Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O.[F:21][C:22]([F:30])([F:29])[C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26]>C(O)(=O)C.S(=O)(=O)(O)O>[F:21][C:22]([F:30])([F:29])[C:23]([C:24]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:25]=1[CH3:26])=[O:28]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(=O)C(F)(F)F)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 26.1 %

Procedure:
To a stirred solution of 50 mg (0.17 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone in 1.5 ml acetic acid was added 0.021 ml (0.18 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 18 mg (25%) 2,2,2-trifluoro-1-[4-(4-methoxy-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a yellow oil. ES-MS m/e (%): 406 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]([NH2:8])=[O:7].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[N:43]1([C:48]2[CH:53]=[CH:52][C:51]([S:54]([O:57][C:58]3[CH:67]=[CH:66][C:61]4[NH:62][C:63](N)=[N:64][C:60]=4[CH:59]=3)(=[O:56])=[O:55])=[CH:50][CH:49]=2)[CH:47]=[CH:46][N:45]=[CH:44]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]([NH:8][C:63]1[NH:62][C:61]2[CH:66]=[CH:67][C:58]([O:57][S:54]([C:51]3[CH:52]=[CH:53][C:48]([N:43]4[CH:47]=[CH:46][N:45]=[CH:44]4)=[CH:49][CH:50]=3)(=[O:56])=[O:55])=[CH:59][C:60]=2[N:64]=1)=[O:7]
Reactant: COC(=O)CCC(N)=O
Reactant: Nc1nc2cc(OS(=O)(=O)c3ccc(-n4ccnc4)cc3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(-n4ccnc4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.9 mg of succinamic acid methyl ester, 25 mg of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and 12 μl diisopropyl-ethylamine were taken up in 0.4 ml dimethylformamide. Reaction mixture was stirred at room temperature for one hour and 5-(4-[1-imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-ylamine was added in 0.2 ml dimethylformamide. Reaction mixture was then stirred at room temperature for 24 hours. Solvent was evaporated in a Jouan model RC 10.10 centrifuge evaporator and title compound was solubilised in 0.5 ml dimethylsulfoxide for LCMS trigged purification yielding 3.9 mg of N-[5-(4-[1-imidazolyl]-phenylsulfonyloxy)-1H-benzimidazole-2-yl]-succinamic-acid-methyl ester. (LC/MS analysis: retention time=2.70 min., mass spectrum: 470.34, [M+H]+).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br[CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)NC1=O
Reactant: CCC(Br)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N(C(CC)C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one (77 mg, 0.205 mmol, Example 124, Step C) in DMF (0.3 mL) was added slowly 9.5 mg (0.24 mmol) of a dispersion of 60% sodium hydride in mineral oil followed by tert-butyl 2-bromobutanoate (92 mg, 0.410 mmol). The reaction was stirred at ambient temperature overnight, quenched with MeOH/HOAc, was diluted with EtOAc and water and extracted to EtOAc. The organics were dried over Na2SO4, filtered and the filtrate was concentrated. Purification by reversed phase preparatory HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.) (eluent: 70% acetonitrile, water, 0.1% TFA) provided the title compound, as well as its stereoisomer, (R)-tert-butyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-1-yl)butanoate.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=O)[CH3:12]>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])=[CH:5][CH:4]=1
Reactant: CC(=O)c1cccs1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Product: CC(=NNc1ccc(F)cc1)c1cccs1

Procedure:
This compound is prepared from commercial 4-fluorophenylhydrazine hydrochloride (Aldrich) and from commercial 2-acetylthiophene (Aldrich), according to the procedure 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:18](=[O:20])[CH3:19])[CH:5]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N)c(C(C)=O)c1
Temperature: 105 °C
Reaction time: 7 h
Yield: 81.4 %

