Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[N:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[N:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)nc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridine-2-carboxylic acid (395 mg), ethyl 3-(methylamino)propanoate (157 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), hydroxybenzotriazole monohydrate (184 mg) and triethylamine (168 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give ethyl 3-[{[5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate (155 mg). Ethyl 3-[{[5-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.6 mL) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (100 mg, 70%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([O:49][C:50]([CH2:52][O:53][C:54](=[O:75])[C@@:55]([CH2:73][OH:74])([CH3:72])[CH2:56][C@H:57]([NH2:71])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[CH:61][CH:60]=1)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([O:49][C:50]([CH2:52][O:53][C:54](=[O:75])[C@@:55]([CH2:73][OH:74])([CH3:72])[CH2:56][C@H:57]([NH:71][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:58][C:59]1[CH:60]=[CH:61][C:62]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[CH:63][CH:64]=1)=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(O)c1c[nH]nn1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)OCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.5 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid benzyloxycarbonylmethyl ester (57.2 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (19 mg; purity 95%). MS m/z [M+H]+ calc'd for C31H32N4O6, 557.23. found 557.2.
Reaction SMILES: [CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7].[C:9]1([CH3:21])[CH:14]=[CH:13][C:12]([S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>CS(C)=O>[C:9]1([CH3:21])[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]([O:7][CH2:6][CH3:5])=[O:20])(=[O:16])=[O:17])=[CH:13][CH:14]=1.[CH2:1]([OH:8])[C:2]#[C:3][C:4]#[C:5][CH2:6][OH:7]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Agent: OCC#CC#CCO
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 255.8 %

Procedure:
A 500-ml tree-neck flask equipped with a stirrer, a dropping funnel and an inlet for feeding argon was charged with anhydrous (additionally dried over 4A molecular sieves) dimethylsulfoxide (DMSO) (200 ml) and 11.0 g (0.1 mol) of 2,4-hexadiyn-1,6-diol. To the vigorously stirred mixture, a solution of p-toluenesulfonyl isocyanate (Aldrich) (40 ml, 0.22 mol) in 50 ml of dry DMSO was added drop-wise for 0.5 h. After stirring for additional 2 hrs at room temperature, the mixture was discharged into 1000 ml of chilled water. The water layer was decanted off the yellow heavy oil, and the oil was triturated with diethyl ether, giving a cake of fine crystals which rapidly attained blue color under effect of UV light. Recrystallization from hot ethanol/ethyl acetate 2:1 mixture gave 45.2 g (yield 90%) of 2,4-hexadiyn-1,6-diol p-toluenesulfonyl urethane as fine white crystals with m.p. 128-130° C. The crystals were readily polymerizable under effect of both UV-irradiation and temperature. Analysis: I.R. (KBr pellet, cm−1: 3080 (Ar—H stretching), 2980+2920 (CH stretching), 1596 (phenyl C═C stretching), 1368 (S—O), 1184 (S—O), 742 (Ar—H). NIR-FT Raman: 2270 cm−1 (diacetylenic monomer —C═C— stretch), 2105 cm−1 (polymer backbone —C≡C— stretch), 1540 cm−1 (polymer backbone —C═C— stretch). Having been held in an oven at 85° C. for 2 hrs and then analyzed as described in Example 1, the compound gave an intense NIR Raman spectrum identical to that shown in FIG. 1(J, top). The simultaneous presence of the two Raman bands in 2300-1900 cm−1 spectral region, one (weak) belonging to ν(—C≡C—) vibrations of the monomer and the other (strong) belonging to ν(—C≡C—) vibrations of corresponding polymer, evidenced for partial polymerization of the compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2.N.[Li]>C(O)C>[OH:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][C:3](=[O:2])[CH2:4]2
Reactant: COc1ccc2c(O)cccc2c1
Agent: N
Agent: [Li]
Solvent: CCO
Product: O=C1CCc2c(O)cccc2C1
Reaction time: 0.17 h

