Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=1[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH3:24]>N1C=CC=CC=1>[CH3:24][N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[CH2:17][CH2:16][C:15]1[CH:25]=[CH:26][CH:27]=[CH:28][C:14]=1[NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Reaction of 4-nitrobenzoyl chloride (6.5 g., 0.035 mole) and 2-(o-aminophenethyl)-1-methylpiperidine (6.0 g., 0.0275 mole) in 35 ml. of pyridine according to the method of Example 25 provides 2'-[2-(1-methyl-2-piperidyl)ethyl]-4-nitrobenzanilide. Crystallization from ethyl acetate provides analytically pure material, m.p. 162°-163.5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[CH:6]=1)=O.O.[NH2:16][NH2:17]>C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[S:9][C:5]([C:3]([NH:16][NH2:17])=[O:2])=[CH:6][C:7]=2[CH:13]=1
Reactant: COC(=O)c1cc2cc(Cl)ccc2s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc2cc(Cl)ccc2s1
Temperature: 0 °C

Procedure:
8.00 g (35.3 mmols) of 5-chloro-2-benzo[b]thiophenecarboxylic acid methyl ester and 10 ml of hydrazine hydrate in 100 ml of absolute ethanol are boiled under reflux for 45 minutes. The cooled suspension is diluted with 100 ml of ice water and the product is filtered off. It is washed with two 40 ml portions of methanol and dried in vacuo. 5-Chloro-2-benzo[b]thiophene-carboxylic acid hydrazide with a melting point of 254°-255° is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:38]Br>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20]([Br:38])=[CH:19][C:18]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccccc1OCc1ccccc1
Reactant: BrBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a −78° C. solution of [(2-Benzyloxy-phenyl)-tert-butoxycarbonylmethyl-amino]-acetic acid tert-butyl ester (6.3 g, 14.7 mmol) in CH2Cl2 (100 mL) was added pyridine (1.8 mL, 22.1 mmol) followed by bromine (0.91 mL, 17.6 mmol) under an Ar atmosphere. After 30 min, the mixture was allowed to warm to room temperature and then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with CH2Cl2/hexane/EtOAc=1:4:0.2 to yield 5.9 g (79%) of 13 as a white solid. Rf=0.43 (in CH2Cl2/hexane/EtOAc=1:4:0.2); 1H NMR (300 MHz, CDCl3) δ 7.45-7.26 (m, 5H), 6.99 (m, 2H), 6.73 (m, 1H), 5.09 (s, 2H), 4.04 (s, 4H), 1.41 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.1, 151.1, 138.7, 136.6, 128.6, 127.9, 127.4, 124.1, 120.5, 117.6, 113.7, 81.2, 71.2, 54.5, 28.0; mass spectrum, calculated for C25H32BrNO5 (MH+) 506.2, Found 505.8.
Reaction SMILES: C([O-])=O.C(OC(=O)[NH:13][CH2:14][CH2:15][C:16]1[O:17][C:18]([CH2:21][CH3:22])=[CH:19][N:20]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:21]([C:18]1[O:17][C:16]([CH2:15][CH2:14][NH2:13])=[N:20][CH:19]=1)[CH3:22]
Reactant: CCc1cnc(CCNC(=O)OCc2ccccc2)o1
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: CCc1cnc(CCN)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ammnonium formate (0.316 g, 5 mmol) is added to a solution of [2-(5-ethyl-oxazol-2-yl)-ethyl]-carbamic acid benzyl ester (step 3) (1.66 mmol) in methanol (15 ml) and 10% Pd on carbon (125 mg) is added under an inert atmosphere. The mixture is stirred at ambient temperature for 2 hours. The catalyst is removed by filtration and the filtrate is evaporated. The residue is diluted with dichloromethane, filtered to remove undissolved solid and the solvent is removed. The residue is dissolved in DCM and treated with 1M aqueous sodium hydroxide solution (5 ml). The organic extract is separated, dried (MgSO4), filtered and the solvent is removed. Crystallisation from ethyl acetate/dichloromethane affords the titled compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:3]=1.[CH2:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[CH2:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:29][CH2:30][N:31]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:4]4[N:5]=[C:6]5[C:11]([CH2:10][CH2:9][C:8](=[O:12])[NH:7]5)=[C:2]([CH3:1])[CH:3]=4)[CH2:32][CH2:33]3)[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: c1cc2c(c(N3CCNCC3)c1)CCC2
Reactant: Cc1cc(OCCCC=O)nc2c1CCC(=O)N2
Product: Cc1cc(OCCCCN2CCN(c3cccc4c3CCC4)CC2)nc2c1CCC(=O)N2