Procedure:
To a solution of 4-amino-3-iodo-benzoic acid methyl ester (11.30 g, 40.77 mmol) in toluene (300 mL) were added tributyl(1-ethoxyvinyl)tin (16.5 mL, 48.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (9422 mg, 8.154 mmol) under nitrogen atmosphere, and the solution was stirred at 105° C. for 7 hours. After cooling to room temperature, water was added, the mixture was extracted with ethyl acetate-tetrahydrofuran, the organic layer was washed with water, and then, evaporated. The residue was dissolved in 280 mL of tetrahydrofuran, 2N hydrochloric acid (80 mL) was added thereto, followed by stirring for 3 hours at room temperature. The reaction mixture was cooled on an ice bath, an aqueous solution of 2N sodium hydroxide (80 mL) was added, an aqueous solution of saturated sodium bicarbonate was further added, and the solution was extracted with ethyl acetate. An aqueous solution of 10% potassium fluoride was added to the organic layer, and the solution was stirred for 3 hours at room temperature. The organic layer was separated, washed with brine, then evaporated, the residue was purified by silica gel column chromatography (hexane-ethyl acetate), and title compound (6.42 g, 33.2 mmol, 81.4%) was obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:42])[N:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:6]2[CH:14]=[C:15]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:17][C:5]=2[O:4][CH2:3]1>C(O)(C(F)(F)F)=O>[NH2:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:16]3[C:15]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:14][C:6]4[N:7]([C:8]5[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=5)[S:2](=[O:1])(=[O:42])[CH2:3][O:4][C:5]=4[N:17]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)S(=O)(=O)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)S(=O)(=O)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 69.8 %

Procedure:
tert-Butyl (1-(4-(2,2-dioxido-7-phenyl-1-(pyridin-3-yl)-1H-pyrido[3,2-e][1,3,4]oxathiazin-6-yl)phenyl)cyclobutyl)carbamate (40 mg, 0.068 mmol) was dissolved in TFA (3 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜3 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (3 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (23 mg, 56% yield). 1H-NMR (500 MHz, MeOD) δ 8.70 (1H, d), 8.65 (1H, dd), 8.00 (1H, dd), 7.61 (1H, dd), 7.44 (2H, d), 7.38 (2H, d), 7.17-7.25 (3H, m), 7.09 (1H, s), 7.06 (2H, d), 5.67 (2H, s), 2.68-2.77 (2H, m), 2.50-2.59 (2H, m), 2.14-2.25 (1H, m), 1.87-2.00 (1H, m). LCMS (Method A) RT=4.00 min, M+2H+=486.07.
Reaction SMILES: C([Li])CCC.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[I:15]CCI.[NH4+].[Cl-]>C1COCC1.O>[I:15][C:7]1[NH:6][C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: c1ccc2[nH]ccc2c1
Reactant: ICCI
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Ic1cc2ccccc2[nH]1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
2-iodoindole is prepared according to the following procedure: n-butyllithium (4.2 mL, 2.5 M in solution in hexane) is added, dropwise, to a solution of indole (1.17 g, 10 mmol) in 20 mL of anhydrous THF at −70° C. The resulting suspension is left under stiffing at this temperature for 30 minutes then gaseous CO2 is bubbled through for 10 minutes. The solution which has become clear is then left under stirring for 10 minutes. The solvent and the excess CO2 are evaporated off under vacuum then the resulting solid residue is put into solution in 20 mL of anhydrous THF and cooled down to −70° C. t-butyllithium (6.2 mL; 1.7 M in solution in pentane) is then added dropwise then the resulting solution is left under stirring for 1 hour. 1,2-diiodoethane (2.82 g; 10 mmol) is then added. The reaction mixture is left at −78° C. for 1 hour then treated with 1 mL of water. The resulting solution is left to return to ambient temperature then it is treated with a saturated aqueous solution of NH4Cl. It is extracted with ether. The organic phase obtained is washed with a saturated aqueous solution of NaCl, dried over anhydrous MgSO4 and evaporated under vacuum. The solid residue obtained is purified by flash chromatography on silica gel (hexane/ether, 4/1) producing 2-iodoindole (2.19 g; 9 mmol) with a yield of 90%. The physical and spectral data are described in the article.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:37][CH2:38]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1)[CH3:2]
Reactant: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(C#Cc2ccccc2CC(=O)OC)n1
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(=O)OC)n1
Reaction time: 18 h
Yield: 56.6 %

