Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:30])[C@@H:19]([CH:20]=[C:21]2[CH2:25][CH2:24][S:23][C:22]2=[O:26])[C@H:18]1[C:27]([OH:29])=[O:28].[O:31]([C:38]1[S:39][CH:40]=[C:41]([CH2:43]O)[N:42]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:30])[C@@H:19]([CH:20]=[C:21]2[CH2:25][CH2:24][S:23][C:22]2=[O:26])[C@H:18]1[C:27]([O:29][CH2:43][C:41]1[N:42]=[C:38]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:39][CH:40]=1)=[O:28]
Reactant: OCc1csc(Oc2ccccc2)n1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C=C1CCSC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)OCc2csc(Oc3ccccc3)n2)[C@@H]1C=C1CCSC1=O
Temperature: 20 °C
Reaction time: 17 h
Yield: 71.6 %

Procedure:
0.11 g of 4-dimethylamino-pyridine and 2 g of dicyclohexylcarbodiimide was added to a solution of 2.04 g of (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid[described in French Pat. No. 70-21682] in 20 ml of methylene chloride and the mixture was stirred at 20° C. for 15 minutes. A solution of 1.7 g of (2-phenoxy-4-thiazolyl)-methanol in 10 ml of methylene chloride was added dropwise to the mixture which was stirred at 20° C. for 17 hours and was filtered. The organic phase of the filtrate was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 2.44 g of (2-phenoxy-4-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate melting at 78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:42][C:43]([O:45]C)=[O:44])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13](S(C3C=CC(Cl)=CC=3Cl)(=O)=O)[C:14]([CH3:16])=[N:15][C:11]=2[C:10]=1[NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])(=[O:33])=[O:32].[Li+].[OH-].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:42][C:43]([OH:45])=[O:44])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:29]=[CH:28][C:12]2[NH:13][C:14]([CH3:16])=[N:15][C:11]=2[C:10]=1[NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])(=[O:32])=[O:33]
Reactant: COC(=O)Cc1ccc(Oc2ccc3c(nc(C)n3S(=O)(=O)c3ccc(Cl)cc3Cl)c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(NS(=O)(=O)c3ccc(Cl)cc3Cl)c(Oc3ccc(CC(=O)O)cc3Cl)ccc2[nH]1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Under an N2 atmosphere, methyl 2-(3-chloro-4-(4-(2,4-dichlorophenylsulfonamido)-1-(2,4-dichlorophenylsulfonyl)-2-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)acetate (0.097 g, 0.127 mmol) was dissolved in tetrahydrofuran (1.5 mL) and 1 N LiOH (1.5 mL) was added. The reaction was stirred at 50° C. for 3 h. The reaction was diluted with water, made acidic with 1N HCl to pH 4, and extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound. LC-MS ESI (pos.) m/z: 541.9 (M+H). 1H NMR (400 MHz) (DMSOd-6) δ 7.63 (d, J=8.5 Hz, 1H); 7.46 (bs, 1H); 7.31-7.22 (m, 3H); 6.94 (d, J=7.6 Hz, 1H); 6.46 (bs, 1H); 6.29 (bs, 1H) 3.51 (s, 2H); 2.48 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:12][CH2:11][O:10][C:9]=2[CH:13]=1)(=[O:4])[CH2:2][CH3:3].[Br:14]Br>C1COCC1>[Br:14][CH:2]([CH3:3])[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:12][CH2:11][O:10][C:9]=2[CH:13]=1)=[O:4]
Reactant: CCC(=O)c1ccc2c(c1)OCC2
Reactant: BrBr
Solvent: C1CCOC1
Product: CC(Br)C(=O)c1ccc2c(c1)OCC2
Yield: 40 %

