Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>C(Cl)(Cl)Cl>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH:2]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cccc2c1CCC2Cl
Reactant: C1CCNCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1CCC2N1CCCCC1
Reaction time: 8 h

Procedure:
A solution of 1-chloro-4-methoxyindan (from Step 3) in chloroform (130 ml) is added over a period of ten minutes to a stirred mixture of piperidine (284 ml) in chloroform (400 ml) under nitrogen. The reaction mixture is heated to reflux for six hours and allowed to stand at RT overnight. The mixture is treated with 10% aqueous HCl and the organic layer separated. The aqueous layer is extracted with methylene chloride and the combined organic extracts washed with 10% aqueous HCl. The organic layer is evaporated in vacuo and the residue partitioned between 5% aqueous HCl and ether. The combined aqueous fraction is washed with ether, made alkaline, and the alkaline layer extracted with ether. The ether extract is washed, dried and concentrated in vacuo yielding the piperidine indan as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C@H:5]2[C@H:7]([NH:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C@H:9]([OH:10])[C@H:4]2[O:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:45][CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=O)=O)=CC=1>CN(C=O)C>[CH2:48]([O:47][CH2:46][CH2:45][O:10][C@@H:9]1[C@H:4]2[O:3][C:2]([CH3:31])([CH3:1])[O:6][C@H:5]2[C@H:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCc2ccccc2)cc1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCOCc1ccccc1)C[C@H]2NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (10 g, 24.0 mmol) (3aR,4S,6R,6aS)-2,2-dimethyl-6-(tritylamino)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol in dry DMF (100 mL) under nitrogen atmosphere was cooled at 0° C. followed by addition of NaH (60%, 1.2 g, 29.0 mmol). After stirring for 30 min at 0° C., 2-(benzyloxy)ethyl 4-methylbenzenesulfonate (7.4 g, 24.0 mmol) was added and the reaction mixture was allowed to warm at room temperature. After stirring for 4 hours, the reaction mixture was quenched with water (100 mL). To the mixture was extracted 3×100 mL of EtOAc. The combined organic phases were dried over MgSO4, filtered and evaporated to the dryness. The pure IIIe was isolated from reaction mixture by chromatography on silica gel column (mobile phase: n-hexane/EtOAc).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][CH:7]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH:23]3[CH2:28][CH2:27][CH:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[CH:18]=2)[CH:13]=1)[C:8]([F:11])([F:10])[F:9].C(O)C.[OH-].[Na+].O.Cl>>[C:29]([CH:26]1[CH2:27][CH2:28][CH:23]([O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([CH:7]([NH:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])[C:8]([F:11])([F:9])[F:10])[CH:21]=[CH:20]3)[CH2:24][CH2:25]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)CCNC(c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C1CCC(Oc2ccc3cc(C(NCCC(=O)O)C(F)(F)F)ccc3c2)CC1
Reaction time: 1 h

Procedure:
3-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino}-propionic acid methyl ester (164 mg, 0.352 mmol) was dissolved in Ethanol (2 mL, 40 mmol) then treated with 1 M of sodium hydroxide in Water (2 mL, 2 mmol). The mixture was stirred vigorously for 1 hour. pH was adjust to 3-4 with 6 N HCl and reaction was then extracted three times with EtOAc. Organics were combined then dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Ethyl ether was then added and a white ppt formed. The ppt. was removed via filtration to give a white solid that 99% pure by NMR and HPLC-traces of ethanol remain. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.83 (s, 9H) 0.93-1.10 (m, 1H) 1.11-1.27 (m, 2H) 1.27-1.42 (m, 2H) 1.73-1.89 (m, 2H) 2.19 (d, J=10.29 Hz, 2H) 2.67 (t, J=6.53 Hz, 2H) 3.03-3.18 (m, 2H) 4.22-4.37 (m, 1H) 5.33-5.51 (m, 1H) 7.13 (dd, J=8.91, 2.38 Hz, 1H) 7.21-7.29 (m, 1H) 7.46 (d, J=8.78 Hz, 1H) 7.76 (d, J=9.04 Hz, 1H) 7.85 (d, J=8.78 Hz, 1H) 7.93 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[C:5](=[O:19])[CH2:4][CH2:3]1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>O1CCCC1>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][N:8]2[C:2](=[O:1])[CH2:3][CH2:4][C:5](=[O:19])[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]2=3)[CH2:24][CH2:23]1)[CH3:21]
Reactant: O=C(O)CCCN1C(=O)CCC(=O)c2ccccc21
Reactant: CCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)CCCN2C(=O)CCC(=O)c3ccccc32)CC1
Yield: 12.2 %

