Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[CH2:19]([O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])=[N:26][CH:27]=1)[CH3:20].N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([O:21][C:22]1[CH:27]=[N:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:16][C@H:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[NH:10][C:7]2[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=2)=[O:31])=[N:24][CH:23]=1)[CH3:20]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: CCOc1cnc(-c2ccccc2C(=O)O)nc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOc1cnc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)nc1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 116 mg, 0.41 mmol), 2-(5-ethoxypyrimidin-2-yl)benzoic acid (Intermediate 47; 100 mg, 0.41 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (84 mg, 0.61 mmol), EDC (118 mg, 0.61 mmol) and triethylamine (0.171 ml, 1.23 mmol) in dry DCM (4 ml) was stirred at room temperature for 4 hours. The reaction was partitioned between DCM and water, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (eluted with acetonitrile/water with 0.1% ammonia) and then by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][CH:32]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([F:27])[CH:19]=2)[CH2:13][S:12](=[O:29])(=[O:28])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:42](C1NC=CN=1)(C1NC=CN=1)=[O:43].Cl>C(#N)C.CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][CH:32]=1)[CH2:8][N:9]1[C@@H:10]2[C@H:15]([C@H:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([F:27])[CH:19]=3)[CH2:13][S:12](=[O:28])(=[O:29])[CH2:11]2)[O:16][C:42]1=[O:43])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3ccc([N+](=O)[O-])c(F)c3)[C@@H]2O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc([N+](=O)[O-])c(F)c4)CS(=O)(=O)C[C@@H]32)c1
Reaction time: 16 h

Procedure:
To a suspension of (3R*,4S*,5S*)-3-(3-tert-butyl-benzylamino)-5-(3-fluoro-4-nitro-benzyl)-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol (4.4 g, 8.7 mmol) in ACN was added at 25° C. the DIPEA and the carbonyl-diimidazole. After addition of a catalytic amount of DMAP, the clear reaction mixture was kept at 25° C. for 16 h. The reaction mixture was poured onto ice-water and acidified with 4N aq. HCl. The precipitate was filtered off and washed with H2O and Et2O, dried under reduced pressure for 6 h at 50° C. to yield the title product as light yellow crystals: TLC (toluene-THF 1:1) Rf=0.66; HPLC RtA=2.25 min; ESIMS [M+NH4]+=508; 1H NMR (400 MHz, DMSO-d6): δ 8.11 (dd, 1H), 7.48 (dd, 1H), 7.38 (s, 1H), 7.28 (m, 3H), 7.12 (d, 1H), 4.41 (d, 1H), 4.20 (m, 2H), 3.72 (m, 2H), 3.42 (dd, 1H), 3.14 (d, 2H), 3.04 (dd, 1H), 2.76 (dd, 1H), 2.64 (m, 1H), 1.25 (s, 9H).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Br)[N:18]=1>C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:18]=1
Reactant: CCCCCCCCCCCCO
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOc1cccc(Br)n1

Procedure:
Dodecanol (1.118 g, 6 mmol) was dissolved in toluene (2 mL) and sodium hydride (60% in mineral oil, 0.120 g, 3 mmol) was added. 2,6-Dibromopyridine (0.710 g, 3 mmol) was added and the reaction was heated to reflux for 16 hours. After cooling, the reaction mixture was filtered through Celite and purified on silica gel (0-5% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]1([C:23](=[O:34])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-])=O)[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:2]=[CH2:3].[Cl-].[NH4+]>CO.C(OCC)(=O)C.[Zn]>[CH2:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]1([C:23](=[O:34])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31])[NH:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])[CH:2]=[CH2:3]
Reactant: C=CCC1CN(C(=O)OC(C)(C)C)CC1(NC(=O)C(F)(F)F)C(=O)Nc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCC1CN(C(=O)OC(C)(C)C)CC1(NC(=O)C(F)(F)F)C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.1 %

