Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[C:8]([N+:13]([O-])=O)[C:9]=1[C:10]([OH:12])=[O:11])([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[C:8]([NH2:13])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)c(C(=O)O)c(N)c1
Yield: 81 %

Procedure:
3,5-dinitro-p-toluic acid (10.0 gm.) is dissolved in methanol (300 ml.) and 5% palladium on charcoal (1.0 gm.) added. Reduction is carried out in a Parr apparatus for one hour at 40 psi of hydrogen. The product precipitates and the reaction mixture warmed until solution is complete. The catalyst is removed by filtration, washed with a few cc of methanol and the filtrate cooled to 0°. The product precipitates in fine needles and is collected by filtration, washed with a few ml. of methanol and dried (5.95 gm., 81% yield, m.p. 218°-220° dec.). The thin layer chromatogram (Silica gel, 5% methanol in chloroform) shows the material to be homogeneous.
Reaction SMILES: CO[C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[NH:10][CH2:11][C:12]([O-:14])=[O:13])=[O:4].[Na+].[S-:16][C:17]#[N:18].[Na+].O.Cl[Si](C)(C)C>CN1CCCC1=O>[O:4]=[C:3]1[NH:18][C:17](=[S:16])[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:6]2[CH2:7][CH2:8][CH2:9][C:5]1=2
Reactant: COC(=O)C1=C(NCC(=O)[O-])CCC1
Reactant: N#C[S-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)Cn1c2c(c(=O)[nH]c1=S)CCC2
Temperature: 117 °C
Yield: 82.6 %

Procedure:
Sodium ({2-[(Methyloxy)carbonyl]-1-cyclopenten-1-yl}amino)acetate (60 g) and sodium thiocyanate (26.6 g) were stirred in N-methylpyrrolidinone (240 ml) and water (2.94 ml) under a nitrogen atmosphere. Chlorotrimethylsilane (73.8 g) was added and the mixture heated to 117±3° C. After 3 hours at this temperature the reaction mixture was cooled to 90° C. and water (480 ml) was added. The mixture was cooled to 2° C. and the product isolated by filtration. It was washed with water (2×120 ml) then acetone (2×60 ml) and dried at 60° C. in an oven under reduced pressure to yield the title compound as an off-white solid (50.69 g, 83%). 1H NMR (d6 DMSO) δ 2.00 (2H, quintet), 2.60 (2H, t), 2.87 (2H, t), 4.95 (2H, broad s), 12.57 (1H, broad s), 13.26 (1H, broad s).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:13]3[N:18]=[CH:17][S:16][C:14]=3[N:15]=2)[CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([NH:19][C:12]2[C:13]3[N:18]=[CH:17][S:16][C:14]=3[N:15]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:30])=[O:2])[N:11]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COC(=O)c1cccc(-c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reaction time: 16 h
Yield: 97.9 %

Procedure:
To a stirred solution of 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid methyl ester (0.85 g, 2 mmol) in 20 mL of THF and 20 mL of methanol was added a solution of NaOH (0.08 g, 20 mmol) in 2 mL of water at room temperature. Then the reaction was stirred at this temperature for 16 hours. The solvent was evaporated and the residue was suspended in 50 mL of THF, then treated by 6N HCl until pH=3. The solvent was evaporated and then dissolved in 30 mL of THF, filtered. The filtrate was evaporated to give 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid (0.8 g, 97.5%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 13.15 (s, 1H), 10.18 (s, 1H), 9.38 (s, 1H), 8.98 (s, 1H), 8.61 (d, 1H, J=8.1 Hz), 8.06 (d, 1H, J=7.5 Hz), 7.84 (d, 1H, J=2.4 Hz), 7.64 (t, 1H, J=7.8 Hz), 7.42 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 6.98 (d, 1H, J=8.7 Hz), 3.82 (s, 3H), 3.77 (s, 3H). LC-MS: 409 [M+H]+, 839 [2M+Na]+, tR=1.74 min. HPLC: 98.38% at 214 nm, 97.29% at 254 nm, tR=3.44 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:22])N(OC)C)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg]Br>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17](=[O:22])[CH3:23])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5 g of 4-(N-methoxy-N-methyl-carbamoyl)-piperidine-1-carboxylic acid benzyl ester (S. Nahm and S. W. Weinreb, Tetrahedron Letters, 22:3815–3818(1981)) in 50 mL of anhydrous THF cooled to 0° C., was added dropwise 6 mL of 3M methylmagnesium bromide in ether over 10 minutes. After stirring for 1 h at 0° C., the resulting mixture was quenched with 50 mL of 1N HCl and extracted with 3×50 mL of ether. The combined extracts were dried over magnesium sulfate and concentrated to dryness under reduced pressure. Drying under vacuum gave 4-Acetyl-piperidine-1-carboxylic acid benzyl ester as a white solid:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18]C)=[O:17])=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:9]=1.[OH-].[Na+]>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([OH:18])=[O:17])=[C:10]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[N:9]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2O)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2O)nc1-c1ccc(C)cc1
Yield: 51.1 %

