Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18](O)=[O:19])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1.C(N(CC)CC)C>ClCCl>[CH3:43][N:40]1[CH2:41][CH2:42][CH:37]([C:31]2[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([NH:27][C:18](=[O:19])[CH2:17][C:10]4[C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)=[CH:8][CH:9]=4)[CH:29]=3)[NH:33][CH:32]=2)[CH2:38][CH2:39]1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Cc4ccc(-c5ccncc5)c5ccccc45)cc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
A stirred suspension of 4-(pyridin-4-yl)naphth-1-ylacetic acid (D7, 0.18 g, 0.7 mmole) in dichloromethane (15 ml) was treated with oxalyl chloride (0.18 ml, 2.1 mmole), then stirred at room temperature for 3 hours, before evaporating to dryness. The solid residue was suspended in dichloromethane (15 ml), cooled to 0° C. and treated with a solution of 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole (D2, 0.13 g, 0.56 mmole) in dichloromethane (15 ml). The mixture was stirred at 0° for 1 hour and then a solution of triethylamine (0.25 ml) in dichloromethane (5 ml) was added dropwise. The mixture was allowed to warm to room temperature and stir overnight, then evaporated to dryness and the residue subjected to flash chromatography on silica gel eluting with CH2Cl2/MeOH/NH4OH (100:5:0.5 to 100:10:1 gradient elution) to afford the title compound as a pale cream powder (0.04 g).
Reaction SMILES: [C:1]1(/[C:7](/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([N:27]=[C:28]=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[C:21]1([NH:27][C:28]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[C:7](\[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)/[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Reactant: S=C=Nc1ccccc1
Solvent: CCN(CC)CC
Product: S=C(Nc1ccccc1)OCCCCC/C=C(\c1ccccc1)c1cccnc1

Procedure:
In the presence of triethylamine, (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (2.0 g, 7.4 mmoles) was reacted with phenyl isothiocyanate (1.0 g, 7.5 mmoles) in the same manner as Example 9 to give 1-phenylaminothiocarbonyloxy-(E)-7-phenyl-7-(3-pyridyl)-6-heptene (Compound Id-28, 2.2 g) as crystals.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].IC.[CH3:39]COC(C)=O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH3:39])[CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1Cl
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)cn(C)c34)no2)cc1Cl
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 3.98 mg) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D7) (80 mg) in dry DMF (2 mL) at RT. After stirring for 5 min, iodomethane (0.016 mL) was added. The resulting solution was stirred at RT for 45 min. EtOAc (50 mL) was added and the resulting solution was washed with aqueous HCl (20 mL), followed by water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 1,1-dimethylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D8) (85 mg) as a pale yellow oil. MS (ES): C27H30ClN3O4 requires 495; found 496.0 (M+H+).
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]1[O:11][C:10]2[C:5](=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[CH:4]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:4]=[C:3]([Si:2]([CH3:14])([CH3:13])[CH3:1])[O:11][C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: C[Si](C)(C)c1cc2c(ccc[n+]2[O-])o1
Product: C[Si](C)(C)c1cc2nccc(Cl)c2o1
Temperature: 100 °C

