Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([Cl:15])=[N:10]2.C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>CCOCC>[Cl:15][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[CH2:4][CH2:3][OH:2])[N:10]=1
Reactant: COC(=O)Cc1cccc2nc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCCc1cccc2nc(Cl)ccc12
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A mixture of 0.35 g (1.46 mmol) (2-chloro-quinolin-5-yl)-acetic acid methyl ester and 10 mL anhydrous THF was cooled to −20° C. in a dry ice/acetone bath. 1.4 mL (1.4 mmol) IM LiAlH4 solution in ether was added dropwise. After 10 min, TLC analysis (ethyl acetate, silica, Rf prod 0.3) showed starting material consumed. The reaction was quenched with 1 mL of 1M aqueous potassium sodium tartrate solution. The product was partitioned between ethyl acetate and 10 ml brine and the product extracted with three 25 mL portions of ethyl acetate. The combined organic extracts were washed with 25 mL of brine, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield 0.29 g (1.37 mmol 99.9%) of 2-(2-chloro-quinolin-5-yl)-ethanol as a white solid. MS(APCI) m/z 208 (M, 100% abundance), 210 (M+2, 32% abundance). 1H NMR (400 MHz) CDCl3 8.38 (d, J=8.9 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.70 (m, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.41 (d, J=8.9 Hz), 3.97 (m, 2H), 3.32 (t, J=6.5 Hz, 2H), 1.45 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH2:25][C:26]1([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:29]([C:26]1([NH:25][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:11][C:10]([CH3:22])([CH3:23])[C:9]4[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[C:7]([Cl:24])[CH:8]=4)[NH:13]3)[CH:20]=[CH:19][CH:18]=2)[CH2:28][CH2:27]1)([OH:31])=[O:30]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Temperature: 25 °C
Yield: 31.4 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (408.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(1-carboxy-cyclopropylamino)-phenyl]-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (130.4 mg, 31.5%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 415.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(Cl)Cl.N1C=CC=CC=1.[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O>[N:20]1([C:26]([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=Cc1ccc(O)c(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(OC(=O)N2CCOCC2)c(F)c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a 250 mL dry round bottom flask were added 3-fluoro-4-hydroxybenzaldehyde (4.76 g, 34.0 mmol), anhydrous CH2Cl2 (40 mL) and pyridine (3.6 mL, 44.2 mmol). The mixture was stirred in an ice-water bath, then 4-morpholinecarbonyl chloride (4.4 mL, 37.4 mmol) was added. The mixture was stirred and warmed slowly to room temperature, then at room temperature overnight. Water (80 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 2-fluoro-4-formylphenyl morpholine-4-carboxylate (7.45 g) as white solid. Yield: 87%. 1H NMR (CDCl3, 300 MHz): δ=9.97 (s, 1H), 7.74-7.70 (m, 2H), 7.45 (t, J=7.8 Hz, 1H), 3.81-3.61 (m, 8H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=189.9, 156.5, 153.1, 151.8, 144.0, 143.8, 135.0, 134.9, 126.7, 126.6, 124.8, 116.7, 116.4, 66.4, 66.3, 45.2, 44.4.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:21]=1[C:22](Cl)=[O:23].N1C=CC=CC=1>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([C:29]([F:30])([F:31])[F:32])[CH:27]=[CH:28][C:20]=2[F:19])[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)c1cc(N)n(Cc2ccc(F)cc2)n1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)n(Cc2ccc(F)cc2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
To a solution of Example 30A (0.7 g, 2.6 mmol) in tetrahydrofuran (20 mL) were added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.46 mL, 3.1 mmol, Aldrich) and pyridine (0.62 mL, 7.6 mmol). After stirring at 60° C. for 16 h, the reaction mixture was cooled and quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, O-25% ethyl acetate in methylene chloride) to afford 0.75 g (67%) of the title compound. MS (ESI+) m/z 438 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH2:9][N+:10]#[C-:11])[N:5]=2)CC1.C1([C:15]2[O:19]N(C)C(NC=O)N=2)CC1.C(N(CC)CC)C.[O:31]=P(Cl)(Cl)Cl>C(Cl)Cl.O>[CH:11]([NH:10][CH2:9][C:6]1[N:5]=[C:4]([CH2:1][O:19][CH3:15])[O:8][N:7]=1)=[O:31]