Procedure:
This compound was prepared according to general method D from methyl 2-(2-(2-hydroxyphenyl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.083 g; 0.213 mmol), sodium hydroxide 10N (0.10 mL; 1.00 mmol) in methanol (1 mL) at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.041 g (51%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][Br:9])=[CH:4][C:3]=1[N+:12]([O-])=O.C1N=CN([C:20](N2C=NC=C2)=[O:21])C=1>C1COCC1.[Pd]>[O:21]=[C:20]1[N:1]=[C:2]2[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][Br:9])=[CH:4][C:3]2=[N:12]1
Reactant: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1N=c2ccc(OCCBr)cc2=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21 %

Procedure:
A solution of 2-(4-amino-3-nitrophenoxy)ethyl bromide (980 mg, 7.59 mmol) in dry THF (20 mL) was shaken over 5% Pd/C (80 mg) under H2 (20-30 psi) for 5 h, then filtered. To the filtrate was added CDI (2.4 g, 14.8 mmol). The mixture was stirred at room temperature under N2 for 4 h, then refluxed for 14 h. The mixture was evaporated, then the residual solid was washed with CHCl3 (3×15 mL), and dried to give 407 mg (21%) of the title compound as an off-white powder, mp 225-6° C. 1H NMR (DMSO-d6): 3.747 (t, 2H, J=5.5), 4.234 (t, 2H, J=5.5), 6.52-6.54 (m, 2H), 6.792 (d, 1H, J=9), 10.399 (s, 1H), 10.521 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14]1([CH2:20][CH2:21][CH2:22][Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:13])[CH2:22][CH2:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Cc1c(Cl)ncc2ccccc12
Reactant: Br[Mg]CCCc1ccccc1
Product: OC(CCCc1ccccc1)c1c(Cl)ncc2ccccc12

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 3-chloro-isoquinoline-4-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cccc(N(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]Cl)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH3:27]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][N:26]([CH3:27])[CH3:25])[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CNC
Solvent: CC(=O)N(C)C
Product: CN(C)C/C=C/[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester was reacted with dimethylamine in N,N-dimethylacetamide at room temperature to yield trans-{2-[4-(3-dimethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 379 (MH+, 1Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[N:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][C:36]=1[CH3:37])[CH2:6][N:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:20][C@@H:21]([CH2:25][CH3:26])[C:22]([OH:24])=[O:23])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.C(C(CCCC)C([O-])=O)C.[Na+:54]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[N:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][C:36]=1[CH3:37])[CH2:6][N:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:20][C@@H:21]([CH2:25][CH3:26])[C:22]([O-:24])=[O:23])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.[Na+:54]
Reactant: CC[C@H](Oc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)C(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC[C@H](Oc1cccc2c1c1ccccc1n2Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)C(=O)[O-]

Procedure:
420 mg of (S)-(+)-2-{9-[3-methoxy-4-(5-methyl-2-phenyl-oxazole-4-ylmethoxy)-benzyl]-9H-carbazole-4-yloxy}butyric acid was suspended in 4.2 mL of ethyl acetate, 125 mg of sodium 2-ethylhexanoate was added thereto, and refluxed for 1 hour. After cooling, the crystalline precipitate was isolated by filtration, washed with ethyl acetate, dried under reduced pressure, and 437 mg of the subject compound was prepared as white crystal. Optical purity 96% ee (HPLC).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]3[C:20]4[N:21]=[C:22]([NH2:24])[S:23][C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:9]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]3[C:20]4[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(Br)cc4)ncn3)cccc2s1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(Br)cc4)ncn3)cccc2s1
Temperature: 90 °C