Procedure:
2-(Trimethylsilyl)furo[3,2-b]pyridine N-oxide (10.51 g, 50.7 mmol) dissolved in POCl3 (47.3 ml, 507 mmol) in a sealed flask and heated at 100° C. for one hour. The reaction was cooled to RT, poured into a beaker washing with minimal DCM, and cooled in a brine bath. Saturated sodium bicarbonate solution was added very slowly and then solid sodium bicarbonate was added portion wise until the solution was at about pH=8. The solution was extracted twice with DCM, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 5-40% EtOAc:Hex) to afford 7-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine as a pale yellow oil. MS: M+H+=226.2
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:14]([CH3:15])[N:13]=[C:12]([C:16]2[CH2:20][CH2:19][CH2:18][CH:17]=2)[C:11]=1[C:21]1[CH:22]=[CH:23][C:24]2[O:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][CH:6]([C:10]1[N:14]([CH3:15])[N:13]=[C:12]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:11]=1[C:21]1[CH:22]=[CH:23][C:24]2[O:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C2=CCCC2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CO
Product: Cn1nc(C2CCCC2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 2-(tert-butoxy)-2-[3-(cyclopent-1-en-1-yl)-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]acetic acid (example 12) (19.7 mg, 0.047 mmol) and palladium on carbon (7 mg) in methanol (2.4 mL) was stirred under hydrogen atmosphere overnight. The mixture was filtered over Millipore and the filtrate was concentrated in vacuo to provide 2-(tert-butoxy)-2-[3-cyclopentyl-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-1H-pyrazol-5-yl]acetic acid (example 19) (19.5 mg, 0.047 mmol, 98%) as a white solid.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C:11]12[CH2:18][CH2:17][C:14]([C:19]3[NH:27][C:26]4[C:25](=[O:28])[N:24]([CH2:29][CH2:30][CH3:31])[C:23](=[O:32])[N:22]([CH2:33][CH2:34][CH3:35])[C:21]=4[N:20]=3)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.O>C(Cl)Cl>[O:32]=[C:23]1[N:22]([CH2:33][CH2:34][CH3:35])[C:21]2[N:20]=[C:19]([C:14]34[CH2:15][CH2:16][C:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])([CH2:12][CH2:13]3)[CH2:18][CH2:17]4)[NH:27][C:26]=2[C:25](=[O:28])[N:24]1[CH2:29][CH2:30][CH3:31]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCP(=O)(OCC)OCC)(CC3)CC4)nc2n(CCC)c1=O
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCP(=O)(O)O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-ethyl}-phosphonic acid diethyl ester (30 mg, 59 μmol) in CH2Cl2 (8 ml) was added TMSBr (excess) and the resulting mixture was stirred at rt overnight. Additional TMSBr was added and the reaction was heated at 55° C. for 6 h. The solvent was removed in vacuo to give an orange solid whose color was discharged upon trituration with water. The material was collected, washed with water and dried (20 mg, 77%). MS: 453 (MH+).
Reaction SMILES: C1C(=O)N(O[C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][CH2:30][CH:31]2[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])=[CH:22][CH:21]=1>CC#N>[O:18]=[C:17]1[CH2:16][CH2:15][C:13](=[O:14])[N:12]1[O:11][C:9]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([O:29][CH2:30][CH:31]2[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])=[CH:24][CH:25]=1)=[O:10]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: CC#N
Product: O=C(Nc1ccc(NC(=O)ON2C(=O)CCC2=O)cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
N,N′-Disuccinimidylcarbonate (16.20 g, 63.26 mmol, 1.1 eq) is added at room temperature to a stirred solution of N-(4-aminophenyl)(fluoren-9-ylmethoxy)carboxamide (20.00 g, 60.53 mmol, 1.0 eq) in CH3CN (1100 mL). After stirring overnight at room temperature, the reaction mixture is filtered to afford 28.50 g of the expected crude product as a white powder.
Reaction SMILES: [C:1]([O:5][P:6](=[O:13])([OH:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].O.[CH2:20](Cl)[Cl:21]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][CH2:20][O:13][P:6](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OP(=O)(O)OC(C)(C)C
Reactant: ClCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: O
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
A mixture of Phosphoric acid di-tert-butyl ester (1 g, 0.0048 mol), NaHCO3 (0.806 g, 0.0096 mol), tetra butyl ammonium hydrogen sulphate (0.163 g, 0.00048 mol), water (40 ml) and DCM (25 ml) were taken. The mixture was cooled to 0° C. and stirred at that temperature for 20 minutes. Chloromethyl chlorosulphatc, (0.943 g, 0.0057 mol) in DCM (15 ml) was added to it at 0° C. The reaction mixture allowed to warm to room temperature and stirred for 18 hours. The organic layer was separated and aqueous layer was extracted with DCM (30 ml). The organic layer was washed with brine (60 ml) solution and dried over Na2SO4. The organic layer was evaporated to obtain Phosphoric acid di-tert-butyl ester chloromethyl ester as colorless oil (0.79 g, 64%).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[Na+]>O.CN(C=O)C>[OH:18][CH:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1O

Procedure:
By following the procedure described in Example 4, Step F, using as the reagents 2-cyclopentyl-2-methyl-6,7-dichloroindan-1,5-diol (Example 5, Step C), (31 g., 0.1 mole), potassium carbonate (15.2 g., 0.11 mole), DMF (200 ml.), ethyl 4-bromobutyrate (23.5 g., 0.11 mole), water (200 ml.) and 10 N sodium hydroxide (40 ml.), there is obtained 4-(1-hydroxy-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)butyric acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:4][N:3]=1.[N+:22]([O-])([OH:24])=[O:23].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([N+:22]([O-:24])=[O:23])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(Cc2cnc(N)nc2N)c2cccnc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2cccnc2c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a cold (5°) solution of 2,4-diamino-5-(7-methoxy-5-quinolylmethyl)pyrimidine (0.28 g, 1.0 mmol) in concentrated sulfuric acid (2 mL) was added dropwise 90% nitric acid (0.10 g, 1.4 mmol). After stirring at 5° for 30 min, the reation was poured onto ice and the resulting solution taken to pH 3 with 5N sodium hydroxide. The tan solid that separated was collected then boiled in water and filtered to remove insolubles. The filtrate was taken to pH 8 with 1M sodium carbonate to precipitate the title compound (0.14 g, 42%); mp >270° dec. Anal. Calcd for C15H14N6O3 : C, 55.21; H, 4.32; N, 25.75. Found: C, 55.02, H, 4.10; N, 25.41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)C(Cc1cc(F)cc(Cl)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)C(Cc1cc(F)cc(Cl)c1)CC2
Yield: 21 %

