Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[C:37]3[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[N:41][CH:42]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:47].O1CCOCC1>CO>[ClH:47].[ClH:47].[ClH:47].[ClH:47].[NH2:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]4[C:24]5[CH:36]=[CH:35][CH:34]=[N:33][C:25]=5[NH:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:22]4=[N:21][C:20]=3[C:37]3[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[N:41][CH:42]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cn1
Reaction time: 23 h
Yield: 88 %

Procedure:
Methyl 5-[3-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-2-yl]pyridine-2-carboxylate (52 mg, 0.085 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at r.t for 23 hours. The mixture was concentrated to afford the desired product (49 mg, 88%) as an orange solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.70-8.68 (m, 1H), 8.65 (br s, 1H), 8.63 (s, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.0 Hz and 2.3 Hz, 1H), 8.10 (dd, J=4.6 Hz and 1.7 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.39-7.35 (m, 3H), 7.29 (d, J=7.4 Hz, 1H), 7.12 (td, J=8.0 Hz and 1.1 Hz, 1H), 6.91 (dd, J=8.6 Hz and 1.1 Hz, 1H), 6.73 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.84 (s, 3H), 2.60-2.56 (m, 2H), 2.55-2.50 (m, 2H), 2.21-2.13 (m, 1H), 1.86-1.77 (m, 1H). LCMS: 515 [M+H].
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-])=O>[Fe].O>[NH2:3][C:6]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N

Procedure:
A mixture of iron powder (4.2 g.), ammonium chloride (0.42 g.), ethaol (60 ml.) and water (30 ml.) and ethyl 2-[2-nitro-3-(2-chlorophenoxy)phenyl]acetate (5 g.) were treated in a similar manner to that of Example 1-(1) to give oily captioned compound (4.3 g.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[C:10]=3I)[CH2:3][CH2:2]1.[CH3:33][N:34](C)C(=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)[C:10]=3[C:33]#[N:34])[CH2:3][CH2:2]1
Reactant: CC(=O)N(C)C
Reactant: CC(C)[Si](Oc1ccc(-n2nc3cc(OCC4CC4)ccc3c2I)cc1)(C(C)C)C(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)[Si](Oc1ccc(-n2nc3cc(OCC4CC4)ccc3c2C#N)cc1)(C(C)C)C(C)C
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6-(cyclopropylmethoxy)-3-iodo-2-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2H-indazole (281 mg), tris(dibenzylideneacetone)dipalladium(0) (92 mg), 1,1′-bis(diphenylphosphino)ferrocene (111 mg), zinc cyanide (88 mg), zinc powder (33 mg) and N,N-dimethylacetamide (3 mL) was stirred at 120° C. for 1.5 hr under an argon atmosphere. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed three times with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (189 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[CH3:33][O:34][C:35](=[O:57])[C@@H:36]([NH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:48][CH:47]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.O>[CH3:33][O:34][C:35](=[O:57])[C@@H:36]([N:44]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:48][CH:47]=1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)OC)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)OC)cc1
Reaction time: 1 h
Yield: 60 %

Procedure:
In an inert atmosphere trans-4-(trifluoromethyl)-cinnamic acid (6.7 g, 31.2 mmol) was dissolved in DCM (150 mL) and 1-chloro-N,N,2-trimethylpropenylamine (4.7 g, 35.5 mmol) was slowly added via syringe. Stirring was continued for 1 h followed by the addition of DIPEA (10.7 mL, 62.6 mmol) and 2-(4-pentyl-benzylamino)-(S)-3-phenyl-propionic acid methyl ester (7.0 g, 20.8 mmol). Stirring was continued for 45 min. Water (250 mL) was added and the product was extracted with DCM (3×150 mL). The combined organic layers were dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silicagel, EtOAc/heptane=¼) to give 6.71 g (59%) of 2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionic acid methyl ester. LC-MS: tR=1.21 min; [M+H]+=538.38.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][CH2:22][N:21](C(OCC4C=CC=CC=4)=O)[CH2:20]3)[C:16]2=[O:35])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:16]2=[O:35])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC3(CCCNC3)C2=O)CC1
Reaction time: 20 h