Procedure:
The title compound was prepared by reductive amination of 4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 1-indan-4-yl-piperazine according to the above procedure. MS: APCI: M+1: 435.6 (Exact Mass: 434.27).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CCO>[CH2:34]([O:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1CC(C(=O)N2CCC(c3ccccc3)CC2)CCc2c(O)cccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1CC(C(=O)N2CCC(c3ccccc3)CC2)CCc2c(OCc3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
600 mg (0.00165 mol) of (±)-1-hydroxy-7-[(4-phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one were dissolved in 100 mL of abs. EtOH under a nitrogen atmosphere, then 228 mg (0.00165 mol) of anhydrous K2CO3 and a catalytic amount of KI were added, followed by 0.216 mL (0.0018 mol) of benzylbromide. The reaction mixture was stirred 3 h at room temperature, then 0.216 mL of benzylbromide were added and the stirring continued overnight. Further 0.216 mL of benzylbromide was added and the reaction stirred overnight. The solvent was then evaporated, the residue was taken up in water, brought to pH 1 with 1N HCl and extracted with AcOEt. The organic phase was dried and the solvent was removed in vacuo, the resulting crude product was purified by flash chromatography, eluting with a mixture Et2O/Hexane 8:2 respectively, yielding 595 mg of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C:33]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])([CH2:37][CH2:38][CH2:39][NH:40][CH:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:42])[C:34]([OH:36])=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN1CCOCC1>CN(C)C=O>[CH2:46]([O:45][C:43](=[O:44])[CH:41]([N:40]1[CH2:39][CH2:38][CH2:37][C:33]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])([NH:32][C:30]([O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:31])[C:34]1=[O:36])[CH3:42])[CH3:47]
Reactant: CCOC(=O)C(C)NCCCC(NC(=O)OC(C)(C)C)(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C(C)N1CCCC(NC(=O)OC(C)(C)C)(NC(=O)OC(C)(C)C)C1=O
Yield: 86.7 %

Procedure:
HATU (1.72 g, 4.5 mmol) was added to a solution of 2,2-bis(tert-butoxycarbonylamino)-5-(1-ethoxycarbonyl-ethylamino)-pentanoic acid (1.31 g, 3.0 mmol) and 4-methylmorpholine in dimethylformamide (50 mL). After 30 minutes the solvent was removed under reduced pressure and the residue was subjected to flash chromatography with eluent of ethyl acetate and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 2-[3,3-bis(tert-butoxycarbonylamino)-2-oxo-piperidin-1-yl]-propionic acid ethyl ester (1.11 g, 2.6 mmol, 86%). C20H34N2O7 calculated 414.2 observed [M+1]+ 415.2; rt=2.77 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:26]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>>[C:33]([N:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:26]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[N:9]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: Nc1nccn2c(C3CCCCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: C=CC(=O)N1CCCCCC1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 32.6 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from 4-(8-amino-3-(azepan-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (intermediate 46) and acryloylchloride, to afford the title compound (11 mg, 32.6%). Data: UPLC(C) Rt: 1.88 min; m/z 482.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[Br-].[CH:18]1([Zn+])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1COCC1>[C:8]([Si:5]([O:4][C:3]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:7])[CH3:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: [Zn+]C1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cccc1C1CCCCC1
Temperature: 25 °C