Procedure:
To a 50 mL, round-bottomed flask containing 4-[6-(4-bromo-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 129(c)), (0.050 g, 0.13 mmol) was added anhydrous toluene (3 mL) and acetic anhydride (0.010 mL, 0.39 mmol, Aldrich). The mixture was heated at 90° C. and the progress of the reaction was monitored by TLC (developed in 50% EtOAc/hexanes). After reaching completion, the reaction mixture was allowed to cool to room temperature, the white precipitate was collected by filtration, washed with MeOH (5 mL), and dried under vacuum to obtain the title compound as a white solid. Mp: 271–272° C. MS (ESI, pos. ion.) m/z: 441 (M+1).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.[CH3:24][C:25]1([CH3:32])[O:29][CH:28]([CH2:30][NH2:31])[CH2:27][O:26]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].O1CCOCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][C:25]1([CH3:32])[O:29][CH:28]([CH2:30][NH:31][C:2]2[N:12]=[CH:11][C:10]3[O:9][CH2:8][CH2:7][N:6]4[CH:13]=[C:14]([C:16]5[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=5)[N:15]=[C:5]4[C:4]=3[CH:3]=2)[CH2:27][O:26]1
Reactant: CC1(C)OCC(CN)O1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(NCC3COC(C)(C)O3)ncc1OCC2

Procedure:
A solution of 10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (90.0 mg, 0.272 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.0353 mL, 0.272 mmol), Palladium Acetate (6.11 mg, 0.0272 mmol), XPhos (13.0 mg, 0.0272 mmol), and Sodium-tert-butoxide (52.3 mg, 0.544 mmol) in 1,4-Dioxane (1.50 mL, 19.2 mmol) was heated in microwave at 115° C. for 20 min. The reaction was filtered thru celite then rinsed with EtOAc. The filtrate was washed water, brine. The organic layer was dried Na2SO4, concentrated to give intermediate N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepin-10-amine to which was added 4.00 M of Hydrogen chloride in dioxane (5.00 mL). The reaction was stirred 3 h. The reaction was concentrated and submitted HPLC purification to give 262. MS: (ESI+)=386.2. 1H NMR (500 MHz, DMSO) δ 7.99 (s, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.44 (s, 1H), 6.36 (s, 1H), 5.86 (dt, J=13.2, 6.6 Hz, 1H), 4.78 (d, J=4.8 Hz, 1H), 4.61-4.46 (m, 3H), 4.46-4.33 (m, 2H), 3.64 (dd, J=11.4, 5.3 Hz, 1H), 3.47-3.34 (m, 3H), 3.21-3.10 (m, 1H), 1.49 (d, J=6.6 Hz, 6H)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:14].O.O.[C:17](O)(=[O:21])[C:18](O)=[O:19]>Cl>[OH:19][C:18]1[C:17]([OH:21])=[N:14][C:3]2[CH:4]=[CH:5][C:6]3[C:7]([C:12]#[N:13])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[N:1]=1
Reactant: O=C(O)C(=O)O
Reactant: N#Cc1cccc2c(N)c(N)ccc12
Agent: Cl
Solvent: O
Product: N#Cc1cccc2c1ccc1nc(O)c(O)nc12
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A mixture of 0,6 g (3,3 mmol) 1,2-diamino-5-cyanonaphthalene and 1,4 g oxalic acid dihydrate in 35 ml 0,5N hydrochloric acid was refluxed for 3 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was recrystallized (dimethylsulfoxide-methanol) to give 0,35 g (45%) 2,3-dihydroxy-7-cyano-benzo[f]quinoxaline.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:11][CH3:13])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 4-chloro-2-methyl-5-nitrophenol (18.8 g, 100 mmol) in DMF (200 ml) was added potassium carbonate (13.8 g, 100 mmol) and methyl iodide (21.3 g, 150 mmol). The mixture was stirred for about two hours at room temperature. 5% Citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with brine, dried with sodium sulphate and evaporated under reduced pressure which gave the title compound (20 G, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[CH3:29][C:30]1([C:33]([N:35]2[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]2)=[O:34])[CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:41]([CH:38]3[CH2:37][CH2:36][N:35]([C:33]([C:30]4([CH3:29])[CH2:32][CH2:31]4)=[O:34])[CH2:40][CH2:39]3)=[O:42])[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: CC1(C(=O)N2CCC(C(=O)O)CC2)CC1
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
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(C(=O)C4(C)CC4)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (200 mg, 0.484 mmol) in DMF (2 mL) was added 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (113 mg, 0.533 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (221 mg, 0.581 mmol) and N,N-diisopropyl ethyl amine (498 μl, 2.90 mmol). The solution was stirred for 3 h at ambient temperature. After diluting with ethyl acetate (15 mL) the solution was washed twice with water (15 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (15 mL) and dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (210 mg, 72%) as a light brown oil. MS m/e: 606.2 [M]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][CH2:2][CH2:3][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCc1cccc2ccccc12
Product: O=S(=O)(NCCc1cccc2ccccc12)c1ccc(Cl)cc1

