Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([N:27]1[CH2:28][CH2:29][CH2:30][C:31]2[N:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[N:24]=[CH:25][C:26]1=2)=[O:15]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1Cl
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(C(F)(F)F)cc1Cl)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a mixture of 2-[2-chloro-4-(trifluoromethyl)phenyl]acetic acid (59 mg, 0.23 mmol) and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (50 mg, 0.23 mmol) in DMF (1 mL) was added Hunig's base (59 mg, 0.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (96 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour, and then was partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine and dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (25 mg, 25%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 0.8H), 7.70 (s, 1H), 7.56-7.44 (m, 4H), 7.38 (s, 0.2H), 7.18-7-14 (m, 2H), 4.14 (s, 2H), 3.82 (m, 2H), 2.85 (m, 2H), 2.08 (m, 2H); MS: (ES) m/z calculated for C21H16ClF4N3O [M+H]+ 438.1, found 438.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]([C:15]1[O:16][CH:17]=[C:18]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:19]=12)O.C([SiH](CC)CC)C.C(OCC)(=O)C>FC(F)(F)C(O)=O.[Pt]=O>[NH2:24][C:22]1[CH:23]=[CH:18][C:17]2[O:16][C:15]([CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[O:6][C:2]=3[CH3:1])=[CH:19][C:20]=2[CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(O)c1occ2cc([N+](=O)[O-])ccc12
Agent: O=[Pt]
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(N)ccc2o1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
alpha-(5-Methyl-2-phenyl-4-oxazolyl)-5-nitro-2-benzofuranmethanol (57 g, 0.16 mol) was dissolved in trifluoroacetic acid (350 ml), while cooling to 0° C. Triethylsilane (64 ml, 0.40 mol) was added. The solution was stirred 1.5 hours at 0° C. and overnight at room temperature. The solution was concentrated to near-dryness and the residue dissolved in ethyl acetate (750 ml). This solution was washed with water. The precipitate formed during the wash was collected. The organic solution was washed with satured sodium bicarbonate, during which more precipitate formed and was collected. The ethyl acetate phase of the filtrate was washed again with saturated sodium bicarbonate, then with brine, dried over sodium sulfate and concentrated. The residue was triturated with isopropyl ether and a solid was obtained. The combined solids obtained hereabove (51 g, 0.15 mol) were placed in a Parr bottle together with platinum oxide (3 g) and ethyl acetate (1.5 1) and hydrogenated at 40 psi for 1.25 hours. The catalyst was filtered through Celite, and after washing the filtering pad with more ethyl acetate, the solvent was removed in vacuo to give a yellow residue which was triturated with isopropyl ether (200 ml). The pale yellow solid was collected (37.1 g, mp 161.5°-162.5° C).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2].[F:15][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CCOC(C)=O>[F:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2ccccc2c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2ccccc2c1F
Temperature: 25 °C

Procedure:
A mixture of 1.95 g (10 mmol) of 2-acetylaminonaphthalene, and 7.1 g (20 mmol) of 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) in 30 mL of CH2CN is heated to reflux under an atmosphere of nitrogen for 24 hours. After cooling to room temperature, 50 mL of EtOAc is added and the mixture is washed with H2O and dried over MgSO4. Evaporation of the solvents gives a syrup that is purified by flash chromatography on silica gel (25% EtOAc/hexane) to give 1-fluoro-2-acetylaminonaphthalene.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:18].[Na+]>O1CCOCC1>[CH3:17][N:8]1[C:4]2[N:5]=[CH:6][NH:7][C:2](=[O:18])[C:3]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9]1
Reactant: Cn1cc(-c2ccccc2)c2c(Cl)ncnc21
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccccc2)c2c(=O)[nH]cnc21
Temperature: 100 °C
Yield: 71 %

Procedure:
To a stirred solution of 4-chloro-7-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidine (1.32 g, 5.42 mmol) in 1,4-dioxane (40 ml) was added 2M sodium hydroxide (aq) solution (40 ml, 80 mmol). The solution was heated to 100° C. for 16 h. The solution was cooled and the organic solvent removed in vacuo. The aqueous mixture was extracted using ethyl acetate (3×40 ml) and the organic extract was discarded. The solid was collected and dried using a sintered funnel under vacuum to afford the title compound (0.86 g, 71%) which was used in the next step without further purification. LCMS RT=0.87 min, M+H+=226.1.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:22][CH3:23])[C:11](=[O:21])[N:12]([CH3:20])[C:13]=3[C:17](O)=[O:18])[C:8]2=[O:24])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:45]([CH3:47])[CH3:46])C2C=CC=CC=2N=N1.CNC>CN(C=O)C>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:22][CH3:23])[C:11](=[O:21])[N:12]([CH3:20])[C:13]=3[C:17]([N:45]([CH3:47])[CH3:46])=[O:18])[C:8]2=[O:24])=[CH:4][CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1c2c(c(C(=O)O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1c2c(c(C(=O)N(C)C)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Reaction time: 24 h

