Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]([CH3:40])[C:11](=[O:39])[NH:12][CH:13]([CH3:38])[CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[CH:19]=[C:18]2[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37]>ClCCl>[Cl:1][C:19]1[N:20]([CH3:24])[C:21]2[C:17]([C:18]=1[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37])=[CH:16][C:15]([CH2:14][CH:13]([NH:12][C:11]([N:10]([CH3:9])[CH3:40])=[O:39])[CH3:38])=[CH:23][CH:22]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(CC(C)NC(=O)N(C)C)cc23)c(OC)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2c(Cl)n(C)c3ccc(CC(C)NC(=O)N(C)C)cc23)c(OC)c1
Reaction time: 0.17 h

Procedure:
N-Chlorosuccinimide (0.437 g) was added in one portion to a stirred solution of methyl 4-[5-[2-(N',N'-dimethylureido)propyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate (1.3 g) in dry dichloromethane (25 ml), under a nitrogen atmosphere. After 10 minutes, the solvent was evaporated, and the product purified by flash chromatography, eluting with 3:7 ethyl acetate:toluene, to give, after crystallization from ethyl acetate, methyl 4-[2-chloro-5-[2-(N',N'-dimethylureido)propyl]-1-methylindol-3-ylmethyl]-3methoxybenzoate (45%) as a white solid; mp 148° C.; NMR (300 MHz, DMSO-d6). 0.96 (d, 3H, CH3), 2.50-2.60 (m, 1H), 2.68 (s, 6H), 2.75-2.85 (m, 1H), 3.68-3.86 (m, 7H), 3.93 (s, 3H, OCH3), 4.02 (s, 2H), 5.87 (d, 1H, NH), 6.95-7.05 (m, 2H), 7.19 (s, 1H), 7.37 (d, 1H), 7.40-7.55 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:5][N:6]([CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=1)[C:7]2=[O:12].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].[ClH:40]>C(O)C.C1(C)C=CC=CC=1.CC(=O)OCC.C(Cl)Cl.CO>[ClH:40].[N:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[N:5][N:6]([CH2:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=2)[C:7]3=[O:12])=[CH:27][CH:26]=1
Reactant: OB(O)c1ccncc1
Reactant: O=c1c2cccc(Br)c2cnn1CCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: O=c1c2cccc(-c3ccncc3)c2cnn1CCc1ccc2ccccc2n1
Temperature: 130 °C
Yield: 72 %

Procedure:
A reaction tube was charged with a solution of 5-bromo-2-[2-(quinolin-2-yl)ethyl]phthalazin-1(2H)-one (70 mg, 0.184 mmol) in 1.5 mL of ethanol and 1.5 mL of toluene under argon. To this suspension, pyridin-4-ylboronic acid (22.63 mg, 0.184 mmol) and a 2M solution of Na2CO3 (39.2 mg, 0.369 mmol) were added. Then, tetrakis-(triphenylphoshine)palladium (21.27 mg, 0.018 mmol) was added. The reaction mixture was heated in a Biotage microwave at about 130° C. for about 30 min. The reaction was monitored by TLC (DCM/methanol=9:1). After completion of the reaction, EA was added followed by the addition of 1 N HCl. The mixture was extracted twice with EtOAc. The organic layer was basified with NaHCO3 and extracted with brine. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was dissolved in isopropanol. Isopropanol containing HCl was added. The precipitate was sucked off and recrystallized from hot isopropanol to give a bright gray solid (55 mg, 72.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH3:13])([O-:12])=[O:11].C[O-].[Na+].C(O)(=O)C.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a solution of 57 g (98%, 0.397 mol) of 4-chlorobenzaldehyde and 24.8 g (0.398 mol) of nitromethane in 461 ml of toluene cooled to 5° C. were added 107.2 g of a solution of sodium methylate in methanol (30%; 0.596 mol) during 45 min. The mixture was subsequently stirred at 0 to 5° C. for 2 h. The suspension was cooled to 0° C. and then 40.0 g (0.666 mol) of anhydrous acetic acid were added, this causing the temperature to rise to 7° C. The mixture was diluted with 290 ml of toluene and methanol was removed by distillation at 100 mbar. 205 g (99%, 1.988 mol) of acetic anhydride were added, the mixture was heated to 50° C. and stirred for 15 h at this temperature. For workup, the mixture was poured onto 725 g of ice water, the phases were separated and the organic phase was extracted with alkaline water (pH 8.5). After concentration at 10 mbar, 74.8 g of the title compound in form of a yellow solid were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[F:26][C:27]1[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33]Br)=[CH:29][CH:28]=1>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11][C:7]=3[N:8]([CH2:33][CH2:32][O:31][C:30]3[CH:35]=[CH:36][C:27]([F:26])=[CH:28][CH:29]=3)[C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Reactant: Fc1ccc(OCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccc(F)cc3)c3cc(Cl)c(Cl)cc23)CC1
Reaction time: 0.42 h
Yield: 79.2 %