Procedure:
Prepared from 1-(2-aminoethyl)naphthalene and 4-chlorobenzenesulphonic acid chloride analogously to Example 1a. The crude product was purified by column chromatography on silica gel using ethylene chloride/cyclohexane (2:1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[I-].[K+].[CH3:15][N:16]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Cl.[Na+].[Cl-]>O1CCOCC1.N1C=CC=CC=1>[CH3:15][N:16]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:17]([CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2)=[O:22]
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: CN(C(=O)CCCCl)C1CCCCC1
Agent: [Cl-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CN(C(=O)CCCOc1cccc2c1CCC(=O)N2)C1CCCCC1

Procedure:
1.6 Grams of 5-hydroxy-3,4-dihydrocarbostyril, 0.8 g of pyridine, 1.8 g of potassium iodide and 2.8 g of N-methyl-N-(4-chlorobutyryl)cyclohexylamine are added to 30 ml of dioxane, and the mixture is refluxed under agitation for 12 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out. The crude crystals are dissolved in 50 ml of chloroform and the organic layer is washed with 1 N sodium hydroxide (50 ml×2), water and then, dried with anhydrous sodium sulfate, followed by removal of the solvent by distillation, and the resultant residue is recrystallized from ethyl acetate to obtain 0.8 g of 5-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless prism-like crystals with melting point of 133°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[NH:18][C:19](=[O:44])[C@H:20]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[NH:21]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=O)=[CH:4][CH:3]=1.CCN(CC)CC.CC(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[NH:18][C:19](=[O:44])[C@H:20]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[N:21]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(OC)cc1C(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2NC1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of methyl N1-[2-[(4-chlorophenyl)carbonyl]-4-(methyloxy)phenyl]-N2-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-α-asparaginate (for a preparation see Reference compound C) (assumed 0.2 mol) in DCM (500 mL) was added Et3N (500 mL, 3.65 mol) and the resulting mixture was refluxed for 24 h before being concentrated. The resulting crude amine was dissolved in 1,2-DCE (1.5 L) and AcOH (104 mL, 1.8 mol) was added carefully. The reaction mixture was then stirred at 60° C. for 2 h before being concentrated in vacuo and dissolved in DCM. The organic layer was washed with 1N HCl and the aqueous layer was extracted with DCM (×3). The combined organic layers were washed twice with water, and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude solid was recrystallised in MeCN leading to the title compound (51 g) as a pale yellow solid. The filtrate could be concentrated and recrystallised in MeCN to give to another 10 g of the desired product Rf=0.34 (DCM/MeOH: 95/5).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[O:3][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: BrCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: FC(F)(F)c1cccc(OCCCCBr)c1
Reaction time: 5 h
Yield: 80.8 %

Procedure:
267 ml of 1.6 N sodium hydroxide solution are added dropwise with stirring at 100° C. within 90 minutes to a mixture of 69.3 g of 3-hydroxybenzotrifluoride and 119 g of 1,4-dibromobutane. The mixture is stirred at this temperature for a further 5 hours and is then allowed to cool. 200 ml of methylene chloride are added, the organic phase is separated off, washed with dilute sodium hydroxide solution, dried over sodium sulfate and concentrated. The residue is distilled in vacuo. 102.6 g of 4-(3-trifluoromethylphenoxy)butyl bromide of b.p. 143° to 144° C. (13 mm Hg=1730 Pa) are obtained.