CH2:24](Br)[CH:25]=[CH2:26].O>CN(C=O)C>[CH2:26]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][C:4]([Cl:3])=[CH:5][C:6]=1[N+:21]([O-:23])=[O:22])[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.2 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in DMF (2.0 ml), 4′-chloro-2′-nitro-p-toluenesulfonanilide (0.30 g (0.92 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, allyl bromide (0.50 ml (5.78 mmol)) was added dropwise. After being stirred for 30 minutes' at 50° C. and for 15 hours at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the crystals separated was filtered and washed to give 0.21 g (62%) of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([O:28][C:29]3[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1C=CC=CC1=O>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([O:28][C:29]3[C:30]([CH3:37])=[CH:31][C:32]([CH3:36])=[CH:33][C:34]=3[CH3:35])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C)c(Oc2nc(F)nc3c2ccn3Cc2ccccc2)c(C)c1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a solution of 4-aminobenzonitrile (101 mg, 0.86 mmol) in 1-methyl-2-pyridone (1 mL) was added NaH (34 mg, 0.86 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine (62 mg, 0.17 mmol) in 1-methyl-2-pyridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water, and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 64 mg (82%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>N1C=CC=CC=1>[CH2:22]([O:21][C:19]([NH:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)=[O:5])=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)COc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCC(=O)c1ccc(OCC(=O)OC)cc1
Yield: 79.5 %

Procedure:
Pyridine (40ml.) was added to a stirred mixture of methyl 4-(aminoacetyl)phenoxyacetate hydrochloride (5.2g.) and ethyl chloroformate (2.3g.). An exothermic reaction occurred and was allowed to continue until a homogeneous solution was obtained. This solution was then cooled and the solid residue which formed was first separated, and then washed successively with ether (2 × 30ml.), water (2 × 30ml.) and ether (2 × 30ml.), before recrystallisation from toluene to give methyl 4-[N-(ethoxycarbonyl)aminoacetyl]-phenoxyacetate (4.7g.), m.p. 128°-129° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:26][OH:27])=[C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:26]=[O:27])=[C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH:18]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)ccc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
Pyridiniumchlorochromate (1.67 g, 7.77 mmol) was added to N-(5-chloro-2-(hydroxymethyl) phenyl) pivalamide (1.34 g, 5.55 mmol) in CH2Cl2 (100 mL) at 0° C. 5 min later, the reaction mixture was stirred at room temperature for 3 hrs. Then it was passed through a thin silica gel pad with CH2Cl2(100 mL), concentrated on rotary vacuum and purified on flash chromatography eluting with 20˜40% EtOAc/hexanes (800 mL) to afford the expected product as a white solid(937 mg, 70% yield). 1H NMR (400 MHz, CHLOROFORM-D) δppm 1.28-1.34 (s, 9H), 7.15 (dd, J=8.31, 2.01 Hz, 1H), 7.53-7.59 (m, 1H), 8.87 (d, J=2.01 Hz, 1H), 9.84-9.88 (m, 1H), 11.42 (s, 1H); Mass spec. 240.07 (MH+), Calc. for C12H14ClNO2 239.07.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][NH:24][S:25]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:14]=1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:15]2[CH:14]=[N:13][C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[S:25]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=2)(=[O:26])=[O:27])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2cnc3ccccc3c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2cnc3ccccc3c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-(quinolin-3-ylmethyl)sulfamoyl)benzoate (step-1 of Example 38).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[N:36]=[C:37]([NH:40]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:38][CH:39]=1)\[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH2:15]I)[CH2:13][S:14][C@H:9]12)=[O:6].[C:60]([C:63]1[S:64][C:65]2[CH:70]=[CH:69][N:68]=[CH:67][C:66]=2[N:71]=1)([OH:62])=[O:61].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>CS(C)=O>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:4](=[N:3]/[O:2][CH3:1])/[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O-:19])=[O:18])=[C:12]([CH2:15][N+:68]4[CH:69]=[CH:70][C:65]5[S:64][C:63]([C:60]([OH:62])=[O:61])=[N:71][C:66]=5[CH:67]=4)[CH2:13][S:14][C@H:9]23)=[O:6])[N:36]=1
Reactant: O=C(O)c1nc2cnccc2s1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: COc1ccccc1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4sc(C(=O)O)nc4c3)CS[C@H]12)c1csc(N)n1