Procedure:
8.8 gr of 2,3-dihydro-6-propionylbenzo[b]furane in 50 ml of anhydrous THF are treated with 2.6 ml of bromine according with already described process. The product so obtained is recrystallized from methanol: 8 gr of 6-(α-bromopropionyl)-2,3-dihydrobenzo[b]furane are obtained.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)=[C:35]([Cl:46])[CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)=[C:35]([Cl:46])[CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (6.5 mL, 22.6 mmol) was added to a THF (10 mL) and MeOH (5 mL) solution of ethyl 3-(5-(5-chloro-2-(((2,4′-dichloro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (3.8 g, 6.5 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo and purified via HPLC to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:17][C@H:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[CH3:19]>>[CH3:27][O:26][C:24]([C:23]1[CH:28]=[CH:29][C:20]([C@@H:18]([NH:17][C:13]([C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[CH3:19])=[CH:21][CH:22]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Yield: 93.2 %

Procedure:
The title compound (D7) (815 mg) was prepared according to the general procedure for amides preparation starting from (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (500 mg, available from Sigma Aldrich #433818), and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (501 mg). Reaction time: 18 hrs
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:17])[CH:16]=[C:12]2[C:11]([CH3:18])=[N:10][N:9]=1.[Br:19]Br>C(O)(=O)C.O>[Br:19][C:16]1[C:15]([OH:17])=[N:14][N:13]2[C:12]=1[C:11]([CH3:18])=[N:10][N:9]=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1nnc(-c2ccccc2F)n2nc(O)cc12
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(-c2ccccc2F)n2nc(O)c(Br)c12
Yield: 94.5 %

Procedure:
To a stirred solution of 7-(2-fluorophenyl)-2-hydroxy-4-methylpyrazolo[1,5-d][1,2,4]triazine (1.48 g, 6.06 mmol) in glacial acetic acid (20 ml) was added, dropwise, bromine (0.343 ml, 6.66 mmol) and the mixture was stirred at room temperature for 20 min. The mixture was then diluted with water (80 ml) and the resulting solid was collected by filtration, washed with water and dried at 60° C. under vacuum to afford 1.85 g (94%) of the title compound as a cream solid: 1NMR (360 MHz, DMSO-d6) δ 2.88 (3H, s), 7.42-7.47 (2H, m), 7.67-7.76 (2H, m); MS (ES+) m/e 323/325 [M+H]+.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH2:20][CH3:21])=[N:16][N:15]=3)=[CH:12][C:8]([C:9](N)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.N([O-])=[O:24].[Na+]>C(O)(C(F)(F)F)=O>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH2:20][CH3:21])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:24])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=N[O-]
Reactant: CCOc1nnc(-c2cc(C(N)=O)c(C)cc2C2CCC2)[nH]1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide (219.8, 0.1 g, 0.33 mmol) in TFA (5 ml) was added NaNO2 (0.046 g, 0.66 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour then at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give a clear oil. Yield: 0.1 g, 100%. m/z (ES−) 300 (M−H)−.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50]O)[CH:46]([O:52]O)[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].B(F)(F)F.CCOCC.[N+](=[C:68]([CH3:70])[CH3:69])=[N-]>C(OCC)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:52][CH:68]([CH3:70])[CH3:69])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OO)C(OO)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CC(C)=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4",3"-dihydroxyoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in diethyl ether (6 ml) is added boron trifluoride etherate (10 ml) followed by freshly prepared 2-diazopropane (100-fold excess). The mixture is stirred at room temperature for 15 min. and quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is separated, washed with sat's NaCl and dried over sodium sulfate. Removal of solvent followed by preparative TLC on silica gives the title compound and its 4" isomer.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH2:19]Br)=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=1.N#N.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH2:18][CH2:19][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH:16]=[C:8]3[C:6]=2[CH:7]=1
Reactant: BrCCOc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)-c1cc3ccccc3n1CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
A solution of compound 2-(5-bromo-2-(2-bromoethoxy)phenyl)-1H-indole (1.97 g, 5 mmol) in 30 mL of DMF was cooled to 0° C. at N2 atmosphere, NaH (600 mg, 15 mmol) was added at the same temperature. The reaction mixture was stirred at room temperature. After 8 hours, the reaction was quenched by water, extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (petroleum ether:EtOAc=50:1) provided 2-bromo-6,7-dihydrobenzo[6,7][1,4]oxazepino[4,5-a]indole as light yellow powder (0.8 g, 51%), which was also prepared from 4-bromo-2-(1H-indol-2-yl)phenol and 1,2-dibromoethane using similar method described in step 5 of Example 1. 1H-NMR (CDCl3, 400 MHz) δ 7.96 (s, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.30˜7.33 (m, 2H), 7.25˜7.27 (m, 1H), 7.16 (t, J=6.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.91 (s, 1H), 4.53˜4.55 (m, 2H), 4.47˜4.49 (m, 2H). MS (M+H)+: 314/316.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16]C[O:18][C:12]=2[CH:11]=1)[CH3:2].C(=O)([O-])[O-:22].[K+].[K+]>S(=O)(=O)(O)O>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:18])[CH:11]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)CC#CCCCc1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCN(CC)CCC(=O)CCCc1ccc(O)c(O)c1