Procedure:
To a solution of tert-butyl 8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.40 g, 1.1 mmol) in DMF (5 mL), sodium hydride (60% dispersion in mineral oil, 68 mg, 1.7 mmol) was added. After 25 min, 4-fluorophenoxy ethyl bromide (0.34 mL, 2.3 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2 h and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (gradient, 9:1 to 17:3) to give 0.43 g (78%) of a white foam: 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=3.8 Hz, 1H), 7.40 (d, J=6.0 Hz, 1H), 6.92 (t, J=8.7 Hz, 2H), 6.70 (m, 2H), 4.40 (t, J=5.3 Hz, 2H), 4.13 (t, J=5.3 Hz, 4H), 3.69 (m, 4H), 3.08 (m, 2H), 2.90 (m, 2H), 1.48 (s, 9H); IR (diffuse reflectance) 1687, 1505, 1468, 1414, 1366, 1296, 1268, 1248, 1218, 1169, 1114, 1105, 865, 827, 746 cm−1; MS (ES+) m/z 493 (M+H+), 516, 515, 366, 364, 265, 253, 138, 94, 91, 85; Anal. Calcd for C25H27Cl2FN2O3: C, 60.86; H, 5.51; N, 5.68, found: C, 60.91; H, 5.61; N, 5.64.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: OCC1CCCN(Cc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCCN(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of (1-benzylpiperidin-3-yl)methanol (820 mg) and triethylamine (0.84 mL) in dichloromethane (10 mL) was added para-toluenesulfonyl chloride (846 mg). The solution was stirred overnight at room temperature. The mixture was partitioned between dichloromethane and water. The layers were separated and the organic layer was dried over sodium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in hexane to give the title compound as a colourless oil (1.15 g, 80%).
Reaction SMILES: N#N.[CH3:3][OH:4].Cl[C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=1>O1CCOCC1.CO>[C:12]([C:10]1[CH:9]=[CH:8][N:7]=[C:6]([O:4][CH3:3])[CH:11]=1)#[N:13]
Reactant: CO
Reactant: N#Cc1ccnc(Cl)c1
Agent: N#N
Solvent: C1COCCO1
Product: COc1cc(C#N)ccn1
Temperature: 10 °C

Procedure:
Under a stream of N2 and with cooling, Na metal (2.7 g) was added to MeOH (36 ml) with a considerable exotherm. After the Na is dissolved, a solution of 2-chloro-4-cyanopyridine (15 g) in dioxane:MeOH (1:1, 110 ml) was added via dropping funnel over a 10 min period. The reaction was heated to reflux for 3.5 h then cooled at ˜10° C. overnight. Solid was filtered off and the solid was washed with MeOH. The filtrate was concentrated to ˜60 ml and H2O (60 ml) was added to redissolve a precipitate. Upon further concentration, a precipitate formed which was washed with H2O. Further concentration produced additional solids. The solids were combined and dried in vacuo overnight at 35° C. to provide 4-cyano-2-methoxypyridine which was used as is.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Li].[O:13]1[C:17](C(Cl)=O)=[CH:16][CH:15]=[N:14]1.Cl>C1COCC1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C:1]([C:17]1[O:13][N:14]=[CH:15][CH:16]=1)=[O:9])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccno1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of diethyl malonate (2.6 ml, 2.74 g) in THF (40 ml) under an atmosphere of nitrogen at −60° C. was added nbutyl lithium (2.5 M, 18.9 ml) dropwise over 15 mins, keeping the temperature constant. The reaction became a cloudy white colour from the formation of the di-lithium salt then became yellowish. After 10 mins, the reaction was cooled to −78° C., when a solution of Isoxazole-5-carbonyl chloride (1 g) in THF (10 ml) was added dropwise over 15 mins. The reaction then warmed to −45° C. and stirred for 1 h, the solution had gone pale brown. The reaction was then poured into 1 M HCl solution (50 ml) with stirring and extracted with CH2Cl2 (2×150 ml). The combined organic layers were washed with sat. NaCO3 soln (1×30 ml), dried over MgSO4, filtered and concentrated in vacuo to give the product as a pale oil which was used as such in the next step. Yield 1.1 g, 35.1%.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C1C=CC=CC=1>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[C:15]([NH:14][CH2:12][CH3:13])=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(C)co1
Reactant: CCN=C=O
Solvent: c1ccccc1
Product: CCCCN(C(=O)NCC)c1nc(C)co1