Reactant: CN1OC(C2CC2)=NC1NC=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCc1nc(CNC=O)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH2Cl2 (100 ml) was charged dropwise with POCl3 (60 mmol) at 0° C. The mixture was then left for 30 minutes with stirring at 0° C., whereafter a solution of Na (60 mmol) in H2O (50 ml) was added. The mixture was heated to room temperature, evaporated in vacuo. The residue was treated with ether, decanted and the solution was evaporated to give the title compound as an oil. The oil was processed without any further purification. The compound was characterized by its IR absorbtion band at 2160 cm-1.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.00 g, 11.5 mmol) and sodium hydride (60%, 0.506 g, 12.6 mmol) in DMF (50 mL) was stirred at ambient temperature for 1 h then 4-fluorobenzaldehyde (1.36 mL, 12.6 mmol) was added. The reaction mixture was heated at 100° C. for 21 h. The reaction mixture was cooled to ambient temperature and the precipitate was collected by filtration, washed with DMF (30 mL) and ether (30 mL), and dried to afford 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzaldehyde as a tan solid (2.80 g, 7.61 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 10.03 (1H, s), 8.46 (2H, d, J=8.4 Hz), 8.39 (1H, s), 8.09 (2H, d, J=8.8 Hz); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 9.71 min. MS: MH+ 365.8.
Reaction SMILES: [CH3:1][C@H:2]([NH2:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH2:8]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]=1[F:21])[C:9]#[CH:10]>>[CH3:1][C@H:2]([NH:7][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:8][C:9]#[CH:10])=[C:13]([F:21])[CH:14]=1)[C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Reactant: C[C@H](N)C(C)(C)C
Product: C#CCOc1ccc(C(=O)N[C@@H](C)C(C)(C)C)cc1F

Procedure:
According to the same method as that of Production Example 1, (1S)-1,2,2-trimethylpropylamine was used in place of 2,2-dimethylpropylamine, and 4-(2-propynyloxy)-3-fluorobenzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-((1S)-1,2,2-trimethylpropyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 25 of the present invention) represented by the formula:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[OH:24][CH2:25][CH2:26][N:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[CH3:28]>>[CH:20]1([NH:23][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:33](=[O:34])[C:32]5[CH:31]=[CH:30][C:29]([N:27]([CH2:26][CH2:25][OH:24])[CH3:28])=[CH:37][CH:36]=5)=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)=[CH:12][CH:13]=2)[CH2:22][CH2:21]1
Reactant: Nc1ccc2c(ccn2-c2ccc(C(=O)O)cc2)c1
Reactant: NC1CC1
Reactant: CN(CCO)c1ccc(C(=O)O)cc1
Product: CN(CCO)c1ccc(C(=O)Nc2ccc3c(ccn3-c3ccc(C(=O)NC4CC4)cc3)c2)cc1

Procedure:
Compound 952 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indol-1-yl)benzoic acid, cyclopropaneamine, and 4-(N-2-hydroxyethyl-N-methylamino)benzoic acid. [M+H]+ calcd for C28H28N4O3: 469.22; found 468.96.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][O:8][C:5]2=[N:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]2[CH:20]=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.[CH3:21][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:23]([CH2:25][CH:26]=[CH2:27])[CH3:24]>[Pd]>[CH3:21][N:22]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH:23]([CH2:25]/[CH:26]=[CH:27]/[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][O:8][C:5]2=[N:6][CH:7]=1)[CH3:24].[CH3:21][N:22]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH:23]([CH2:25]/[CH:26]=[CH:27]/[C:12]1[CH:13]=[C:14]2[CH:20]=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1)[CH3:24]
Reactant: Brc1cnc2occc2c1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: [Pd]
Product: CC(C/C=C/c1cnc2[nH]ccc2c1)N(C)C(=O)OC(C)(C)C
Product: CC(C/C=C/c1cnc2occc2c1)N(C)C(=O)OC(C)(C)C

Procedure:
Other polycyclic aromatic compounds of the present invention can be prepared by the Heck reaction. Thus both 5-bromofuro[2,3-b]pyridine and 5-bromo-1H-pyrrolo[2,3-b]pyridine can undergo palladium catalyzed coupling with the previously described olefinic amine side chain, N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine, to give (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-furo[2,3-b]pyridinyl)-4-penten-2-amine and (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(5-1H-pyrrolo[2,3-b]pyridinyl)-4-penten-2-amine respectively. Subsequent removal of the tert-butoxycarbonyl group with trifluoroacetic acid will provide (4E)-N-methyl-5-(5-furo[2,3-b]pyridinyl)-4-penten-2-amine and (4E)-N-methyl-5-(5-1H-pyrrolo[2,3-b]pyridinyl)-4-penten-2-amine. The requisite 5-bromofuro[2,3-b]pyridine and 5-bromo-1H-pyrrolo[2,3-b]pyridine can be made from 2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine respectively, by bromination (bromine and sodium bicarbonate in methanol) and dehydrogenation (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), using chemistry described by E. C. Taylor et al., Tetrahedron 43: 5145-5158 (1987). 2,3-Dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine are, in turn, made from 2-chloropyrimidine (Aldrich Chemical Company), as described by A. E. Frissen et al., Tetrahedron 45: 803-812 (1989), by nucleophilic displacement of the chloride (with the sodium salt of 3-butyn-1-ol or with 4-amino-1-butyne) and subsequent intramolecular Diels-Alder reaction. Using similar chemistry, 2,3-dihydrofuro[2,3-b]pyridine and 2,3-dihydropyrrolo[2,3-b]pyridine are also produced from 3-methylthio-1,2,4-triazene (E. C. Taylor et al., Tetrahedron 43: 5145-5158 (1987)), which in turn is made from glyoxal and S-methylthiosemicarbazide (W. Paudler et al., J. Heterocyclic Chem. 7: 767-771 (1970)).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+].[CH2:24](I)[CH3:25].[CH3:27][C:28](C)=O>>[CH2:27]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:24][CH3:25])[N:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:28]
Reactant: CCI
Reactant: CCOC(=O)c1c(O)cc(O)nc1C(F)(F)F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1c(OCC)cc(OCC)nc1C(F)(F)F
Yield: 82.9 %

Procedure:
This material was prepared in 82.9% yield from product of Example 1 (1 eq), K2CO3 (2 eq) and excess ethyl iodide. The reaction mixture was refluxed in acetone for 18 hours and filtered. The filtrate was concentrated. The residue was dissolved in ether. The ether solution was washed with 10% K2CO3, dried (MgSO4) and concentrated to give the product as an oil, nD25 1.4534.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O-]S([O-])(=O)=O.[Ca+2].[N+](C1C=CC=CC=1)([O-])=O.[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N+:1]([C:23]1[CH:24]=[CH:25][C:20]([CH3:26])=[CH:21][CH:22]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 89 %

Procedure:
A 100 gram portion of the powdered, soluble anhydrite (Drierite) was added to 100 milliliters toluene and mixed therein. A 13.6 gram portion of anhydrous nitric acid was added to the mixture of toluene and soluble anhydrite drop by drop over a 30 minute period. After all of the nitric acid was added to the toluene-soluble anhydrite mixture, the reaction was permitted to continue for 3 hours at 25° C. Then 26 grams nitrobenzene was added to the reaction medium and the medium was stirred for an additional 30 minutes. The reaction medium then was filtered and the filtrate was analyzed by gas chromotography using the added nitrobenzene as the internal standard. Results showed that a yield of 89% mononitrotoluene, based on the nitric acid, was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[CH3:16])[N:3]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.O1CCCC1.C(N(C(C)C)CC)(C)C>ClCCl>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]3[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=3[CH3:16])[N:3]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(Br)cc2)n1
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A mixture of 2,4-dichloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazine (2.5 g, 9.1 mmol), 4-bromoaniline (1.6 g, 9.3 mmol), tetrahydrofuran (60 ml), and diisopropylethylamine (1.6 ml, 9.2 mmol) was stirred for 1 hour. The solution was treated with dichloromethane (200 ml), washed with saturated aqueous sodium chloride solution (50 ml), and concentrated under reduced pressure. The residual solid was treated with hydrochloric acid (1 M, 25 ml) and stirred vigorously for 30 minutes. Filtration and drying under reduced pressure provided the title compound (3.2 g, 86% yield). 