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate [VIIa] (466 mg, 0.5 mmole) and 2-carboxythiazolo[4,5-c]pyridine [prepared according to the procedure of Zhur. Obshchei Khim., 26, 613 (1956); C.A., 50, 13906 (1956)] (90 mg, 0.5 mmole) in 2 ml of DMSO was stirred at room temperature for 1.5 hours and diluted with ethyl acetate-ether to give 375 mg of crude quaternary salt, which was treated with 5 ml of TFA and 0.1 ml of anisole at room temperature for 15 minutes. The mixture was evaporated in vacuo and triturated with ether to give 213 mg of crude Iv. The crude product was dissolved into a small volume of phosphate buffer (pH 7.0) and chromatographed on a column of packing (20 ml) in PrepPAK/C18 cartridge. The column was eluted with water (200 ml) and 10% aqueous CH3OH (150 ml) to afford 51 mg (17%) of the title compound (Iv) as an amorphous powder. Mp. 144°~160° C. (dec.). Estimated purity by HPLC: 85%.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:7]=1[CH3:17])O.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:7]=1[CH3:17])[CH2:3][C:2]([CH3:19])([CH3:18])[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)cc1C(O)CC(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3,3-dimethyl-1-(2-methyl-5-phenylfuran-3-yl)butan-1-ol (1.1 g) in toluene (15 mL) was added thionyl chloride (0.6 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.1 g, 100%) as an oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[CH3:45][NH:46][CH2:47][CH2:48][S:49]([CH3:52])(=[O:51])=[O:50].CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([N:46]([CH3:45])[CH2:47][CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])=[O:15])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: CNCCS(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)N(C)CCS(C)(=O)=O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). N-methyl-2-(methylsulfonyl)ethanamine (10.60 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-45% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (12 mg, 57% yield). 1H NMR (500 MHz, CD3OD) δ 0.77 (d, J=6.5 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 2.41-2.49 (m, 1H), 2.97 (s, 3H), 3.05 (s, 3H), 3.36 (t, J=6.5 Hz, 2H), 3.78 (t, J=6.5 Hz, 2H), 4.81-4.96 (m, 2H), 5.36 (d, J=11.0 Hz, 1H), 7.97 (d, J=2.5 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H), 12.39 (s, 1H). [M+H] calc'd for C18H23FN4O4S, 411; found, 411.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[C:34]1[S:35][CH:36]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:38]=1)(=O)C1C=CC=CC=1.[O-]CC.[Na+]>C(O)C>[C@@H:11]1([C:34]2[S:35][CH:36]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:38]=2)[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: CCOC(=O)c1csc([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1csc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The crude ethyl-(2′,3′,5′-tri-O benzoyl-β-D-ribofiuranosyl)thiazole-4-carboxylate (4, 15.00 g) was dissolved in dry ethanol (100 ml) and treated with sodium ethoxide powder (1.36 g, 20 mmol) under argon atmosphere. The reaction mixture was stirred at room temperature for 12 hr under argon. The solution was neutralized with Dowex 50W-X8 H+ resin, filtered and washed with methanol (100 ml). The filtrate was evaporated to dryness. The residue was partitioned between water (100 ml) and chloroform (I50 ml). The aqueous layer was washed with chloroform (100 ml) and evaporated to dryness. The residue was dissolved in methanol (100 ml), silica gel (15 g) was added and evaporated to dryness. The dried compound adsorbed silica gel was placed on top of the silica column (5×20 cm) packed in CH2Cl2. The column was eluted with CH2Cl2/acetone (7:3; 500 ml) followed by CH2Cl2/methanol(95:5; 1000 ml). The CH2 C12/methanol fractions were collected together and evaporated to give pure 5. A small amount was crystallized from 2-propanol/ether as colorless product. Yield 4.8 g (83%); mp 62-64° C. 1H NMR (DMSO-d6); δ 1.36 (t, 3 H), 3.52 (m; 2 H), 3.84 (m, 2 H), 4.06 (m, I H), 4.28 (m, 2 H), 4.94 (t, 1H), 4.98 (d, 1 H), 5.08 (d, I H), 5.46 (d, I H) and 8.52 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]=[O:11].[H][H]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11]
Reactant: O=CCCc1ccccc1O
Reactant: [H][H]
Product: OCCCc1ccccc1O