Procedure:
To a stirred slurry of 8.0 g. (0.048 mole) of 6-methoxy-1-naphthol and 200 ml. of liquid ammonia held below the reflux temperature by external cooling there is added 1.05 g. (0.15 g. - atom) of lithium ribbon over 25 minutes. After a further 10 minutes at this temperature, 20 ml. of ethanol is added over 30 minutes. As the blue color fades, the ammonia is evaporated and the residue stirred overnight under nitrogen with 50 ml. of water, 50 ml. of tetrahydrofuran and 35 ml. of conc. hydrochloric acid. Extraction with three 100 ml. portions of chloroform followed by drying and solvent removal gives 7.24 g. of solid. Recrystallization (4:1 ) hexane-ethyl acetate gives 5.04 g. (68%) of ketone, m.p. 168°-171° (lit m.p. 155°-162° dec.), JACS 80, 2887 (1958).
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]([CH3:29])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:21][CH2:20][C@H:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:28])[CH3:27])[CH2:18][C:16]3=2)[CH:11]=[N:10]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:6][C@H:7]([CH3:29])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:21][CH2:20][C@H:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:28])[CH3:27])[CH2:18][C:16]3=2)[CH:11]=[N:10]1
Reactant: CC(=O)NCCO[C@H]1COc2ccc3cnn(C[C@@H](C)O[Si](C)(C)C(C)(C)C)c3c2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)NCCO[C@H]1COc2ccc3cnn(C[C@@H](C)O)c3c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the product from Step C (0.41 g, 0.92 mmol) and tetrabutylammonium fluoride (1 M, 1.84 mL, 1.84 mmol) in THF (30 mL) was stirred at ambient temperature for 4 h, mixed with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate. The dried extracts were evaporated to a residue which was purified by chromatography (silica, gradient, ethyl acetate to 10% methanol in ethyl acetate) a colorless solid (0.23 g, 75%): mp 165-166° C. LCMS (+ESI) m/z 334 (M+H).
Reaction SMILES: B.CSC.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](=O)[C@@H:13]([CH2:22][C:23](O)=[O:24])[O:12][C@H:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]4[O:32][CH2:33][CH2:34][O:35][C:27]=34)[C:10]=2[CH:36]=1>O1CCCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]([CH2:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:14][C@@H:13]([CH2:22][CH2:23][OH:24])[O:12][C@H:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]4[O:32][CH2:33][CH2:34][O:35][C:27]=34)[C:10]=2[CH:36]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2cccc3c2OCCO3)c2cc(Cl)ccc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)CN1C[C@@H](CCO)O[C@H](c2cccc3c2OCCO3)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
Borane-methyl sulfide complex (2.0M in tetrahydrofuran; 5.9 mL, 11.8 mmol) was added to a solution of the ethyl ester of trans-7-chloro-5-(2,3-ethylenedioxyphenyl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzoxazepine-3-acetic acid (1.44 g, 2.95 mmol; Example 1D) in tetrahydrofuran (4.4 mL) under a nitrogen atmosphere. The reaction was stirred at ambient temperature for 18 hours and then cooled to 0° C. and quenched by slow addition of methanol. Once gas evolution ceased, an additional amount of methanol was added and the resulting mixture stirred 1 hour. The reaction mixture was then concentrated and the resulting residue taken up in water and extracted with ethyl acetate (3×). The combined organics were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (3:1 hexanes/ethyl acetae) to give 835 mg (66%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[N:14]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:13](=[O:23])[C@@H:12]([NH:24][C@H:25]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:11][S:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([C@@H:8]1[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:23])[C@@H:12]([NH:24][C@H:25]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:11][S:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@H](Cc2ccccc2)N(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@H](Cc2ccccc2)N(CC(=O)O)C1=O
Yield: 77.6 %