Procedure:
A solution of tert-butyl 4-allyl-3-[(2-nitrophenyl)carbamoyl]-3-[(trifluoroacetyl)amino]pyrrolidine-1-carboxylate (0.816 g, 1.68 mmol) in methanol (30 mL) was treated with ammonium chloride (0.897 g, 16.8 mmol) and zinc (2.19 g, 33.5 mmol). After stirring at room temperature for 40 min, the mixture was diluted with ethyl acetate (30 mL) and filtered through a pad of Celite. The pad was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was re-diluted with ethyl acetate (25 mL) and water (20 mL), and the layers were separated. The organic phase was washed with water (10 mL) and saturated aqueous sodium chloride (10 mL), dried over Na2SO4 and concentrated and dried under high vacuum for ˜2 h to give the tert-butyl 4-allyl-3-[(2-aminophenyl)carbamoyl]-3-[(trifluoroacetyl)amino]pyrrolidine-1-carboxylate intermediate (760 mg, 3:2 mixture of diastereomers) as a off-white foam that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.C(N(CC)C(C)C)(C)C.[NH2:34][CH2:35][CH:36]1[CH2:38][CH2:37]1.[Cl-].[Na+].O.O>CN(C=O)C>[CH:36]1([CH2:35][NH:34][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH2:38][CH2:37]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: NCC1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCC3CC3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (64 mg, 0.2 mmol) in DMF (0.3 mL) was added N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uranium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (129 mg, 1.0 mmol) and aminomethylcyclopropane (19 μL, 0.22 mmol) and the resulting mixture stirred at room temperature for 1 h. The resulting mixture was then poured into a mixture of brine:water (1:1) and extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 25:75) afforded the title compound (55 mg, 74%) which was obtained as a yellow solid. MS: m/e=373.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:17])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8]2.[CH3:18][N:19]1[C:23]([NH2:24])=[CH:22][CH:21]=[N:20]1>>[CH3:18][N:19]1[C:23]([NH:24][C:15]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=23)=[O:17])=[CH:22][CH:21]=[N:20]1
Reactant: COCc1cc2c(C(=O)O)ccc(OC)c2o1
Reactant: Cn1nccc1N
Product: COCc1cc2c(C(=O)Nc3ccnn3C)ccc(OC)c2o1
Yield: 34.6 %

Procedure:
Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (93 mg) and 2-methyl-2H-pyrazol-3-ylamine (40 mg). Purification by column chromatography on silica eluting with ethyl acetate afforded the title compound as a white solid (43 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25])#[N:2]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C#N)cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A mixture of 5-cyanoindole (10 g) and freshly prepared silver carbonate on diatomaceous earth (40.66 g) was stirred and heated under reflux in toluene (100 ml) for 18 h, under an atmosphere of nitrogen. The mixture was cooled to room temperature, methyl 4-bromomethyl-3-methoxybenzoate (22.7 g) added, and stirring continued for 4 h. Ethyl acetate (200 ml) was added, the mixture filtered through diatomaceous earth, the filter pad washed with ethyl acetate and the filtrate evaporated. The dark oil obtained was purified by flash chromatography, eluting with 45:45:10 hexane:methylene chloride:ethyl acetate, to give a foam which was crystallized from toluene to give methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate (11.8 g, 53%) as white crystals; mp 148-149°; partial NMR (250 MHz, DMSO-d6): 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.08(s, 2H, ArCH2Ar'), 8.00(s, 1H, H4 -indole), 11.49(br s, 1H, H1 -indole).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[CH3:12][NH:13][CH3:14]>[OH-].[Na+]>[CH3:12][N:13]([CH3:14])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: Nc1ccc(OCCCl)cc1
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCOc1ccc(N)cc1
Reaction time: 21 h

Procedure:
11.15 g (0.065 Mol) of 4-(2-Chloro-ethoxy)-phenylamine is suspended in 150 mL (1.18 Mol) of dimethylamine (40% in water; Fluka 38940) and heated under stirring in a steel pressure reactor at 4 bar for 21 h. After cooling the reaction mixture is diluted with 150 mL of 2N NaOH and extracted with ethyl acetate. The combined organic layers are washed with water, dried (Na2SO4), filtered and evaporated under reduced pressure to obtain 4-(2-dimethylamino-ethoxy)-phenylamine. Title compound: ES-MS: 181 [M+H]+; single peak at tR=1.10 min (System 1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH:32]=[CH:31][C:25]([CH2:26][NH:27][C:28](=[O:30])[O-:29])=[CH:24][CH:23]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:25]([CH2:26][NH:27][C:28](=[O:30])[O:29][C:25]([CH3:31])([CH3:26])[CH3:24])=[CH:31][CH:32]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CC1(C)OB(c2ccc(CNC(=O)[O-])cc2)OC1(C)C
Reactant: CCCCCOc1cccc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOc1cccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 11 h
Yield: 113.6 %