Procedure:
A solution of 2-butylamino-4-methyloxazole (15.0 g, 0.0972 mol) and ethyl isocyanate (7.6 g, 0.107 mol) in dry benzene was heated under reflux for 2 hours and then evaporated to dryness. The residual oil was dissolved in ether and the solution was washed with 2N HCl, dried and evaporated. The residue was distilled under vacuum b.p. 128° C./1.0 mm. IR 3275, 1696, 1590 cm-1.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC

Procedure:
As described in Example 50 the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.105 g, 0.36 mmol) was reacted with 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline from Example 7A (0.134 g, 0.5 mmol), and Cs2CO3 (0.325 g, 1 mmol) in isopropanol (8 mL) at 70° C. for 4 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.69 (s, 1H), 7.84 (m, 1H), 7.51 (m, 1H), 7.44 (t, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.28 (m 1H), 6.49 (s, 1H), 4.33 (t, 2H), 4.00 (s, 3H), 3.76 (t, 2H), 3.34 (s, 3H), 1.28 (s, 9H).
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>CCCCCC>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)=[N:9][CH:10]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: NCc1ccncc1
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCc3ccncc3)ncc2Cl)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (229 mg, 0.550 mmol) obtained in Example 54 and 4-aminomethylpyridine (200 μl) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=1:3 eluate was concentrated under reduced pressure to give the title compound (37 mg, 0.076 mmol, 14%) as an amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.Cl.Cl[C:14](OC(Cl)(Cl)Cl)=[O:15].O>C(Cl)Cl.CCCCCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:14](=[O:15])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
To the suspension of 4-chlorobenzhydrazide (8.53 g, 0.05 mole) in methylene chloride (100 ml), equipped with a magnetic stirring bar, a nitrogen inlet, a dropping funnel, and an outlet connected to diluted base solution for trapping the HCl gas, was dropwise added trichloromethyl chloroformate (5.94 g, 0.03 mole). After addition, the reaction mixture was heated to reflux for 2 hr. The reaction was cooled down to room temperature and poured into a mixture of water (500 ml) and hexane (200 ml) and stirred for 10 to 20 min. The resultant precipitate was collected by suction-filtration and was washed with hexane to give a solid product. The product was dried in air at room temperature overnight yielding 5.5 g (60% yield) of 2-(4-chlorophenyl)-1,3,4-oxadiazolin-5-one as a solid, m.p.=225°-227° C. NMR and IR spectra showed the desired structure. Without further purification, this product was subjected to the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][C@@H:25]1[CH2:29][S:28](=[O:31])(=[O:30])[NH:27][CH2:26]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[CH2:26][C@H:25]([CH3:24])[CH2:29][S:28]4(=[O:31])=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 24.2 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (130 mg) described in Preparation Example 113 and (S)-4-methylisothiazolidine 1,1-dioxide (84 mg) described in Preparation Example 4 and by the reaction and treatment in the same manner as in Example 1, the title compound (32 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]([OH:25])=O)=[O:15])=[CH:4][CH:3]=1.C(OC(Cl)=O)C(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=1.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.C(N(CC)CC)C>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH2:42][C:23](=[O:25])[CH2:22][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][N:16]2[C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:15])=[CH:37][CH:36]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Cc1nc(C(=O)N2CCCCC2CC(=O)O)c(-c2ccc(F)cc2)s1
Agent: CC(C)COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCCCC2CC(=O)CC(=O)c2ccc(F)cc2)c(-c2ccc(F)cc2)s1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
(1-{-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]-methanoyl}-piperidin-2-yl)-acetic acid (0.500 g) was dissolved in dry tetrahydrofuran (15 ml) and cooled to −20° C. under an atmosphere of argon. Triethylamine (0.231 ml) and isobutylchloroformate (0.215 ml) were added and the solution was stirred at −20° C. for 1 hour. The solution was then cooled to −78° C. B. A solution of 4′-fluoroacetophenone (0.229 g) in THF (15 ml) was cooled to 20° C. under an atmosphere of argon. A solution of lithium diisopropylamide (0.830 ml; 2M solution in THF) was added and stirring continued at −20° C. for 30 minutes. The solution was then cooled to −78° C. C. The solution from part B was added to the stirred solution of part A by way of a cannula. Stirring was continued at −78° C. under an atmosphere of argon for 2 hours before being quenched by the addition of saturated ammonium chloride solution. After reaching room temperature, the reaction solution was partitioned between ethyl acetate and water. The organic solution was washed with brine, dried (MgSO4) and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 75% ethyl acetate in hexane. The title compound was obtained as a colourless oil (0.560 g) mass spectrum (API+) 483 [MH+], (API−) 481 [(M-H)−] C26H24F2N2O3S requires 482.
Reaction SMILES: [F:1][CH2:2][C:3]([N:5]([CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][C@@:22]1([OH:36])[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:32])[CH:28]=2)[C@@H:23]1[CH:33]([CH3:35])[CH3:34])[CH3:19])[CH2:6][C:7]([CH2:12][O:13][CH3:14])([CH3:11])[CH2:8][O:9][CH3:10])=O>C1COCC1>[F:32][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH:33]([CH3:34])[CH3:35])[C@:22]([CH2:21][CH2:20][N:18]([CH2:17][CH2:16][CH2:15][N:5]([CH2:3][CH2:2][F:1])[CH2:6][C:7]([CH2:8][O:9][CH3:10])([CH3:11])[CH2:12][O:13][CH3:14])[CH3:19])([OH:36])[CH2:31][CH2:30]2
Reactant: COCC(C)(COC)CN(CCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C)C(=O)CF
Solvent: C1CCOC1
Product: COCC(C)(COC)CN(CCF)CCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
To a solution of 2.24 g of 2-fluoro-N-(3-{[2-((1S,2S)-6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl]-methyl-amino}-propyl)-N-(3-methoxy-2-methoxymethyl-2-methyl-propyl)-acetamide in anh. THF (35 mL) was added dropwise at 0° C. for 20 min a 1M solution of borane-THF complex in THF (44 mL). The mixture was stirred for 10 min at rt then for 1.5 h at 65° C. It was cooled down to 0° C., quenched with 1M-NaOH and extracted with DCM. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude as borane complex was dissolved in MeOH (42 mL) and treated with ethylene diamine (1.18 mL) under microwave conditions (120° C. for 180 s). The mixture was concentrated in vacuo and the resulting residue was taken up in DCM. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated in vacuo. The oily crude was purified by CC using EtOAc/MeOH/NEt3 from 100/0/1 to 92/8/1 as eluant to yield 1.51 g of (1S,2S)-6-fluoro-2-[2-({3-[(2-fluoro-ethyl)-(3-methoxy-2-methoxymethyl-2-methyl-propyl)-amino]-propyl}-methyl-amino)-ethyl]-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ol as yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[N:6]1.[Cl:13]CCCl>S(Cl)(Cl)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][Cl:13])[CH:7]=[N:6]1
Reactant: ClCCCl
Reactant: COC(=O)Cn1cc(CO)cn1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cn1cc(CCl)cn1
Yield: 36 %