1H NMR (DMSO-d6) 10.75-10.80 (m, 1H), 7.85-7.92 (m, 1H), 7.50-7.65 (m, 4H), 7.40 (m, 1H), 2.58 (s, 3H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]2[C:31]([C:34]([OH:36])=[O:35])=[CH:32][N:33]=[C:17]12)=[O:14])([CH3:11])([CH3:10])[CH3:9]>ClCCl.CO>[C:8]([O:12][C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]2[C:31]([C:34]([O:36][CH3:1])=[O:35])=[CH:32][N:33]=[C:17]12)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(=O)O)cnc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(Trimethylsilyl)diazomethane (2.0 M in ether; 173 μL, 0.35 mmol) was added to a solution of (6S,9R)-9-[(tert-butoxycarbonyl)amino]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine-3-carboxylic acid (47 mg, 0.12 mmol) in dichloromethane (1.5 mL) and methanol (0.5 mL). After 1 h, additional (trimethylsilyl)diazomethane (2.0 M in diethyl ether; 50 μL, 0.10 mmol) was added. After 4 h, the reaction mixture was concentrated. MS 422.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:24])[CH2:20][C:21](Cl)=[O:22]>>[CH3:17][O:18][C:19](=[O:24])[CH2:20][C:21]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)=[O:22]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1
Product: COC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1
Yield: 75 %

Procedure:
The title compound is prepared in analogy to example 1 from 4-(4-fluoro-benzyloxy)-phenylamine and chlorocarbonyl-acetic acid methyl ester. Yield: 75%. Colorless solid. MS: m/e=318.2 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH2:16])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.[C:18](C1NC=CN=1)(C1NC=CN=1)=[O:19].[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]2=[O:46])[CH2:32][CH2:31]1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:16][C:18]([N:30]1[CH2:31][CH2:32][CH:33]([N:36]2[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]2=[O:46])[CH2:34][CH2:35]1)=[O:19])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: COC(=O)C(N)Cc1cc(C)c2[nH]ncc2c1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: COC(=O)C(Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of (±)-2-amino-3-(7-methyl-1H-indazol-5-yl)-propionic acid methyl ester (162.9 mg, 0.698 mmol) in methylene chloride (3 mL) at room temperature was treated with carbonyl diimidazole (113.2 mg, 1 equiv). After 1.5 h at room temperature, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one (161.5 mg, 1 equiv.) was added. The mixture was stirred at room temperature overnight. A white precipitate had formed that was shown to be the desired product. The solvent was evaporated and the residue triturated with methylene chloride. The product was collected by filtration, washed with methylene chloride and dried in vacuo to give a white solid (241.5 mg, 71%). Some product remained in the mother liquors. 1H-NMR (dimethylformamide-d7, 500 MHz) δ 1.75 (4H, m), 2.78 (3H, s), 2.7-3.1 (4H, m), 3.35 (2H, m), 3.86 (3H, s), 4.44 (2H, s), 4.57 (1H, m), 4.72 (1H, m), 7.11 (3H, m), 7.31 (1H, s), 7.34 (2H, m), 7.72 (1H, s), 9.34 (1H, s). Mass spec.: 491.13 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.C(O)C>[Fe].O>[S:11]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1)[C:12]#[N:13]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: N#CSc1ccc(N)c(N)c1
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
To a suspension of 2-nitro-4-thiocyanato-aniline, 22.3 g. of powdered iron, 40 ml. of 96% ethanol and 50 ml. of water a solution of 2,2 g. of ferrous(II)chloride and 4 ml. of water is added dropwise under stirring at the boiling point of the mixture. Stirring is continued for a further 10 minutes, whereupon the reaction mixture is filtered. To the filtrate 200 ml. of water are added. On cooling crystals precipitate, which are filtered off. Thus 12.3 g. of 4-thiocyanato-1,2-diamino-benzene are obtained. Yield: 74.5%. M.p.: 108°-110° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH:30]2[CH2:32][O:31]2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][CH:30]([OH:31])[CH2:32][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: CCc1ccc(OCC2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CCc1ccc(OCC(O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 170 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(4-ethylphenoxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 480 [M+H]; Rt=1.09 min.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>C1(C)C=CC=CC=1>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 6 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in toluene (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in toluene was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 6 hours. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 162.9 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.