Procedure:
A solution consisting of (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (0.832 g, 2.73 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.070 g, 0.14 mmol) and dry THF (5 mL) was treated with cyclohexylzinc(II) bromide (7.0 mL, 3.5 mmol, 0.5 M in THF). The resultant mixture was heated for 45 minutes at 50° C., cooled to rt, and concentrated to dryness. The resultant residue was subjected to FCC purification to the title compound (0.841 g, 89%) which was used without purification.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12]/[N:13]=C(\OCC)/C)(=[O:11])=[O:10].O1CCOCC1.Cl(O)(=O)(=O)=O>>[NH2:13][O:12][S:9]([C:2]1[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=1[CH3:19])(=[O:10])=[O:11]
Reactant: CCO/C(C)=N\OS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1COCCO1
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 0 °C

Procedure:
The ethyl (1Z)—N-[(mesitylsulfonyl)oxy]ethanimidoate (5.0 g, 18 mmol) was dissolved in 1,4-dioxane (4.5 mL, 58 mmol) and cooled in an ice bath under nitrogen. Perchloric acid (2.3 mL, 38 mmol) was added drop wise over 3 minutes. The reaction slowly became a thick mixture after 20 minutes. Ice (50 mL) was added to the reaction. The reaction was extracted with ethyl ether. The combined organic layer was washed with brine, dried over potassium carbonate (solid) and the volume was reduced to about 40 mL. LCMS calculated for C9H14NO3S (M+H)+: m/z=216.0. found: 215.9.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([N+:37]([O-])=O)[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[C:10]2[S:11][C:12]([C:14]3[N:19]=[C:18]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:17]=[CH:16][CH:15]=3)=[CH:13][C:9]=2C=[CH:7][CH:6]=1.[NH4+:40].[Cl-].CCO>[Fe].O>[NH2:37][C:35]1[CH:34]=[CH:33][C:3]([O:4][C:5]2[CH:6]=[CH:7][N:40]=[C:9]3[CH:13]=[C:12]([C:14]4[N:19]=[C:18]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH:17]=[CH:16][CH:15]=4)[S:11][C:10]=23)=[C:2]([F:1])[CH:36]=1
Reactant: COCCN(Cc1cccc(-c2cc3cccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1)C(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1)C(=O)OC(C)(C)C
Yield: 103.8 %

Procedure:
A solution of 58 (1 g, 1.81 mmol) and NH4Cl (97 mg, 1.8 mmol) in a 2:1 mixture of EtOH and water (30 mL) was treated with iron powder (605 mg, 10.8 mmol) and stirred at reflux for 1 hour. The reaction mixture was then filtered through a celite pad and concentrated yielding title compound 59 (980 mg, 100% yield) that was used in the next step (scheme 18) without further purification. MS (m/z): 525.2 (M+1).
Reaction SMILES: P(=O)(O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[I-:20].[K+].O[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]>CCOCC.O>[I:20][CH:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[C:38]([OH:40])=[O:39]
Reactant: [I-]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCC(I)C(=O)O
Temperature: 110 °C
Yield: 7.6 %