Procedure:
A process as claimed in claim 1, wherein the 3-(hydroxyphenyl)propionaldehyde I obtained as the product in a first step is hydrogenated in a second step by reaction with hydrogen in the presence of a hydrogenation catalyst at from 0° to 250° C. and under from 0.1 to 300 bar to obtain the corresponding 3-(hydroxyphenyl)propanol of the formula II ##STR14## where R1, R2, R3 and R4 have the same meanings as in claim 1.
Reaction SMILES: [NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[NH:4][C:3]1=[O:14].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1.C(Cl)Cl>CCCCCC.CCOC(C)=O>[NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[CH:26][CH:25]=2)[C:3]1=[O:14]
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2Cc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 64.7 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 93 from 1 g of 3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and 0.984 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silica using DCM and then a DCM/AcOEt mixture (70/30; v/v) as the eluent gives 1.053 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:5]([C:7]([N:9]2[CH2:16][C@H:15]3[C@H:11]([CH2:12][C:13]([F:18])([F:17])[CH2:14]3)[C@H:10]2[CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])[N:6]=1.O.NN>CCO>[NH2:20][CH2:19][C@H:10]1[N:9]([C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[O:8])[CH2:16][C@H:15]2[C@@H:11]1[CH2:12][C:13]([F:18])([F:17])[CH2:14]2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A mixture of (1S,2S,5R)-2-[3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-7,7-difluoro-3-azabicyclo[3.3.0]oct-2-ylmethyl)-isoindole-1,3-dione (130 mg), hydrazine monohydrate (0.078 mL) in EtOH (10 mL) was stirred at reflux for 1 h 45. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM, washed twice with water, brine, dried (MgSO4), filtered and concentrated to yield the title compound (90 mg, 92%) as a colorless oil which was used for the next step without further purification. LC-MS: tR=0.79 min; [M+H]+=392
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Cl:9][C:10]1[C:19]([N+:20]([O-])=O)=[C:18]([NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>O>[NH2:20][C:19]1[C:10]([Cl:9])=[N:11][C:12]2[C:17]([C:18]=1[NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1c(N)c(Cl)nc2ccccc12
Yield: 62.9 %

Procedure:
A solution of Na2S2O4 (10.3 g, 50.4 mmol) in water (40 mL) was added to a solution of tert-butyl 2-[(2-chloro-3-nitroquinolin-4-yl)amino]ethylcarbamate (3.70 g, 10.1 mmol). A white solid precipitated immediately and after 30 min the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure, was diluted with saturated aqueous sodium bicarbonate, and was extracted with dichloromethane three times. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to a pale yellow oil. Purification by flash chromatography (silica gel, gradient elution with 2:1 to 1:1 hexanes/ethyl acetate) afforded tert-butyl 2-[(3-amino-2-chloroquinolin-4-yl)amino]ethylcarbamate (2.14 g) as a colorless oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C:33]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])([CH2:37][CH2:38][CH2:39][NH:40][CH:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:42])[C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN1CCOCC1>CN(C)C=O>[CH2:46]([O:45][C:43](=[O:44])[CH:41]([N:40]1[CH2:39][CH2:38][CH2:37][C:33]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])([NH:32][C:30]([O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:31])[C:34]1=[O:36])[CH3:42])[CH3:47]
Reactant: CCOC(=O)C(C)NCCCC(NC(=O)OC(C)(C)C)(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1CCCC(NC(=O)OC(C)(C)C)(NC(=O)OC(C)(C)C)C1=O
Yield: 86.7 %

Procedure:
HATU (1.72 g, 4.5 mmol) was added to a solution of 2,2-bis(tert-butoxycarbonylamino)-5-(1-ethoxycarbonyl-ethylamino)-pentanoic acid (1.31 g, 3.0 mmol) and 4-methylmorpholine in dimethylformamide (50 mL). After 30 minutes the solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluent of ethyl acetate and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 2-[3,3-bis(tert-butoxycarbonylamino)-2-oxo-piperidin-1-yl]-propionic acid ethyl ester (1.11 g, 2.6 mmol, 86%). C20H34N2O7 calculated 414.2 observed [M+1]+415.2; rt=2.77 min.
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([O:15][C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])=[C:11]([F:26])[CH:10]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([O:15][C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])=[C:11]([F:26])[CH:10]=1
Reactant: CCCCCC[C@@H](C)OC(=O)c1ccc(OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(O)cc1F
Reaction time: 24 h