Procedure:
The title compound was synthesized from methyl 6-(3-chloro-5-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.055 g, 0.18 mmol) and lithium hydroxide (0.076 g, 1.8 mmol, in 2 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (4 mL) was used. The resulting product was purified by reverse phase chromatography from MeOH and water (0.1% formic acid) to afford a light brown solid: 11 mg, 21% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.97-2.17 (m, 1H) 2.30-2.53 (m, 3H) 2.69 (dd, J=13.52, 8.69 Hz, 1H) 3.09 (dd, J=13.52, 4.69 Hz, 1H) 3.33-3.40 (m, 1H) 6.56 (s, 1H) 6.85 (dd, J=9.54, 1.64 Hz, 1H) 6.94-7.07 (m, 2H); 19F NMR δ ppm −114.14 (t, J=0.8 Hz); LCMS-MS (ESI−) 292.0 (M−H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:33].[N:34]1[CH:39]=[CH:38][C:37]([CH:40]=O)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][N:28]([CH2:40][C:37]5[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=5)[CH2:27][CH2:26]4)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:33]
Reactant: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C1CCNCC1
Reactant: O=Cc1ccncc1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C1CCN(Cc2ccncc2)CC1

Procedure:
Intermediate 85 was coupled with pyridine 4-carboxaldehyde following procedure E. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 557. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 8.4 (d, 2H), 8.2 (d, 1H), 8.1 (s, 1H), 7.8 (d, 1H), 7.4-7.3 (m, 2H), 7.2-7.1 (m, 3H), 7.0 (d, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 3.6 (s, 4H), 3.4 (d, 2H), 3.1 (d, 2H), 2.7 (m, 3H), 1.9-1.8 (m, 4H), 1.6-1.4 (m, 4H), 0.94 (t, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C=O)C>[CH2:1]([NH:8][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Reaction time: 18 h

Procedure:
0.28 ml (2.52 mmol) of benzylamine is added to a solution of 150 mg (0.50 mmol) of 4′-nitrobiphenyl-4-sulfonyl chloride in 2.0 ml of DMF. After 18 h at room temperature, 2.5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction and dried under high vacuum. 159 mg (74.4% of theory) of the title compound are obtained and reacted further without further purification.
Reaction SMILES: C([C:4]1([CH:12]=[CH:11][C:10]([CH2:13][O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:9][CH2:8]1)[C:5]([OH:7])=[O:6])(=O)C.[OH-].[Na+]>CO>[NH:18]1[CH2:17][CH2:16][CH:15]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=2)[CH2:20][CH2:19]1
Reactant: CC(=O)C1(C(=O)O)C=CC(COC2CCNCC2)=CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(COC2CCNCC2)cc1
Yield: 89.7 %