Procedure:
630 mg of t-butyl α-{3(S)-benzyl-6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer B) synthesized as described in Example 33 was subjected to de-t-butylation with trifluoroacetic acid in the same manner as described in Example 3, to give 438 mg of the title compound as an amorphous solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:16][CH:17]1[CH2:22][NH:21][CH:20]([CH3:23])[CH2:19][N:18]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25]>>[CH3:16][CH:17]1[CH2:22][N:21]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH:20]([CH3:23])[CH2:19][N:18]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)C(C)CN1
Product: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)C(C)CN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 13 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)piperazine to give (2RS,5SR)-2,5-dimethyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 13% yield;
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[C:15]([F:18])([F:17])[F:16])[C:8]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=3)=[O:20])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[C:15]([F:17])([F:18])[F:16])[C:8]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)=[O:20])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(C(=O)c2nn(C3CCCC3)c3c(C(F)(F)F)cccc23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1cccc(O)c1)c1nn(C2CCCC2)c2c(C(F)(F)F)cccc12
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A solution of [1-cyclopentyl-7-(trifluoromethyl)-1H-indazol-3-yl](3-methoxyphenyl)methanone (0.19 g, 0.49 mmol) in 10 mL of CH2Cl2 containing 0.2 mL cyclohexene was cooled to −78° C. under an argon atmosphere. Boron tribromide (0.185 mL, 1.95 mmol) was added in one portion and the reaction mixture was allowed to warm to ambient temperature. The reaction was quenched by the careful addition of methanol. The reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). The solvents were removed in vacuo and the residue purified by flash chromatography to give 0.15 g of the title compound as a light yellow solid, (mp 152° C.).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.I[CH2:16][C@@H:17]([CH3:20])[CH2:18][CH3:19]>>[CH3:1][C@:2]1([CH2:16][C@@H:17]([CH3:20])[CH2:18][CH3:19])[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:7]1
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Reactant: CC[C@H](C)CI
Product: CC[C@H](C)C[C@]1(C)N[C@@H](c2ccccc2)COC1=O

Procedure:
The title compound was prepared from (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1 g, 5.28 mmol, see WO-A-02/051983) and (2S)-1-iodo-2-methylbutane according to the procedure outlined in Preparation 1. The total amount of compound synthesised was 0.586 g.
Reaction SMILES: [N:1]1[C:11]2[C:10](=O)[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[NH:23][C:10]1[C:11]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[NH:6][C:7](=[O:13])[CH2:8][C:9]2=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCC(=O)c2ncccc2N1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CC(=O)Nc1cccnc1-3
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
5H-Pyrido[3,2-b]azepine-6,9(7H,8H)-dione (484 mg; 2.74 mmol), (4-methoxyphenyl)hydrazine hydrochloride (527 mg, 3.02 mmol), and sodium acetate (242 mg; 3.02 mmol) were suspended in glacial acetic acid (30 mL) and stirred for 30 min. at 70° C. After cooling to room temperature, the mixture was poured into a 5% aqueous sodium acetate solution. The precipitate, consisting of the corresponding phenyl hydrazone, was filtered off with suction, washed successively with 5% aqueous sodium acetate solution and water and was then refluxed 4 h in 70 mL ethanol. After cooling, 206 mg (27%) of a brown powder precipitated, m.p. >330° C.; IR (KBr): 3269 cm−1 (NH), 1669 cm−1 (C═O); 1H-NMR (d6-DMSO, 400 MHz): δ (ppm)=3.66 (s, 2H, azepine-CH2), 3.81 (s, 3H, OCH3), 6.84 (dd, 1H, 8.8/2.4 Hz, arom. H), 7.21 (d, 1H, 2.3 Hz, arom. H), 7.35-7.40 (m, 2H, arom. H), 7.60 (dd, 1H, 8.2/1.4 Hz, arom. H), 8.46 (dd, 1H, 4.5/1.4 Hz, arom. H), 10.20 (s, 1H, NH), 11.54 (s, 1H, NH); 13C-NMR (DMSO-d6, 100.6 MHz): δ (ppm)=55.4 (OCH3), 31.8 (azepine-CH2), 99.6, 112.7, 113.6, 122.3, 129.3, 144.2 (tert. arom. C-atoms), 108.7, 126.6, 131.9, 132.7, 133.0, 140.6, 153.5 (quat. arom. C-atoms), 171.2 (C═O). purity: 99.8% (HPLC, ts=3.57 min, acetonitrile/water: 25/75); EI/HRMS for C16H13N3O2 (279.30) calculated: 279.10077. found: 279.10010.
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:8])[O:6][CH3:7].[CH2:9]1[C:13]2([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10]1.CC(O)=O>C1COCC1>[O:19]=[C:18]1[CH:17]([C:5]([O:6][CH3:7])=[O:8])[CH2:16][CH2:15][CH2:14][C:13]21[CH2:9][CH2:10][CH2:11][CH2:12]2
Reactant: O=C1CCCCC12CCCC2
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1CCCC2(CCCC2)C1=O
Temperature: 80 °C