Procedure:
Procedure 3, Step A, for the preparation of methyl 16-=iodohexadecanoate (9), follows Takahashi et al, Appl. Radiat. Isot., 42, 801 (1991), incorporated herein by reference. To a mixture of phosphoric acid, (840 mg, 8.6 mmol) and phosphorus pentoxide (ca 450 mg), potassium iodide (868 mg, 5.2 mmol) and 16-hydroxyhexadecanoic acid (353 mg, 1.3 mmol), available from Aldrich Chemical Co., is added at room temperature and the mixture is heated at 110° C. for 3.5 h. The mixture is cooled to room temperature, and water (25 ml) and ether (120 ml) are added. The ether layer is separated, decolorized by shaking with 10% sodium thiosulfate solution (100 ml), washed with saturated NaCl aqueous solution (200 ml) , and evaporated to give crude 16-=iodohexadecanoic acid (38 mg). To a suspension of the sample in absolute MeOH (30 ml) thionyl chloride (6.5 ml) is added dropwise at 0° C. The mixture is stirred at 0° C. for 15 min and then refluxed for 30 min. After removal of the solvent, the residue is purified by preparative TLC (hexane/CH2Cl2 =7/3) to give 9 (26 mg). The procedure is performed on a 1-mole scale to provide enough material for Step C below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC(=O)C[N:6]1[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][C:9](=[O:17])[C:8]2[CH:18]=[C:19]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])[C:20](=[O:23])[CH:21]=[CH:22][C:7]1=2)C.Cl>>[O:17]=[C:9]1[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[NH:6][C:7]2[CH:22]=[CH:21][C:20](=[O:23])[C:19]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:18][C:8]1=2
Reactant: CCOC(=O)COc1cc2c(=O)cc(C(=O)OCC)n(CC(=O)OCC)c2ccc1=O
Agent: Cl
Product: O=C(O)COc1cc2c(=O)cc(C(=O)O)[nH]c2ccc1=O
Temperature: 25 °C

Procedure:
A mixture of 4,7-dihydro-4,7-dioxo-2-ethoxycarbonyl-6-[(2-ethoxy-2-oxoethyl)oxy]-1H-cyclohepta[b]pyridine-1-acetic acid ethyl ester (0.617 g, described in Example 15) and 19% hydrochloric acid (4.2 ml) is refluxed for 1 hr and cooled to room temperature. The precipitate is collected and washed with water, acetone and ether to obtain the title compound, mp > 270° C.
Reaction SMILES: C1C2C(=CC(S[C:11]3[C:12]4[CH:20]=[CH:19][CH:18]=[N:17][C:13]=4[N:14]=[CH:15][N:16]=3)=CC=2)CC1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH2:26][CH2:25]2>O>[CH2:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:11]3[C:12]4[CH:20]=[CH:19][CH:18]=[N:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:30][CH:29]=2)[CH2:25][CH2:26]1
Reactant: c1cnc2ncnc(Sc3ccc4c(c3)CCC4)c2c1
Reactant: Nc1ccc2c(c1)CCC2
Solvent: O
Product: c1cnc2ncnc(Nc3ccc4c(c3)CCC4)c2c1
Temperature: 130 °C
Yield: 40 %