Procedure:
To a mixture of 1-bromo-3-pentyloxybenzene (0.365 g), tert-bytyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) benzyl]carbamate (0.575 g), sodium carbonate (0.318 g), water (1.3 mL) and N,N-dimethylformamide (6.5 mL) was added tetrakis(triphenylphosphine) palladium(0) (0.087 g), and the resulting mixture was stirred at 80° C. for 11 hours. The reaction mixture was cooled to room temperature and then partitioned between ethylacetate (35 mL) and water (10 mL). The organic layer was washed successively with water/brine (2/1, 15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=6/1) to give the title compound (0.437 g)
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][C:19]([F:23])=[CH:18][C:15]=1[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:21]([Cl:22])=[CH:20][C:19]([F:23])=[CH:18][C:15]=1[C:16]#[N:17])=[N+:2]=[N-:3]
Reactant: N#Cc1cc(F)cc(Cl)c1N
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(F)cc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A solution of 4-azido-5-fluoro-3-pyridinecarboxaldehyde (1.0 g, 6.02 mmol) and 2-amino-3-chloro-5-fluorobenzonitrile (1.03 g, 6.02 mmol) in anhydrous DCM (20 mL) was cooled in an icebath and triethylamine (2.52 mL, 18.07 mmol) was added, followed by titanium (IV) chloride (1 N in DCM, 3.6 mL, 3.6 mmol). The reaction mixture was stirred at 0° C. for 3 hours and then at room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound as a pale brown solid (1.67 g, 89% yield), which was used directly in the next step without purification. LCMS (Method C): RT=3.74 min, m/z: 291 [M+H+−N2].
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1([C:17](=[NH:20])[NH:18][OH:19])[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1([C:17]2[NH:20][C:27](=[O:28])[O:19][N:18]=2)[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1(C(=N)NO)CC12CCCCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(c2noc(=O)[nH]2)CC12CCCCC2
Yield: 69.8 %

Procedure:
To a solution of [1-(N-hydroxycarbamimidoyl)-spiro[2.5]oct-1-ylmethyl]-carbamic acid tert-butyl ester (5.8 g, 19.5 mmol) in THF (250 mL) was added CDI (4.74 g, 29.3 mmol). After 3 hours at reflux another portion of CDI (1 g) was added. The solution was heated to reflux for an additional 4 hours and then the solvent was removed under reduced pressure. The residue was partitioned between ether (200 mL) and 1N NaOH (75 mL). The organic layer was extracted with 1N NaOH (2×75 mL). The combined aqueous layers were washed with ether (100 mL). The aqueous layer was acidified to pH=3 by the addition of potassium hydrogen sulfate with ice bath cooling while layered over methylene chloride (100 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (2×200 mL). The combined organic layers were washed with water (75 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give an off white foam. The residue was chromatographed on a wet-packed silica gel column (6.5×28 cm) eluting with 3-4% methanol in methylene chloride. The appropriate fractions were combined and evaporated to give 4.4 g (70%) of [1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-spiro[2.5]oct-1-ylmethyl]-carbamic acid tert-butyl ester as a white foam: 1H NMR (300 MHz, CDCl3) δ0.78 (d, J=5.3 Hz, 1H), 1.44 (s, 9H), 1.3-1.7 (m, 11H), 3.24 (dd, J=5.0, 13.9 Hz, 1H), 3.84 (dd, J=5.0, 13.9 Hz, 1H), 4.97 (s, 1H); MS (APCI) m/z 324 [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([NH:27][C@H:28]([C:36](OC)=O)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:26])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.ClCCl>[CH2:29]([C:28]1[NH:27][C:25](=[O:26])[N:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][CH2:20]2)[CH:36]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)NC1CCN(Cc2ccccc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=c1[nH]c(Cc2ccccc2)cn1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
Diisobutylaluminum hydride (1M, 2.53 mL, 2.53 mmol) was added to a solution of methyl N-{[(1-benzylpiperidin-4-yl)amino]carbonyl}phenylalaninate (800 mg, 2.02 mmol) in toluene (7.5 mL) and dichloromethane (7.5 μL) at −78° C. and stirred for 30 min and then warmed to ambient temperature. After 5 min at room temperature, the reaction was quenched with saturated potassium sodium tartrate solution (20% solution), extracted with dichloromethane and treated with a 4 N HCl solution (50 mL). After 30 min. the mixture was extracted with water, basified to pH=7, and extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 0 to 8% {1% ammonium hydroxide/methanol} in methylene chloride gradient elution), gave the title compound (250 mg). MS 348.3 (M+1)
Reaction SMILES: [N:1]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][C@H:2]1[C:3]([N:5]([CH3:20])[C@@H:6]([C:17](O)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:31][C@H:32]([C:41]([O:43][C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45])=[O:42])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37]C=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][C@H:2]1[C:3]([N:5]([CH3:20])[C@@H:6]([C:17]([NH:31][C@H:32]([C:41]([O:43][C:44]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:45])=[O:42])[CH2:33][C:34]1[CH:35]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: N[C@@H](CCc1ccccc1)C(=O)OC(=O)c1ccccc1
Reactant: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(=O)c1ccccc1
Yield: 83 %