Procedure:
In a flask containing NaH (4.73 g, 118.20 mmol) in THF (30 mL) was added dimethylcarbonate (8.30 mL, 98.52 mmol). The mixture was heated at 80° C. To the mixture was added a solution of spiro[4.5]decan-10-one, 59, (6.00 g, 39.41 mmol) in THF dropwise (25 mL). The reaction was heated for 6 hrs at 80° C. The mixture was cooled to room temperature and hydrolyzed with AcOH. The solvent was evaporated and the crude residue was diluted with water and extracted with EtOAc. The organic layer was washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo.
Reaction SMILES: N1C=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]=2[NH2:22])[CH2:13]1)=O)C.S(OC)(OC)(=O)=O>O>[N:22]1([C:18]2[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=3[CH:15]=[C:14]3[C:19]=2[CH2:20][CH2:21][NH:12][CH2:13]3)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: c1ccncc1
Reactant: CCOC(=O)N1CCc2c(cc3ccccc3c2N)C1
Solvent: COS(=O)(=O)OC
Solvent: O
Product: c1ccc2c(-n3cccc3)c3c(cc2c1)CNCC3
Reaction time: 8 h

Procedure:
3 ml of pyridine are added to a mixture of 27.0 g of 5-amino-1,2,3,4-tetrahydrobenzo[g]isoquinolin-2-ylcarboxylic acid ethyl ester in 50 ml of water. 50.4 g of dimethyl sulphate are added dropwise to this mixture within 10 minutes and the mixture is stirred for 8 hours at 55° - 60°. The resulting clear solution is diluted with 100 ml of water, and is extracted several times with chloroform. The extracts are washed neutral with water, are dried over sodium sulphate and concentrated by evaporation. The oily residue is taken up in ether, is made acid with ethereal hydrochloric acid solution and the precipitated product is filtered off and recrystallized from ethanol/ether. M.Pt. of 5-methylamino-1,2,3,4-tetrahydrobenzo[g]isoquinolin-2-ylcarboxylic acid ethyl ester hydrochloride 214° - 215°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11]C)[CH:6]=[C:5]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]>O1CCCC1.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]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]
Reactant: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(N)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Yield: 98 %

Procedure:
A solution of (F') (0.56 g) in tetrahydrofuran (30 ml) was hydrogenated in the presence of palladium-on-carbon (10% w/w; 0.1 g), as described for the amino ester (H) in Example 4, to give methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (S) (0.50 g, 98%) as pale yellow foam; NMR: 3.6(s, 3H, NCH3), 3.8(s, 3H, COOCH3), 3.9(br s, 5H, OCH3 and CH2Ar), 4.45(br, 2H, NH2), 6.54(m, 2H), 6.86(s, 1H), 7.04(m, 2H), 7.40(m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:13][O:12][C:11]1[C:5]2[NH:4][C:3]([CH2:2][N:18]3[CH2:23][CH2:22][N:21]([CH2:2][C:3]4[NH:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=[C:9]([O:16][CH3:17])[C:10]=1[O:14][CH3:15]
Reactant: COc1cc2nc(CCl)[nH]c2c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2nc(CN3CCN(Cc4nc5cc(OC)c(OC)c(OC)c5[nH]4)CC3)[nH]c2c(OC)c1OC