Procedure:
To a solution of benzyl 2-(cis-4-[tert-butyl(dimethyl)silyl]oxy cyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (18.0 g, 35.9 mmol) in methanol (150 mL) was added 10% palladium on carbon (Aldrich, cat #: 520888) (1.8 g, 1.5 mmol) under the atmosphere of nitrogen. The reaction mixture was hydrogenated and shaken at 50 psi for 20 h. The reaction mixture was filtered through a pad of Celite and then washed with methanol (300 mL). The filtrate was concentrated under reduced pressure to give the desired product as a white solid in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[CH:15](=O)[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:15]([N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:13][CH2:12][CH2:11][CH2:10]1)[CH3:16]
Reactant: CC=O
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN1CCCOc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
1.00 M of Potassium hydroxide in Water (25 mL) was added to 2-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (2.84 g, 10.7 mmol) in 2-Methoxyethanol (50 mL) and the reaction was heated at 110° C. After overnight heating, the mixture was cooled, extracted with DCM (2×50 mL); the combined organics were washed with water (50 mL) and brine (50 mL), dried and conc. in vacuo. The residue was chromatographed (120 g SiO2, ISCO, 0-20% EtOAc:Hex) to afford 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as an orange solid (1.64 g, 79%). 1697d) 2-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (278 mg, 1.43 mmol) was dissolved in Acetonitrile (15 mL) and Acetaldehyde (0.80 mL, 14 mmol) was added. Acetic acid (0.15 mL, 2.6 mmol) was added, followed by Sodium triacetoxyborohydride (0.85 g, 4.0 mmol), and the mixture was stirred under an atmosphere of Nitrogen at room temperature for 1 h. The solution was diluted with ethyl acetate (50 mL) and satd. sodium bicarbonate (50 mL). The layers were separated, the organic washed with brine (50 mL) and dried over sodium sulfate. Conc. in vacuo followed by chromatography (ISCO, g SiO2, 0-50% EtOAc:Hex) afforded 9-Ethyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as an orange oil (272 mg, 85%). 1H-NMR (CDCl3) 7.58 (m, 2H), 6.87 (d, 1H, J=8.1 Hz), 4.31 (t, 2H, J=5.2 Hz), 3.40 (t, 2H, J=5.2 Hz), 3.33 (q, 2H, J=6.8 Hz), 2.05 (tt, 2H, J=5.2, 5.2 Hz), 1.24 (t, 3H, J=6.8 Hz).
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH:37]1([CH:45]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:48]([CH:57]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]3)[NH:47][NH:46]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[NH2:46][CH:45]([CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH:48]([NH2:47])[CH:57]1[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: C1CCCC(C2CCCCCCCCC(C3CCCCCCC3)NN2)CCC1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: NC(CCCCCCCCC(N)C1CCCCCCC1)C1CCCCCCC1

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 65 g (0.168 mol) of 3,12-dicyclooctyl-1,2-diazacyclododecane and correspondingly reduced amounts of catalyst and solvent, with otherwise the same procedure, there is obtained, after chromatographic purification, 43.6 g (66% of theory) of 1,10-diamino-1,10-dicyclooctyldecane as colourless oil (nD20 =1.5050; IR (liquid) inter alia bands at 3333, 3278 and 1613 cm-1).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5](C(C)(C)C)=[CH:4][CH2:3]1.CC1(C)C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2C=CC1>>[CH3:1][C:2]1([CH3:27])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH2:3]1
Reactant: CC(C)(C)C1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C=CCC3(C)C)cc1
Product: CC1(C)CC=Cc2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoic acid (Compound 80), 25.3 mg (0.08 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 72) was converted into the title compound (colorless solid) using 8.0 mg (0.14 mmol) of LiOH in H2O.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[C:12]1([NH:11][C:8]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]2)=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
Cyclopropane-1,1-dicarboxylic acid monomethyl ester (0.4 g, 2.78 mmol) was, dissolved in DMF (5.55 mL) and aniline (0.380 mL, 4.16 mmol) was added, followed by diisopropylethylamine (2.424 mL, 13.88 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.782 g, 5.55 mmol). The reaction mixture was stirred at room temperature for 18 hours and was then diluted with ethyl acetate (70 mL) and washed with 10% aqueous lithium chloride (3×40 mL), saturated aqueous ammonium chloride (40 mL), saturated aqueous sodium bicarbonate (40 mL) and brine (40 mL). The organic layer was dried over magnesium sulfate and evaporated to yield a dark brown oil. It was purified by silica gel chromatography (0 to 20% ethyl acetate/hexane) to yield methyl 1-(phenylcarbamoyl)cyclopropanecarboxylate (0.607 g, 100% yield) as a light peach solid. 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 7.58 (d, 2H), 7.28 (t, 2H), 7.04 (t, 1H), 3.66 (s, 3H), 1.37 (m, 4H); MS (ESI) m/z: 220.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[CH:16]([N:19]([CH3:30])[C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=2[N:24]=1)([CH3:18])[CH3:17]>>[CH:16]([N:19]([CH3:30])[C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH:29][C:9](=[O:10])[CH:8]=[CH:7][C:6]3[CH:12]=[CH:13][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=3)[CH:26]=[CH:25][C:23]=2[N:24]=1)([CH3:18])[CH3:17]
Reactant: CC(C)N(C)c1nc2ccc(N)cc2s1
Reactant: O=C(Cl)C=Cc1ccc(C(F)(F)F)cc1
Product: CC(C)N(C)c1nc2ccc(NC(=O)C=Cc3ccc(C(F)(F)F)cc3)cc2s1
Yield: 25.9 %