Procedure:
tert-Butyl 4-(3-ethyl-4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I42) (311 mg, 0.499 mmol) was dissolved in ethanol (20 mL), and a slurry of Pd/C (150 mg) in ethanol (2 mL) was added. The mixture was stirred under hydrogen for 18 hours, filtered through celite, washing the celite with ethanol (20 mL) and the filtrate concentrated. The mixture was taken up in ethanol (20 mL), and a slurry of Pd/C (150 mg) in ethanol (2 mL) was added followed by triethylamine (20 μL). The mixture was stirred under hydrogen for 18 hours, filtered through celite, the celite washed with ethanol (10 mL) and the combined filtrates evaporated. The residue was taken up in DMF (10 mL), a slurry of Pd/C (150 mg) in DMF (2 mL) was added and the mixture stirred under hydrogen. After 16 hours the mixture was filtered through celite, and the celite washed with ethyl acetate (100 mL). The combined filtrate was evaporated to give a pale green oil. Chromatography (12 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I43) (177.1 mg, 57% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=0.5 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.25-7.16 (m, 4H), 7.12-7.07 (m, 2H), 7.06 (s, 1H), 4.25 (br s, 2H), 3.72 (s, 2H), 3.67 (s, 3H), 3.14-3.01 (m, 4H), 2.81 (t, J=12.2 Hz, 2H), 2.72-2.59 (m, 3H), 1.84 (d, J=13.0 Hz, 2H), 1.69-1.56 (m, overlaps with water in solvent), 1.49 (s, 9H), 1.26 (t, J=7.1 Hz, 3H). LCMS: rt 7.16 min; m/z 627.2 [M+H]+; 571.1 [M-tBu+2H]+; m/z 625.2 [M−H]−.
Reaction SMILES: [F:1][C:2](=[C:16]([F:18])[F:17])[CH2:3][P:4](=[O:15])([O:10]C(C)(C)C)[O:5]C(C)(C)C.Cl>CO>[F:1][C:2](=[C:16]([F:18])[F:17])[CH2:3][P:4](=[O:5])([OH:15])[OH:10]
Reactant: CC(C)(C)OP(=O)(CC(F)=C(F)F)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: O=P(O)(O)CC(F)=C(F)F
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
The above di-t-butylphosphonate (0.5 g) was dissolved in 3 mL of methanol and treated with 0.5 mL of 3 N HCl and allowed to stand at r.t. for 30 min. The solution was concentrated and the residue was redissolved in 10 mL of water and washed with 10 mL of ether. Evaporation of the aqueous layer gave 0.14 g of 2,3,3-trifluoro-2-propenylphosphonic acid as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Na].[K].[Li].[C:14](OCC)(=O)CC(OCC)=O.C(OC)(=O)CC(OC)=O>>[CH3:14][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [K]
Agent: [Li]
Agent: [Na]
Solvent: COC(=O)CC(=O)OC
Product: Cc1cccnc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In Scheme 1, step a, chloro-nitropyridine 1 is added in portions to an alkali metal salt of a malonic acid diester in excess malonic diester, such as for example the sodium, potassium or lithium salt of the malonic acid diester in an excess of the malonic acid diester, such as for example diethyl malonate or dimethyl malonate, at a temperature of about 50° C. to about 70° C. The alkali metal salt of the malonic acid diester may be prepared, for example, by adding an alkali metal, such as for example sodium metal, to an excess of the malonic acid diester as is well known to one skilled in the art. After about three hours at about 50° C. to about 70° C., the mixture is allowed to stand at ambient temperature for about 12 to about 24 hours. If the reaction is incomplete, the mixture is heated to about 80° C. for about 2 hours to about 4 hours, then concentrated to remove excess malonic acid diester, and then treated with a concentrated mineral acid such as for example hydrochloric acid or sulfuric acid and water. The mixture is heated at about 100° C. to about 110° C. for about 5 hours to about 9 hours to effect decarboxylation. After standing about 12 to about 24 hours at ambient temperature the mixture is washed with a suitable solvent, such as for example ethyl ether and ethyl acetate, basified to about pH 8 to about pH 9 with an alkali metal hydroxide, such as for example sodium hydroxide or potassium hydroxide, and extracted with a suitable organic solvent, such as for example ethyl acetate. The organic extract is filtered and concentrated under reduced pressure to afford the desired methyl-nitropyridine 2. Preparation of 2 by this “step a” procedure is referred to as a “two step, one pot synthesis”.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=3[O:13][CH3:12])[N:4]2[N:8]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2nc(Cl)nn12