Procedure:
Add mercuric sulphate (0.27 g) to a swirled solution of 1-diethylamino-6-(3,4-methylenedioxyphenyl)hex-2-yne (3 g) in 10% aqueous sulphuric acid (15 cc) and heat the mixture for 90 minutes at 75° in an atmosphere of nitrogen. Filter the cooled reaction mixture and add solid potassium carbonate to pH 8.5. Extract the product with ether; wash and dry and evaporate the solvent to leave as residue crude 1-diethylamino-6-(3,4-dihydroxyphenyl)hexan-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH:25]=O)=[CH:17]1.N1CCCCC1>C(O)C>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](/[CH:25]=[CH:14]/[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:15])=[CH:17]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Yield: 65.9 %

Procedure:
3',4',5'-Trimethoxyacetophenone (42.0 g) and indole-3-carboxaldehyde (29.0 g) were dissolved in ethanol (200 ml), and piperidine (17.0 g) was added thereto, followed by heating under reflux for 48 hours. The reaction solution was ice-cooled, and the precipitated crystals were collected by filtration to give Compound 1 (44.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH2:13][CH2:14][CH2:15][CH3:16]>CN(C=O)C>[CH2:13]([N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCI
Reactant: COc1ccc[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cccc(OC)c1=O
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
To a solution of 3-methoxy-2(1H)-pyridone (2-034-01) (5.0 g) in DMF (40 mL) was added sodium hydride (60% wt, 2.2 g) at room temperature. After the reaction mixture was stirred for 20 min, 1-iodobutane (15.5 g) was added to the reaction mixture, and the reaction mixture was stirred for 40 min. After the reaction was quenched with water, the solvent was removed. To the residue were added a saturated aqueous solution of ammonium chloride and ethyl acetate, and the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (toluene/acetone=4/1) to give 1-butyl-3-methoxy-2-pyridone (2-034-02) (6.7 g, 93%) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[N+:18]([O-])=O>C(O)C.[Pd]>[NH2:18][C:3]1[CH:4]=[C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: COC(=O)C(c1ccc(O)c([N+](=O)[O-])c1)C1CCCC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(c1ccc(O)c(N)c1)C1CCCC1

Procedure:
5.6 g (20 mmol) of the compound from Example XI are hydrogenated at 4 atm. in 100 ml of ethanol with the addition of 0.5 g of palladium/carbon (10% strength). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is further reacted without further purification (quantitative yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[CH:20]=[CH:21][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:33])[F:34])[CH:18]=2)[CH:25]=1
Reactant: O=C(O)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Yield: 66.6 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-(trifluoromethyl)phenylamino)benzamide was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.220 g; 0.951 mmol), 3-(3-(trifluoromethyl)phenylamino)benzoic acid (0.294 g; 1.05 mmol), HATU (0.470 g; 1.24 mmol) and N,N-diisopropylethylamine (0.439 mL; 2.38 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.290 g (65%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:19]([CH2:35][NH:36][CH3:37])[CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[CH2:24][CH2:23]2)[CH:15]=[CH:16][C:17]=1[Cl:18]>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[O:34])[CH2:26][CH2:27]2)[CH2:35][N:36]([CH3:37])[C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CNC[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccc(F)cc1