Procedure:
Prepare according to Method D (Example 17), using 4-trifluoromethylcinnamoyl chloride (526 mg, 2.24 mmol) (Example 17) and N2-isopropyl-N2-methyl-benzothiazole-2,6-diamine (332 mg, 1.50 mmol), to afford the title compound (163 mg, 26%). mass spectrum (m/e): 420.2 [M+H], 418.2 [M−H]. 1H NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 8.25 (d, 1H, J=1.8 Hz), 7.87-7.78 (m, 4H), 7.64 (d, 1H, J=15.8 Hz), 7.43 (dd, 1H, J=8.6, 1.9 Hz), 7.39 (d, 1H, J=8.4 Hz), 6.96 (d, 1H, J=15.4 Hz), 4.32 (m, 1H), 2.97 (s, 3H), 1.22 (d, 6H, J=7.0 Hz).
Reaction SMILES: C(OP([CH2:9][S:10]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])(OCC)=O)C.[Br-].[Li+].C(=O)CC.[CH2:36]1[CH2:46]CN2C(=NCCC2)[CH2:38][CH2:37]1>C1COCC1.ClCCl>[CH3:29][C:21]1[CH:20]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([S:10](/[CH:9]=[CH:46]/[CH2:36][CH2:37][CH3:38])(=[O:12])=[O:11])[CH2:18][CH2:17]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOP(=O)(CS(=O)(=O)N1CCN(c2cc(C)nc3ccccc23)CC1)OCC
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCC=O
Solvent: ClCCl
Product: CCC/C=C/S(=O)(=O)N1CCN(c2cc(C)nc3ccccc23)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 13.6 %

Procedure:
4-[4-(Diethoxyphosphorylmethylsulfonyl)piperazin-1-yl]-2-methyl-quinoline (47 mg, 0.106 mmol) was dissolved in anhydrous THF (1 ml), lithium bromide (11.1 mg, 0.128 mmol) and propionaldehyde (9.2 μl, 0.128 mmol) were added with stirring and the mixture was cooled to −10° C. DBU (15.2 μl, 0.102 mmol) was added, and the temperature was raised to room temperature. Stirring was continued for 30 minutes, the reaction mixture was diluted with dichloromethane, washed with 5% sodium bicarbonate solution (2×), water and evaporated to dryness. The residue was purified with preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile). 5 mg of a solid were obtained (0.014 mmol, 14%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:4][C:3]=1[C:19]([OH:21])=O.O.O[N:24]1C2C=CC=CC=2N=N1.[NH4+].[Cl-].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:4][C:3]=1[C:19]([NH2:24])=[O:21]
Reactant: On1nnc2ccccc21
Reactant: Nc1c(C(=O)O)sc2cncc(Oc3ccc(Cl)cc3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: NC(=O)c1sc2cncc(Oc3ccc(Cl)cc3)c2c1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of Example 131C (96 mg, 0.3 mmol) in DMF (2 mL) is treated with 1-hydroxybenzotriazole hydrate (67 mg, 0.44 mmol), NH4Cl (61 mg, 1.14 mmol) and 4-methylmorpholine (100 μL, 0.9 mmol), cooled to 0° C., treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol), warmed to room temperature, stirred overnight, poured into saturated NaHCO3, collected, washed with water and dried. The residue is recrystallized from methanol/toluene/hexanes to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22](=[O:27])[CH2:23][C:24](Cl)=[O:25]>>[CH3:20][O:21][C:22](=[O:27])[CH2:23][C:24]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]2[CH:16]=[CH:17][C:3]([C:2]([F:18])([F:19])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)=[O:25]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Product: COC(=O)CC(=O)Nc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Yield: 71 %