Procedure:
10% Palladium on charcoal (0.3 g), was added to a solution of compound 23 (8.20 g, 23 mmol) in ethyl acetate (200 ml). The solution was evacuated and left stirring with hydrogen at atmospheric pressure for 24 h. The catalyst was filtered off and the solvent removed in vacuo to yield a yellow oil which was purified by column chromatography (dichloromethane) on silica to yield the pure colourless oil. Yield 4.68 g (76%). [α]D=−28.39° at 25° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[C:24]1([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:29]=[CH:28][C:27]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:14])([F:15])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:26][CH:25]=1
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Product: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccc(-c2ccccc2)cc1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-(phenyl)phenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 455 ([M+H]+); Anal. Calcd for C28H17F3N2O: C, 74.00; H, 3.77; N, 6.16. Found: C, 73.99; H, 3.81; N, 5.92.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.C1(C2C=CC(O)=CC=2)CCCCC1.C([O:41][C:42](=O)[C:43]([S:46][CH3:47])=[CH:44]O)C>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:42](=[O:41])[C:43]([S:46][CH3:47])=[CH:44][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=CO)SC
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Agent: ClC[C@H]1CO1
Agent: Oc1ccc(C2CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CSc1cn2c(nc1=O)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Temperature: 80 °C
Yield: 35.4 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.91 g, 3.34 mmol) (prepared in accordance with the procedures set forth in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol) in toluene (50 mL) was added 3-hydroxy-2-methylsulfanyl-acrylic acid ethyl ester (1.08 g, 6.68 mmol) prepared in accordance with the procedures in Step 1 of Example 87 The reaction mixture was heated at 80° C. for 18 hours. The reaction mixture was concentrated and loaded onto a silica gel column and eluted with 0-5% 2-propanol/CH2Cl2 to afford 0.44 g of the title compound. [α]D25 +18.24 (c 0.537, CHCl3)
Reaction SMILES: [Cl:1][C:2]1([S:8](Cl)(=[O:10])=[O:9])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][S:8]([C:2]2([Cl:1])[NH:6][C:5]([Cl:7])=[CH:4][S:3]2)(=[O:10])=[O:9])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Product: O=S(=O)(NC1CC1)C1(Cl)NC(Cl)=CS1

Procedure:
In analogy to Example 2, the N-cyclopropyl-2,4-dichlorothiazolesulphonamide was prepared by reacting 2,4-dichlorothiazole-sulphonyl chloride from Example 1 with anhydrous cyclopropylamine. Following recrystallization from toluene, 24.4 g of product were obtained (89.2% of the theoretical yield), m.p.: 90°-91° C.
Reaction SMILES: [Cl-].[CH2:2]([N+:4]1[CH:8]=[CH:7][N:6]([CH3:9])[C:5]=1[CH3:10])[CH3:3]>C1COCC1>[CH2:2]([N:4]1[CH2:8][CH2:7][N:6]([CH3:9])[C:5]1=[CH2:10])[CH3:3]
Reactant: CC[n+]1ccn(C)c1C
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C1N(C)CCN1CC
Temperature: 25 °C
Reaction time: 60 h
Yield: 70 %

Procedure:
5.96 g (37.12 mmol) 1-ethyl-2,3-dimethyl-imidazolium chloride and 2.98 g (74.24 mmol) KH are mixed in a 250 ml flask in a glove box. 100 ml THF is added to the solution, and this is stirred for 60 h at room temperature. The reaction mixture obtained is filtrated over celite, and all components which are volatile at room temperature are condensed from the solution. Subsequently, the product is distilled at 160° C./0.1 mbar in a Schlenk tube cooled with nitrogen. Yield: approx. 70% (colorless liquid extremely sensitive to humidity, which quickly colors yellow under partial decomposition at room temperature).