Procedure:
4-Fluorobenzoyl chloride (0.093 mL) was reacted with (S)-1′-[3-(3,4-dichloro-phenyl)-4-methylamino-butyl]-[1,4′]bipiperidinyl-2-one (0.325 g) in dichloromethane (8 mL) overnight. The reaction was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic extracts were dried, evaporated, and purified by chromatography, with dichloromethane:methanol (gradient 97:3, 94:6) as eluent to give the title compound (0.33 g). Rf=0.41 in methylene chloride:methanol (95:5). MS: m/z=534 (M+). The product was dissolved in methanol (2 mL) and citric acid was added. The solution was concentrated and the residue was triturated with ether. The product was obtained as a white foam(0.11 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[NH:15])[C:13]3[C:16]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25]C=C(OC)[CH:22]=4)=[N:17][NH:18][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.O1[CH2:34][CH2:33][O:32][CH2:31]C1.[OH-].[Na+]>O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][C:14]2[N:15]=[CH:10][N:11]=[C:12]3[NH:18][N:17]=[C:16]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:34]=[C:33]([O:32][CH3:31])[CH:22]=4)[C:13]=23)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CNc2n[nH]c3ncn(-c4cccc(Cl)c4)c(=N)c23)c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 5 °C

Procedure:
A mixture of 0.417 g (1 mmol) of 5-(3-chloro-phenyl)-1,5-dihydro-4-imino-3-(3-methoxy-benzylamino)-4H-pyrazolo[3,4-d]pyrimidine hydrochloride (Example 45, title compound II), 20 ml of dioxane, 19 ml of water and 1 ml of 1N sodium hydroxide solution is heated under reflux for 10 hours. Cooling to approx. 5° C., filtering, washing the filter residue with water and drying under a HV at 120° C. yield the title compound (see Example 45); m.p. 192-193° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](=O)[CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][OH:22].Cl>CCO>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[N:21][OH:22])[CH3:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CC(=NO)c1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2
Temperature: 23 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
A solution of 7-acetyl-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (1.2 g, 4.35 mmol) in EtOH was treated with NH2OH.HCl (0.57 g, 8 mmol). The resulting solution was stirred at 23° C. for 3 h in presence of Amberlist A-21 (2.0 g). The mixture was filtered and the solvent was evaporated. The residue was dissolved in EtOAc, washed with aqueous NaHCO3 and then brine. After drying (MgSO4), the organic layer was evaporated and the crude oxime was purified by chromatography (SiO2, 10-25% EtOAc in hexane) to give 1.08 g (86%) of the title compound as a white solid (m.p: 134-37° C.).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:15](C(OC(C)(C)C)=O)[NH:16][C:17](=[O:44])[C:18](=[O:43])[CH:19]([NH:27][C:28]([C@H:30]1[CH2:34][CH2:33][C:32](=[O:35])[N:31]1[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:36]([N:31]1[C:32](=[O:35])[CH2:33][CH2:34][C@@H:30]1[C:28]([NH:27][CH:19]([C:18](=[O:43])[C:17]([NH:16][NH:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:44])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:29])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NNCc1ccccc1)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (TFA) (0.2 mL, 2.60 mmol) was added to a solution of tert-butyl 1-benzyl-2-(3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-oxo-4-phenylbutanoyl)hydrazinecarboxylate (110 mg, 0.184 mmol) in DCM (2 mL). After stirring for 4 h the solvent was removed in vacuo and the residue obtained was triturated with diethyl ether providing the title compound (48 mg, 43%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][C@H:40]([C:48](O)=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:48](=[O:49])[C@H:40]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
300 mg (0.702 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 223 mg (0.842 mmol) of (S)-N-tert.-butyloxycarbonyl-phenylalanine, 214 mg (0.842 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 215 μl (1.54 mmol) of triethylamine. The title compound is obtained as mixture of diastereomers in the form of a yellow oil. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.37, FD-MS: M+ =674.