Procedure:
(4-Hydroxymethyl-pyrazol-1-yl)-acetic acid methyl ester (194 mg) was dissolved in 1,2-dichloroethane (2 mL) and thionylchloride (0.7 mL). The solution was refluxed for 2.5 hours. The reaction was cooled and concentrated in vacuo. The residue was poured into ice/water and basified with sat. Na2CO3 to pH 11. The aqueous phase was then extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=100:0 to 50:50) to give the title compound as a colorless oil (81 mg, 36%). MS (EI)=188.0 [M+].
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].ClC1C=CC=C(C(OO)=[O:17])C=1.C(OCC)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:8][O:17]1
Reactant: C=CCCCCCBr
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: BrCCCCCC1CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
7-Bromo-1-heptene (5.10 g) was dissolved in chloroform (29 ml), the solution was added with m-chloroperbenzoic acid (6.21 g) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with diethyl ether and saturated aqueous sodium thiosulfate, the layers were separated, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under ordinary pressure to obtain the title compound (5.27 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1>[Pd].C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1ccc(O)cn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
The mixture of ethyl 3-(5-hydroxypyridin-2-yl)acrylate (2.30 g, 11.9 mmol, step 1 of Example 5) and 10 wt. % palladium on carbon (230 mg) in ethanol (5 mL) was stirred under hydrogen (1 atom) at room temperature for 24 h. The mixture was filtered through a pad of Celite, and washed with ethanol and the filtrate was concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:1) to give 1.51 g (65%) of the title compound as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=2[O:30][CH3:31])[C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1.Cl[C:37]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:42]=1>>[CH2:37]([O:23][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:12]([NH:11][S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:34][CH3:35])(=[O:9])=[O:10])[CH:13]=2)=[CH:26][CH:25]=1)[CH3:42]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(OC)c1OC
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3cc(Cl)ccc3OC)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(5-Chloro-2-methoxy-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=519.2 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 4-[3-(5-chloro-2-methoxy-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D