Procedure:
On the basis of the method described by M. K. Dhaon et al. in J. Org. Chem. 47 (1982) p. 1962, reaction of 4-(2,5-dioxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)butanoic acid (0.06 g) from step b and 1-ethylpiperazine (0.25 mmol, 0.03 g) in the presence of EDC.HCl (N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride) (0.36 mmol, 0.07 g), Et3N (0.48 mmol, 0.05 g) in tetrahydrofuran (5 ml) afforded 10.0 mg of the title compound.
Reaction SMILES: [CH:1]1([NH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH2:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][S:14][C:15]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[C:16]=1[C:17](O)=[O:18]>>[CH:1]1([NH:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][C:17](=[O:18])[C:16]2[C:20]([C:28]([F:29])([F:30])[F:31])=[CH:21][C:22]([C:24]([F:25])([F:26])[F:27])=[CH:23][C:15]=2[S:14][CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: NC1CCCC1NC1CCCC1
Product: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1NC1CCCC1

Procedure:
The title compound, light pink solid, MS: m/e=455.3 [(M+H)+], was prepared in accordance with the general method of example 5 from (1RS,2SR)—N-Cyclopentyl-cyclopentane-1,2-diamine (intermediate AE) and 2-methylthio-4,6-bis(trifluoromethyl)benzoic acid (CAS 896120-49-3).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]#[N:12])=[CH:7][CH:8]=2)[NH:3]1.Cl[C:14]1[N+:19]([O-:20])=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]2)=[CH:16][CH:15]=1.[H-].[Na+]>CN1CCCC1=O>[OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:21][N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[CH:18][N+:19]=1[O-:20])=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[CH:5]=2
Reactant: O=C1CN(Cc2ccc(Cl)[n+]([O-])c2)CCN1
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(-c3ccc(CN4CCNC(=O)C4)c[n+]3[O-])c(O)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Oxoindoline-6-carbonitrile (0.063 g, 0.397 mmol) was added to a suspension of 4-[(6-chloro-1-oxidopyridin-3-yl)methyl]piperazin-2-one (0.080 g, 0.33 mmol) and sodium hydride (0.042 g, 1.75 mmol) in 1-methyl-2-pyrrolidone (3 mL). The mixture was stirred at room temperature for 10 min, heated at 90° C. for 1 h and finally quenched with methanol (0.5 mL). Trituration with acetonitrile and drying in vacuo gave the crude 2-hydroxy-3-{1-oxido-5-[(3-oxopiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-6-carbonitrile as a solid. The crude intermediate was suspended in chloroform (5 mL) and phosphorus trichloride (0.5 mL, 5.73 mmol) was added. The mixture was stirred at 60° C. for 3 h and then concentrated in vacuo. Purification using preparative HPLC (XTerra®PrepMS C8 column 10 μm, 30×150 mm; 0.1 M NH4OAc buffer/acetonitrile, (80:20-20:80), as the eluent) gave a yellow solid that was dissolved in dichloromethane/methanol, (9:1), and treated with HCl in diethyl ether (1 M) at 0° C. The resulting yellow crystals were collected by filtration, washed with diethyl ether, and dried to obtain 0.036 g (26% yield) of the title compound: 1H NMR (D2O, 400 MHz) 8.16 (d, J=2 Hz, 1H), 7.96 (dd, J=9, 2 Hz, 1H), 7.80 (d, J=9 Hz, 1H), 7.61 (d, J=8 Hz, 1H), 7.35 (dd, J=8, 1 Hz, 1H), 7.31 (s, 1H), 4.11 (s, 2H), 3.62 (s, 2H), 3.51 (t, J=5H, 2H); MS (ESP) m/z 348 (M++1).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][N:7]([CH3:21])/[CH:8]=[CH:9]/[C:10]([C:12]1[CH:13]=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=12)=O.[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[Na+]>C(Cl)Cl.CO>[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[Cl:3]/[C:10](/[C:12]1[CH:13]=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=12)=[CH:9]\[CH:8]=[N+:7]([CH3:21])[CH3:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)/C=C/C(=O)c1cnn2ccccc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C[N+](C)=C/C=C(\Cl)c1cnn2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
POCl3 (0.951 mL, 10.20 mmol) was added to a solution of (E)-3-(dimethylamino)-1-(pyrazolo[1,5-a]pyridin-3-yl)prop-2-en-1-one (2.153 g, 10 mmol) in CH2Cl2 (15 mL) at 20° C. (using ice/water cooling) over a period of 3 minutes under N2. The resulting solution was stirred at r.t. for 0.5 h and was then concentrated in vacuo. The residue was dissolved into a minimum amount of CH3OH (100 mL). This solution was added over a period of 2 minutes to a solution of sodium hexafluorophosphate(V) (3.36 g, 20.00 mmol) in CH3OH (40 mL). After 5 minutes the precipitate was collected by filtration, washed well with CH3OH cooled to −50° C. and dried by suction under a stream of N2 to give the title compound (3.40 g, 90%) as a yellow powder, which was used without further purification; 1H NMR: 3.63 (6H, d), 7.36 (2H, m), 7.71-7.90 (1H, m), 8.45 (1H, d), 8.81 (1H, d), 9.05 (2H, d); m/z: ES+ M+ 234.
Reaction SMILES: FC(F)(F)C(O)=O.[Si:8]([O:25][CH:26]([CH2:48][O:49]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:27][O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[Si:8]([O:25][CH:26]([CH2:48][OH:49])[CH2:27][O:28][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])([C:21]([CH3:22])([CH3:24])[CH3:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 3 h
Yield: 54 %