Procedure:
1-acetyl-4-[(piperidin-4-yloxy)methyl]benzoic acid (Preparation 102, 20 g, 72 mmol), aqueous sodium hydroxide solution (5 M, 75 ml), and methanol (75 ml) were heated to 100° C. for 4 h, and then evaporated to give a thick suspension. The crystals were filtered off, dissolved in water and the pH adjusted to 1 with hydrochloric acid (2 M, 200 ml) at 0° C. The cloudy solution was evaporated to dryness and the white solid recrystallised from isopropyl alcohol to give the title compound (15.2 g, 90%).
Reaction SMILES: C([O:5][C:6](=[O:72])[C@H:7]([CH2:63][CH2:64][C:65]([O:67]C(C)(C)C)=[O:66])[NH:8][C:9](=[O:62])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:60])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([O:42][C:43](=[O:59])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:23][O:24][C:25](=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:12][C:11]=1[F:61])(C)(C)C>FC(F)(F)C(O)=O>[C:43]([O:42][CH:22]([CH2:23][O:24][C:25](=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:21][S:20][CH2:19][CH2:18][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:72])=[O:5])[CH2:63][CH2:64][C:65]([OH:67])=[O:66])=[O:62])=[C:11]([F:61])[CH:12]=1)=[O:60])(=[O:59])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(F)c1)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c(F)c1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 4-(6,7-bis(palmitoyloxy)-4-thiaheptanoyl)amino-2-fluorobenzoylglutamic acid di-t-butyl ester as obtained in Example 50 (205 mg) in trifiuoroacetic acid (5 ml) was stirred at room temperature for 4 hours, followed by concentration, to yield the title compound (183 mg, yield 100%) as a colorless crystal.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Cl.Cl[C:28]1[S:32][C:31]([S:33]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)(=[O:35])=[O:34])=[CH:30][CH:29]=1>>[CH3:42][N:39]1[CH2:38][CH2:37][N:36]([S:33]([C:31]2[S:32][C:28]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:29][CH:30]=2)(=[O:35])=[O:34])[CH2:41][CH2:40]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)s2)CC1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: Cl
Product: CN1CCN(S(=O)(=O)c2ccc(C#Cc3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)s2)CC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 1-(5-chloro-thiophene-2-sulfonyl)-4-methyl-piperazine hydrochloride (example B.41) (159 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (48 mg, 16%). MS (ISP) 600.2 [(M+H)+]; mp 250° C.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH:18]([CH3:28])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:22]1([NH:21][C:19](=[O:20])[CH:18]([O:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:15]=[CH:16][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[CH:9][CH:10]=2)[CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(Br)C(=O)Nc1ccccc1
Reactant: N#Cc1ccc(Oc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Oc1ccc(Oc2ccc(C#N)cc2)cc1)C(=O)Nc1ccccc1
Yield: 68.8 %

Procedure:
To 30 ml of acetone were added 1.06 g of 4-(4-cyanophenoxy)-phenol, 0.99 g of α-bromopropionanilide and 0.83 g of anhydrous potassium carbonate, and the mixture wask subjected to reflux for 16 hours with stirring. After the reaction mixture was cooled and separated from inorganic salts through filtration, acetone was distilled away therefrom. The residue was purified through a column-chromatography [silica gel, developed with ethyl acetate/n-hexane=1/1(V/V)] to give 1.07 g of the title compound (yield 60%), which was recrystallized from a mixed solvent of benzene-n-hexane to afford a crystal of melting point 133°-134° C.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:5]=1[C:12](=O)[CH3:13].[C:15]([S-:17])#[N:16].[K+].Cl>C(O)C.O>[Cl:11][C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]2[C:5]=1[CH:12]([CH3:13])[NH:16][C:15](=[S:17])[NH:3]2
Reactant: N#C[S-]
Reactant: CC(=O)c1c(Cl)ccc(Cl)c1N
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1NC(=S)Nc2c(Cl)ccc(Cl)c21
Temperature: 65 °C
Yield: 68.1 %

Procedure:
At a temperature of 65° C., sodium borohydride (0.13 g, 3.4 mmol) was added to a solution of 1-(2-amino-3,6-dichloro-phenyl)-ethanone (1.16 g, 5.7 mmol) in ethanol (12 ml), and the mixture was heated overnight (65° C.). Water (14.4 ml), KSCN (0.61 g, 6.3 mmol) and concentrated aqueous hydrogen chloride solution (3.6 ml) were then added subsequently, and the mixture was again heated (3 h, 65° C.). The majority of the title compound precipitated upon cooling and could be isolated in pure form by filtration and washing with water and ethanol to yield a light yellow solid (0.96 g, 69%).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19]1[CH2:26][CH:25]2[CH:21]([CH2:22][CH2:23][C:24]2=[O:27])[CH2:20]1)C1C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]([N:19]1[CH2:26][CH:25]2[CH:21]([CH2:22][CH2:23][C:24]2=[O:27])[CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2CN(Cc3ccccc3)CC12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: O=C1CCC2CN(C(=O)OCc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
Benzyloxycarbonyl chloride (5.14 ml, 36.0 mmol) was added dropwise to a solution of 7-benzyl-2-oxo-7-azabicyclo[3.3.0]octane (5.20 g, 24.2 mmol) in dichloromethane (50 ml) under cooling with ice, followed by stirring at room temperature for 24 hours. The mixture was again cooled with ice, and benzyloxycarbonyl chloride (5.14 ml, 36.0 mmol) was added thereto dropwise. After removing the solvent by evaporation, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 4.52 g (17.4 mmol, 72%) of the title compound as a colorless oily substance.