Procedure:
A suspension of 4-(5-indanylthio)-pyrido[2,3-d]pyrimidine (2.79 g, 10 mM) and 5-aminoindan (3.996 g, 30 mM) in water (100 ml) is heated in a sealed tube at 130° C. for 20 h. Then the water is evaporated under vacuum and the residue chromatographed on silica gel by using dichloromethane/methanol mixtures as eluant. Thus almost pure title compound is obtained in about 40% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH3:36])[C:16](=[O:35])[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[NH:24][C:25](=[O:34])[C:26]4[C:31]([CH:32]=3)=[C:30]([CH3:33])[CH:29]=[CH:28][CH:27]=4)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:36][N:15]([CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:16](=[O:35])[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[NH:24][C:25](=[O:34])[C:26]3[C:31]([CH:32]=2)=[C:30]([CH3:33])[CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:22]=1
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)CC4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)CC4CCNCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
To 4-({methyl-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (170 mg, 0.35 mmol) in CH2Cl2 (5 mL) was added 4M HCl/dioxane (2 mL) and the reaction mixture stirred at RT for 4 h. The solvent was removed in vacuo and the crude product purified by reverse phase preparative HPLC-MS to obtain N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-piperidin-4-ylmethyl-benzamide as a pale orange solid (44 mg, 33%).
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:13].Cl.[NH:15](C(OCC1C=CC=CC=1)=O)[C@H:16]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH2:69])=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CO.[Pd]>[NH2:15][C@H:16]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:67]([NH2:69])=[O:68])[CH2:61][C:62]1[N:66]=[CH:65][NH:64][CH:63]=1)=[O:58])[C@H:53]([CH2:55][CH3:56])[CH3:54])=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[ClH:13].[ClH:13]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Agent: [Pd]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1ccccc1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
3.14 g of the dihydrochloride of Z-Phe-His-Leu-Val-Ile-His-NH2 from Example 1 are hydrogenated for 4 hours at normal pressure in 100 ml of water/methanol (5:95) in the presence of 350 mg of palladium-on-carbon (5%). After removing the catalyst by filtration, evaporating off the solvent and drying in a high vacuum, H-Phe-His-Leu-Val-Ile-His-NH2.2HCl is obtained in the form of a colourless powder. Rf (B11)=0.26.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[OH-].[Na+]>O>[F:10][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)=[C:4]([CH:9]=1)[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(F)ccc1-c1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(F)ccc1-c1ncccn1
Temperature: 72 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a solution of 5-fluoro-2-pyrimidin-2-ylbenzoic acid methyl ester (1.72 g, 7.407 mmol) in 2-methyl-THF (20 mL) was added sodium hydroxide (0.74 g, 18.517 mmol) and water (20 mL). The mixture was heated to 72° C. and stirred for 2 h. The layers were separated and the aqueous layer was extracted with additional MTBE. A 50% HCl(aq) solution was then dripped into the aqueous layer until a pH of 1 was reached. The resulting solids were filtered to provide the desired product as an off-white solid (1.34 g, 83% yield). 1H NMR (400 MHz, CD3OD): 8.82 (d, J=5.0 Hz, 2H), 7.89 (dd, J=8.6, 5.4 Hz, 1H), 7.53 (dd, J=9.0, 2.7 Hz, 1H), 7.39 (m, 2H).
Reaction SMILES: [OH-].[Na+].Cl.[CH:4]1([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[NH:15])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:16]([NH:21][CH2:22][CH2:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]>O.CC(C)=O>[C:16]([NH:21][CH2:22][CH2:23][C:24]1[S:28][C:27]([S:29]([N:12]2[CH2:13][CH2:14][N:10]([CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]3)[C:11]2=[NH:15])(=[O:31])=[O:30])=[CH:26][CH:25]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: N=C1NCCN1C1CCCCC1
Reactant: CCCC(=O)NCCc1ccc(S(=O)(=O)Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCC(=O)NCCc1ccc(S(=O)(=O)N2CCN(C3CCCCC3)C2=N)s1
Reaction time: 18 h

Procedure:
20 ml (0.02 mol) of 1 N sodium hydroxide solution are added dropwise over the course of 10 minutes, whilst stirring, to a mixture of 2.04 g (0.01 mol) of 1-cyclohexyl-2-imino-imidazolidine hydrochloride and 2.96 g (0.01 mol) of 5-(2-butyramido-ethyl)-2-thiophenesulphonyl chloride in 45 ml of water-acetone (1:2), at 25°C. In the course thereof, the reaction temperature rises to 33°C. The reaction mixture is stirred for a further 18 hours at 24°-25°C and the acetone is then evaporated off with the aid of a rotary evaporator. The oil-water mixture which remains is extracted twice with 30 ml of ethyl acetate at a time. The extracts are washed with 20 ml of saturated sodium chloride solution, then combined, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on a column of 120 g of silica gel which is eluted with a mixture of chloroform and methanol (95:5). The eluate is evaporated with the aid of a rotary evaporator and the residue is recrystallized from toluene. Colourless crystals of 1-[5-(2-butyramido-ethyl)-2-thienylsulphonyl]-2-imino-3-cyclohexyl-imidazolidine of melting point 121°-125°C are obtained.