Procedure:
4 ml of trifluoroacetic acid is slowly dropped into a solution of 4 (4.65 mmol) in 50 ml of dichloromethane at room temperature. After 3 hours, this is washed with water and saturated sodium hydrogen carbonate solution. The combined organic phases are dried over MgSO4, filtrated and concentrated. The residue is purified on silica gel by flash chromatography using isohexane/ethyl acetate (7:1). Yield: 54% of a colorless oil.
Reaction SMILES: [O:1]=[C:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[BH4-].[Na+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([OH:1])[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH3:7]
Reactant: CCOC(=O)C(=O)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(O)c1cccs1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of ethyl 2-oxo-2-(thiophen-2-yl)acetate (5.00 g, 27.1 mmol) in ethanol (50 mL) is cooled at 0° C. with an ice bath. NaBH4 (0.31 g, 8.14 mmol) is added in four portions under stirring. The mixture is stirred at 0° C. for 10 minutes, then allowed to warm at RT and stirred for additional 30 minutes. Reaction is concentrated under vacuum and the residue is partitioned between Et2O and ice-cooled water. The organic layer is separated, washed with water and brine, dried over Na2SO4, filtered and evaporated to give a colorless liquid (5.05 g, 91% yield).
Reaction SMILES: [C:1]1([S:7][C:8]2[NH:9][C:10](=O)[C:11]3[NH:12][CH:13]=[N:14][C:15]=3[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:29])=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:1]1([S:7][C:8]2[N:16]=[C:15]3[C:11]([NH:12][CH:13]=[N:14]3)=[C:10]([Cl:29])[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(Sc2ccccc2)nc2nc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: Clc1nc(Sc2ccccc2)nc2nc[nH]c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a flame-dried round bottom flask (200 mL) was added 2-Phenylsulfenylhypoxanthine 2 (1.22 g, 5.0 mmol), tetrabutyl-ammonium chloride (anhydrous, 2.78 g, 10.0 mmol) and N,N-dimethylaniline (0.63 mL, 5.0 mmol), followed by dissolving them in acetonitrile (anhydrous, 50 mL). To the solution phosphorus oxychloride (2.8 mL, 30.0 mmol) was added dropwise. The reaction was refluxed under argon. After 2 hours, the reaction was cooled to 0° C. on an ice bath and quenched by addition of saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (4×100 mL). The combined organic layers were dried over sodium sulfate, and were concentrated on the rotary evaporator. The crude product was further purified by re-crystallization from methanol to afford desired product 3 as white solid (0.94 g, 72%). 1H NMR (400 MHz, (CD3)2SO) 7.50 (m, 3H), δ 7.65 (m, 2H), 8.53 (s, 1H); MS (ES) calculated for C11H7ClN4S [MH+] 263.02, found: 263.00.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH:10]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:11][CH:10]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(NCc3ccccc3)C(C)C2)cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CC(CNc2ccccc2)CCC1NCc1ccccc1