Procedure:
Condensation of BocProOH (4.63 g.) and MeDTrpOMe (5.00 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-MeDTrpOMe in 69% yield. Demethylation of BocPro-MeDTrpOMe (6.33 g.) using aqueous sodium hydroxide gave BocPro-MeDTrpOH in 77% yield. Condensation of BocPro-MeDTrpOH (3.60 g.) and HPheOBz (3.70 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MeDTrp-PheOBz in 83% yield. Debenzylation of BocPro-MeDTrp-PheOBz (4.60 g.) by hydrogenation with palladium catalyst gave BocPro-MeDTrp-PheOH in 100% yield.
Reaction SMILES: [OH:1][CH2:2][C:3](=[C:14]1[S:18][C:17](=[O:19])[NH:16][C:15]1=[O:20])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[O:1]=[CH:2][C:3](=[C:14]1[S:18][C:17](=[O:19])[NH:16][C:15]1=[O:20])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)C(=C(CO)c2cccc3ccccc23)S1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=CC(=C1SC(=O)NC1=O)c1cccc2ccccc12
Yield: 98.2 %

Procedure:
To a solution of 5-[2-hydroxy-1-(1-naphthalenyl)ethylidene]-2,4-thiazolidinedione (10.13 g, 35.5 mmol) in acetone (250 mL) at 0° C. was added Jones reagent (8N, 10.26 mL, 82 mmol). After 30 min 2-propanol (10 mL) was added. The reaction mixture was filtered and concentrated in vacuo. The resulting oil was taken up in ether and washed with water (2×). The organic phase was dried over magnesium sulfate, filtered and concentrated to give a foam (9.88 g). Recrystallization (chloroform/ethyl acetate) gave crystals (6.87 g) of the E-isomer. m.p. 184°-185° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH2:38][C:39]([O:41]CC)=[O:40])[C:30]5[C:35]([C:36]=4[CH:37]=3)=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:24])=[O:23])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].Cl>O1CCOCC1.CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH2:38][C:39]([OH:41])=[O:40])[C:30]5[C:35]([C:36]=4[CH:37]=3)=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:24])=[O:23])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)Cn1c2ccccc2c2cc(S(=O)(=O)NC(Cc3ccc4[nH]cnc4c3)C(=O)N3CCC(C)CC3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc3c(c2)c2ccccc2n3CC(=O)O)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 0.6 g (0.001 Mol) of ethyl [3-[[1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethyl]sulphamoyl]-carbazol-9-yl]-acetate in 5 ml of dioxane and 5 ml of methanol are added dropwise 4 ml of 1N sodium hydroxide solution and the mixture is stirred at 20° C. for one hour. It is then diluted with 20 ml of water and mixed with 4 ml of 1N hydrochloric acid. The organic solvent is eliminated in vacuo, the product precipitated is suction filtered, washed with water and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:7]([Cl:26])=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:7]([Cl:26])=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:31]([CH:28]2[CH2:30][CH2:29]2)=[O:32])[CH2:24][CH3:25])[CH:11]=1)[CH3:2]
Reactant: O=C(O)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cnc(Cl)c(CC(=O)OCC)c1
Product: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)cnc1Cl

Procedure:
[2-Chloro-5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and cyclopropanecarboxylic acid were reacted as described in Example 8, Step 6 to provide (2-chloro-5-{2-[(N-cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][NH2:11]>C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:11][CH3:10])[CH:7]=1
Reactant: Cc1cc(Cl)cc(Cl)n1
Reactant: CN
Solvent: CCO
Product: CNc1cc(Cl)cc(C)n1
Temperature: 100 °C
Yield: 12 %

Procedure:
A mixture of 2,4-dichloro-6-methylpyridine (7.0 g) (West German Patent DE 2162238) and 33% w/v methylamine in ethanol (25 ml) was heated in a sealed tube at 100° C. for 8 hours. The solvent was removed by evaporation and the residual solid was purified by flash chromatography (Merck 9385 Silica, 100 g), using as eluant first an increasing gradient [20%-100% v/v] of diethyl ether in petrol (b.p. 60°-80° C.) and then an increasing gradient of up to 5% v/v methanol in dichloromethane. There was thus obtained 4-chloro-6-methyl-2-methylaminopyridine (0.8 g, 12% yield), m.p. 69°-70° C.; NMR: 2.2-2.3(3H,s, CH3), 2.7-2.8(3H,s,NHCH3), 6.25(1H,s, pyridine-3H), 6.4(1H,s, pyridine-5H), 6.55-6.7(1H,br,NH).