Procedure:
2-Chloromethyl-4,5,6-trimethoxybenzimidazole (250 mg) and piperazine (34 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=C1C>[OH-].[Na+]>[NH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:9][NH:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCN1CC(c2ccccc2)N=C1C
Agent: [Na+]
Agent: [OH-]
Product: COCCNCC(N)c1ccccc1

Procedure:
Ten grams of the methoxyethylmethylphenylimidazoline product of Example I is refluxed with 50 ml 30% aqueous sodium hydroxide solution for 24 hours. The mixture is then permitted to separate into two phases, and the aqueous layer is extracted with methylene chloride. The extract is concentrated and the resulting oil, which is identified as the intermediate amide, is refluxed with 20% aqueous sulfuric acid for six hours.
Reaction SMILES: [CH2:1]([C:8]1[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>BrCC(C)CCl>[CH3:1][CH:2]1[CH2:7][C:1]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:11]3=[N:10][N:9]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:3]1
Reactant: c1ccc(Cc2nnc3n2CCCCCC3)cc1
Agent: CC(CCl)CBr
Product: CC1CC(c2ccccc2)(c2nnc3n2CCCCCC3)C1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
3-Benzyl-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (287.6 mg) and 1-bromo-3-chloro-2-methylpropane (140 μL) were dissolved in anhydrous, deoxygenated tetrahydrofuran, and the solution was cooled to −40° C. under an argon atmosphere. Potassium bis(trimethylsilyl)amide (KHMDS, 0.5M in toluene, 2.5 mL) was added dropwise. After 30 minutes, a second aliquot of KHMDS (2.5 mL) was added. After 30 additional minutes, KHMDS (2.15 mL) was added again, and the solution was allowed to slowly warm to room temperature. After one hour, the reaction was quenched with water and added to brine. After extraction with ethyl acetate, the organic layer was dried with magnesium sulfate, filtered, evaporated and purified by silica gel chromatography to give 3-[1-(4-chlorophenyl)-(Z)-3-(methoxymethoxy)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (4-10) as a ca. 1.2:1 mixture of isomers.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16]C(=O)C(F)(F)F)[C@@H:13]3[CH2:23][C@H:10]2[CH2:11][CH2:12]3)=[O:8])[N:6]=1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[C@@H:13]3[CH2:23][C@H:10]2[CH2:11][CH2:12]3)=[O:8])[N:6]=1
Reactant: Nc1nc(C(=O)N2[C@@H]3CC[C@@H](C3)[C@H]2CNC(=O)C(F)(F)F)c(-c2cccc(F)c2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NC[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A solution of N-{(1R,3S,4S)-2-[2-Amino-5-(3-fluoro-phenyl)-thiazole-4-carbonyl]-2-aza-bicyclo[2.2.1]hept-3-ylmethyl}-2,2,2-trifluoro-acetamide (0.98 mmol) in MeOH (3.2 mL) is treated with a sat. aq. K2CO3 solution (0.3 mL) and stirred at 60° C. for 6 h. After stirring at rt for additional 14 h the mixture is concentrated in vacuo and the residue is made basic by addition of aq. NaOH solution. A 1:1 mixture of TBME and EtOAc is added and the mixture is stirred vigorously for 1 h. The layers are separated and the aq. layer is extracted with a 1:1 mixture of TBME and EtOAc. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to give the desired product which is used without further purification. LC-MS (basic): tR=0.68 min; [M+H]+=347.1.