Procedure:
A mixture comprising toluene-4-sulfonic acid 4-benzylamino-3-methyl-cyclohexylmethyl ester (350 mg, 0.90 mmol), aniline (126, mg, 1.35 mmol) and potassium carbonate (250 mg, 1.80 mmol) in MeCN (1 mL) is heated using microwave radiation at 180° C. for 1 hour. The reaction mixture is partitioned between DCM and water and passed through a phase separator. The solvent is removed in vacuo and purification of the crude residue by chromatography on silica eluting with iso-hexane:EtOAc (25:1 increasing to 10:1) affords the title compound. [MH+309.34].
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O>[N:32]([CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[N+:33]=[N-:34]
Reactant: CS(=O)(=O)OCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 17 h
Yield: 80.9 %

Procedure:
A suspension of 60.0 g of (N-triphenylmethyl-4-piperidyl)methyl methanesulfonate and 17.9 g of sodium azide in 300 ml of dried N,N-dimethyl-formamide was stirred at 70° C. for 17 hours. After the reaction, an insoluble matter was filtered off and the filtrate was concentrated. The resulting residue was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting solid was washed successively with ethanol and n-hexane to give 42.6 g of colorless crystals. Recrystallization from a mixture of methanol and diethyl ether gave colorless crystals having the melting point of from 103.5 to 105.5° C.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.I[CH3:12]>>[CH3:12][NH:6][C:5]1[CH:7]=[CH:8][C:9]2[O:10][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: CI
Reactant: Nc1ccc2c(c1)OCO2
Product: CNc1ccc2c(c1)OCO2
Yield: 18 %

Procedure:
The title compound was prepared from 3,4-(methylenedioxy)aniline and iodomethane by the procedure described in example 2 in 18% yield. 1H NMR (CDCl3): 6.67 (d, J=8.3, 1H), 6.25 (d, J=2.2, 1H), 6.04 (dd, J=2.2, 8.3, 1H), 5.85 (s, 2H), 3.50 (br s, 1H), 2.79 (s, 3H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>C(O)(C)(C)C.O.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CC(C)(C)O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O

Procedure:
15.0 g of Z-Asn-Leu-OMe are dissolved in 400 ml of t-butanol-water (9:1) and are hydrogenated in the presence of 2 g of palladium-charcoal (10 %Pd). After completion of the hydrogenation the catalyst is filtered off and the solution evaporated at 40°C. The residue is directly further used.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8]2)[O:4][N:3]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:15][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[C:7]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1(c2cc(C)no2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(c2onc(C)c2Br)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
To a solution of ethyl 1-(3-methylisoxazol-5-yl)cyclopropanecarboxylate (9.49 g, 48.6 mmol) in anhydrous DMF (50 mL) was added N-bromosuccinimide (10.31 g, 57.9 mmol). The reaction mixture was stirred at room temperature for 24 h. To the orange mixture was added water and the aqueous layer was extracted with MTBE (3×). The combined organic layers were washed with aqueous 10% sodium thiosulfate, water (2×) and dried to provide the product ethyl 1-(4-bromo-3-methylisoxazol-5-yl)cyclopropanecarboxylate (12.5 g, 45.6 mmol, 94% yield) as a light yellow oil. The product was used directly in the subsequent reaction without further purification. LC/MS m/z 274 [M+H]+.
Reaction SMILES: [NH:1]1[C:42](=[O:43])[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[NH:35][C:33](=[O:34])[C@@H:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:24][C:22](=[O:23])[C@H:17]([CH2:18][C:19](=[O:21])[OH:20])[NH:16][C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C([O-])(O)=[O:45].[Na+]>C1COCC1>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@@H:25]([C:33]([NH:35][C@H:36]([C:42]([OH:45])=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])[CH2:18][C:19](=[O:21])[OH:20])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: O=C([O-])O
Reactant: N=C(N)NCCC[C@@H]1NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CC(=O)O)NC(=O)CNC1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: N=C(N)NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(=O)O
Reaction time: 4 h