Procedure:
2-Chloro-5-(2-methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.5 g, 2.15 m mol) and 2-methoxy-4-trifluoromethylbenzeneboronic acid (0.71 g, 3.23 mmol), in a manner analogous to Example 2c. Product was isolated as a foam (0.5 g, 70%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.73 (m, 1H), 7.67 (d, J=7.3 Hz, 1H), 7.61 (d, J=8.1 HZ, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.303 (s, 1H), 7.10 (d, J=7.3 Hz, 1H), 3.87 (s, 3H). MS=328 (MH)+. 236b) 7-[5-(2-Methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-5-(2-Methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.5 g, 1.5 mmol), and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.6 g, 2.0 mmol). Product was isolated as a foam (0.27 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.69 (d, J=7.99 Hz, 1H), 7.56-7.51 (m, 2H), 7.41 (d, J=7.99 Hz, 1H), 7.32-7.28 (m, 2H), 7.06-7.02 (m, 1H), 6.97-6.93 (m, 1H), 6.75 (brs, 1H), 3.86 (s, 3H), 3.62-3.48 (m, 4H), 2.91-2.77 (m, 4H) 1.52 (s, 9H). MS=554 (MH)+. 236c) [5-(2-Methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepin-7-yl)-amine was prepared from 7-[5-(2-methoxy-4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-bezazepine-3-carboxylic acid tert-butyl ester (0.27 g, 0.490 mol) in a manner analogous to Example 234c. Product was isolated as a foam (0.20 g, 90%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.70 (d, J=7.9 Hz, 1H), 7.56-7.50 (m, 2H), 7.40 (d, J=7.9 Hz, 1H), 7.32-7.23 (m, 2H), 7.03 (d, J=7.9 Hz 1H), 6.96-6.92 (m, 2H), 6.80 (brs, 1H), 3.86 (s, 3H), 3.03-2.92 (m, 4H), 2.91-2.84 (m, 4H). MS=454 (MH)+.
Reaction SMILES: [CH2:1]([N:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:6](=[O:16])[CH:7](Br)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH:2]=[CH:3][CH3:4].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C.Cl>C1(C)C=CC=CC=1>[CH2:3]([CH:2]1[CH2:1][N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:6](=[O:16])[CH:7]1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:4]
Reactant: CC=CCN(C(=O)C(Br)c1ccc(F)cc1)c1cccc(C(F)(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCC1CN(c2cccc(C(F)(F)F)c2)C(=O)C1c1ccc(F)cc1
Reaction time: 1 h

Procedure:
N-(2-Butenyl)-N-(3-trifluoromethylphenyl)-2-bromo-2-(4-fluorophenyl)acetamide (1.9 g) was added to 20 ml of toluene, followed by the addition of 1.2 ml of tributyltin hydride and an extremely small amount of α,α-azobisisobutyronitrile (AIBN) under stirring at 70° C. After the reaction mixture was continuously stirred for 1 hour, 60 ml of 20% hydrochloric acid were added, followed by extraction with toluene. After the extract was dried over anhydrous sodium sulfate, the extract was concentrated in an evaporator and then subjected to chromatography on a silica gel column. The 3,4-trans isomer (0.9 g) and the 3,4-cis isomer (0.27 g) were obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:11][C:12]([OH:14])=[O:13])[CH2:5][C:4](=[O:28])[O:3]1.C(N(CC)CC)C.[NH2:36][CH:37]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49].Cl>CN(C)C=O.[OH-].[Na+]>[C:19]([CH2:18][N:17]([CH2:16][CH2:15][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:6]([CH2:7][C:2](=[O:1])[NH:36][CH:37]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[CH2:5][C:4]([OH:28])=[O:3])[CH2:22][C:23]([OH:25])=[O:24])([OH:21])=[O:20]
Reactant: CCCCCCC(N)CCCCCCCCCCC(=O)O
Reactant: CCOC(=O)CN(CCN(CCN1CC(=O)OC(=O)C1)CC(=O)O)CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCC(CCCCCCCCCCC(=O)O)NC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.33 g (38 mmol) of N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid (Example 13a of EP 0 331 616) is suspended in 100 ml of dimethylformamide and mixed in an ice bath with 21.07 ml (152 mmol) of triethylamine and 11.36 g (38 mmol) of 12-aminooctadecanoic acid. After stirring overnight at room temperature, it is concentrated by evaporation in a vacuum, and the residue is absorptively precipitated with 500 ml of diethyl ether. It is suctioned off and the dried reaction product is dissolved in 50 ml of 2 n sodium hydroxide solution. After three hours of stirring, it is neutralized with dilute hydrochloric acid, evaporated to dryness in a vacuum and recrystallized from water. 15.64 g (61% of theory) of a gray powder is obtained.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C1C=CC=CC=1.[OH-].[Na+]>[C:14]([O:13][C:11](=[O:12])[CH2:10][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CNCc1ccccc1
Reaction time: 1 h
Yield: 89 %

Procedure:
To 71.0 g of benzylamine in 100 ml of benzene was added with stirring 25.0 g of tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C for an additional one hour. At the end of this period, the reaction mixture was taken up in 70 ml of 2N NaOH solution and 80 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 32.7 g (89.0 percent) of N-benzylglycine tert-butyl ester, B.P. 120°-125° C/2 mmHg.