Procedure:
In analogy to example 1, the title compound is prepared from 4-(4-trifluoromethyl-benzyloxy)-phenylamine and chlorocarbonyl-acetic acid methyl ester. Yield: 71%. Colorless solid. MS: m/e=368.1 (M++H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([CH3:33])=[C:15]([CH3:32])[C:16]=1[C:17]([C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:28])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=1)=[O:18].Cl[S:35]([C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[C:40]([OH:47])[CH:39]=1)(=[O:37])=[O:36]>>[CH3:32][C:15]1[C:16]([C:17]([C:19]2[CH:20]=[C:21]([CH:29]([CH3:31])[CH3:30])[C:22]([O:28][S:35]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[C:40]([OH:47])[CH:39]=3)(=[O:37])=[O:36])=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:24]=2)=[O:18])=[C:12]([CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[O:13][C:14]=1[CH3:33]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccc3ccccc3c2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Product: Cc1oc(Cc2ccc3ccccc3c2)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 55 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-naphthalen-2-ylmethyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.681 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.209 g, 0.885 mmol). Purification on Dynamax C18 (80% CH3CN/H2O) gave 0.240 g (55%) of the title compound as a yellow solid, mp 130-135° C. 1H NMR (DMSO-d6) δ1.03 (d, 12H), 1.83 (s, 3H), 2.20 (s, 3H), 3.09 (septet, 2H), 4.01 (s, 2H), 7.18 (d, 1H), 7.43-7.48 (m, 5H), 7.51 (s, 2H), 7.77-7.79 (m, 2H), 7.82-7.86 (m, 1H), 8.05 (d, 1H). IR (KBr) 3400, 2950, 1700, 1375 and 1190 cm−1. mass spectrum (−ESI) m/z 639 (M−H). Anal. Calcd. for C37H36O8S: C, 69.36; H, 5.66; N, 0.00. Found: C, 69.04; H, 5.77; N, 0.04.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.[CH2:22](O)[CH2:23][OH:24].CN(C=O)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:21][C:10]1[C:11]([S:17](=[O:19])(=[O:18])[NH2:20])=[CH:12][C:13]([C:14]([O:16][CH2:22][CH2:23][OH:24])=[O:15])=[C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)[CH:9]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: OCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)OCCO)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.9 %

Procedure:
To a solution of furosemide (OnBio, Canada, 5.2 g, 15.6 mmol) in a mixture of CH2Cl2/DMF (15 mL /20 mL) was added ethylene glycol (Aldrich, Wis., U.S., 4.4 mL, 78.0 mmol) and DMAP (377.5 mg, 3.1 mmol). A solid formed upon the addition of the DMAP and additional DMF (15 mL) was added followed by EDAC (3.9 g, 20.3 mmol). The reaction mixture was allowed to stir at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue redissolved in CH2Cl2 (100 mL). The sample was washed with H2O (3×50 mL), brine, and the sample dried (MgSO4). The residue after evaporation was chromatographed on silica gel eluting with 1:1 hexanes/EtOAc to give the title compound (1.4 g, 24% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.45-8.43 (m, 2H), 7.64 (s, 1H), 7.35 (s, 2H), 7.09 (s, 1H), 6.42-6.41 (m, 1H), 6.37-6.36 (m, 1H), 4.92 (t, J=5.4 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 4.28 (br t, 2H), 3.71-3.65 (m, 2H). Mass Spectrum (API-TIS) m/z 375 (MH+).
Reaction SMILES: [Mg].[Br-].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([C:15](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O1CCCC1>[C:3]1([CH:16]([OH:17])[C:15]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Reactant: c1ccccc1
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCC(=Cc1ccccc1)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 115.2 %

Procedure:
In a 2-liter three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 13.2 g of magnesium and 300 milliliters of tetrahydrofuran were introduced and stirred violently. Then, a solution of 83.2 g of benzene bromide in 100 milliliters of tetrahydrofuran was added dropwise for 40 minutes. At that time, cooling was carried out with an ice bath if required. After the dropwise addition was ended, stirring was carried out at room temperature for 1 hour, and thereafter 108.2 g of α-n-hexyl cinnamaldehyde was added dropwise. After stirring for one day and one night, the solution was poured in ice water containing dilute hydrochloric acid, and extracted with 1 liter of ethyl acetate. After the solution was washed with an aqueous solution of sodium hydrogencarbonate and water, it was dried with anhydrous magnesium sulfate. After removing the solvent off by a rotary evaporator, 169.6 g of 1,3-diphenyl-2-n-hexyl-2-propen-1-ol was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])(=[O:5])[CH3:4].Cl[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[C:3]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:5])[CH3:4]
Reactant: CC(=O)N1c2ccccc2SC1c1ccccc1O
Reactant: CCOC(=O)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1C1Sc2ccccc2N1C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the suspension of 1.59 g of sodium hydride in 30 ml of anhydrous DMF, the solution of 8.13 g of 3-acetyl-2-(2-hydroxyphenyl)benzothiazoline in 30 ml of anhydrous DMF is added dropwise under nitrogen atmosphere at room temperature. After the addition, the reaction mixture is stirred for 20 minutes at room temperature. To the reaction mixture, the solution of 4.95 g of ethyl 4-chlorobutyrate in 15 ml of anhydrous DMF is added and stirred for 5 hours at 70° C. After cooling to room temperature the reaction mixture is poured into ice-water and extracted with ethyl acetate.