Procedure:
6 g of BOC-Aha-N-succinimidyl ester are added to a solution of 3.05 g of cyclo-(Arg-Gly-Asp-D-Phe-Lys)(SEQ ID NO: 176) in 40 ml of 5% aqueous NaHCO3 and 40 ml of THF. The mixture is stirred for 4 hours and worked-up in the customary manner, affording cyclo-(Arg-Gly-Asp-D-Phe-Lys (BOC-Aha))(SEQ ID NO: 13); RT [C] 27.7; FAB 817. After the BOC group has been eliminated in HCl/dioxane, cyclo-(Arg-Gly-Asp-D-Phe-Lys(Nε-Aha)(SEQ ID NO: 14)×2 TFA; RT [C] 14.76; FAB 717 is obtained after the customary working-up. Cyclo-(Arg-Gly-Asp-D-Phe-Lys(Nε-FCA-Aha))(SEQ ID NO: 15)×TFA; RT [B] 23.8; FAB 1075 is obtained, in analogy with Example 1, by subsequent reaction with FCA-N-succinimidyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][N+:3]=1[O-:13].CCN(C(C)C)C(C)C.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>CC(O)(C)C>[C:29]([O:28][C:27]([NH:26][CH2:25][CH2:24][NH:23][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][N+:3]=1[O-:13])=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)Cc1ccc(Cl)[n+]([O-])c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(NCCNC(=O)OC(C)(C)C)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 32.2 %

Procedure:
To 2-chloro-5-(2-methoxy-2-oxoethyl)pyridine 1-oxide (2.5 g) in t-BuOH (50 mL) was added DIEA (3.4 mL) and tert-butyl 2-aminoethylcarbamate (3.0 g). The resulting reaction mixture was stirred at 80° C. for 2 days. The solvent was then removed and the residue purified by reverse phase chromatography to afford the desired product (1.3 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH:19]=[CH:18]1>C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:17](=[O:23])/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(NC(=O)/C=C\C(=O)O)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
N-(3,5-di tert.butyl-4-hydroxyphenyl)maleamic acid was prepared by adding to the benzene solution of 2,6-di tert.butyl-4-aminophenol in 15 minutes at 15° C. to 31° C. a solution of 9.8 grams of maleic anhydride in 50 milliliters of benzene. The mixture was stirred for 2 hours and the solid product was filtered off and dried. The yield was 19.5 grams and the product melted at 206° C. to 207° C. (with decomposition).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:22]([N:19]1[CH2:20][CH2:21][CH:16]([O:15][C:12]2[CH:13]=[CH:14][C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[S:10][C:9]=3[CH:11]=2)[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cc2ccc(OC3CCN(C(C)C)CC3)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3cc(C(=O)O)sc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144 %

Procedure:
The above prepared 6-(1-isopropyl-piperidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.359 g, 1.033 mmol) was dissolved in 2 mL of THF/ethanol=1/1 and treated with 0.517 mL of aq. NaOH (3M, 1.5 eq.). The mixture was stirred for 1 h at ambient temperature and was then neutralized by adding 0.77 mL of 2M HCl (1.5 eq.). Careful evaporation of all solvents and drying afforded then 0.475 g of the title compound as white solid contaminated with innocouos inorganic salts.