Procedure:
To a solution of 6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (0.14 g, 0.40 mol) in DMF was added BOP (0.515 g, 1.167 mmol) and the dimethylamine (2.0 M in THF) (0.035 g, 0.778 mmol). After 24 hours, the product mixture was concentrated under vacuum. The residual material was purified using reverse phase HPLC eluting with 5-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to give 6-(4-fluorobenzyl)-4-methoxy-N,N, 2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (ES MS M+1=388). A solution of this product (0.1 g, 0.3 mmol) in CH2Cl2 was treated with HBr (30 wt % in acetic acid) (0.104 g, 1.29 mmol) and after stirring at room temperature for 24 hours, concentrated under vacuum. The residual material was purified using reverse phase HPLC eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.Br[CH2:30][CH2:31][CH3:32].N>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: CCCBr
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Agent: N
Product: CCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(OC)cc3C(F)(F)F)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (23 mg, 69%) from (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) and 1-bromopropane (20 mg, 0.15 mmol). 1H NMR (CDCl3, 300 MHz) δ 0.98 (t, J=7.3 Hz, 3H), 1.78-1.92 (br, 2H), 2.11-2.25 (m, 5H), 2.28-2.42 (m, 1H), 2.53-2.80 (m, 5H), 3.05-3.25 (br, 2H), 3.31 (dt, J=10.2, 3.6 Hz, 1H), 3.37-3.45 (br, 1H), 3.60-3.72 (br, 1H), 3.89 (s, 3H), 6.85 (s, 1H), 6.87 (s, 1H), 7.05 (dd, J=8.7, 2.6 Hz, 1H), 7.21-7.27 (m, 2H) ppm. MS (CI, NH3): 431.2 (base, M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9](=O)[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[CH2:26]([O:28][NH2:29])[CH3:27]>C(O)C>[Br:1][C:2]1[C:3]([C:9](=[N:29][O:28][CH2:26][CH3:27])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CCON
Reactant: O=C(NCC(=O)c1ncc(Br)cc1Br)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To 200 mg of N-[2-(3,5-dibromopyridine-2-yl)-2-oxoethyl]-2-(trifluoromethyl)benzamide in 1.4 ml of ethanol, 63 mg of ethoxyamine hydrochloride was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the resulting residue was mixed with 4 ml of water and extracted with ethyl acetate (4 ml×2), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 195 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([NH2:47])[CH3:46])[CH:40]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:47][CH:45]([C:41]3[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=3)[CH3:46])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(N)c1cccnc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4cccnc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 79 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-pyridin-3-yl-ethylamine: yield 79%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH3:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:29]=[C:30]=[O:31])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH3:12])[CH:19]2[CH2:20][CH2:21][N:22]([C:30]([NH2:29])=[O:31])[CH2:23][CH2:24]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(C2CCNCC2)C(C)c2ccccn2)c(C)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: Cc1cnc(CN(C2CCN(C(N)=O)CC2)C(C)c2ccccn2)c(C)c1
Yield: 90.7 %

Procedure:
To a solution of (3,5-Dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(1-pyridin-2-yl-ethyl)-amine (194 mg, 0.60 mmol) in 2-propanol (3 mL) was added trimethylsilyl-isocyanate (85 μL, 0.63 mmol). The resultant solution was stirred at room temperature overnight then concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) gave COMPOUND 262 (200 mg, 88%) as a white solid. 1H NMR (CDCl3) δ 0.96-1.02 (m, 1H), 1.45-1.49 (m, 4H), 1.52-1.86 (m, 2H), 2.26 (s, 3H), 2.27 (s, 3H), 2.53-2.62 (m, 1H), 2.71-2.80 (m, 1H), 2.89-2.96 (m, 1H), 3.77-3.97 (m, 5H), 4.37 (s, 2H), 7.10-7.25 (m, 2H), 7.39 (d, 1H, J=7.8 Hz), 7.57-7.62 (m, 1H), 8.19 (br s, 1H), 8.51 (d, 1H-J=3.9 Hz); 13C NMR (CDCl3) δ 13.61, 15.79, 16.16, 27.90, 28.13, 42.22, 42.27, 49.35, 52.87, 55.61, 119.60, 121.54, 129.51, 130.57, 133.80, 136.93, 144.14, 146.25, 152.72, 156.04, 160.52; ES-MS m/z 368 (M+H). Anal. Calcd. For C21H29N5O.0.8H2O: C, 66.05; H, 8.08; N, 18.34. Found: C, 65.9281; H, 7.73; N, 18.18.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14](Cl)([Cl:16])=[O:15].N1C=CC=CC=1>O1CCCC1>[Cl:16][S:14]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:13])[O:9][CH:10]([CH3:11])[CH3:12])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CC(C)OC(=O)Nc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)OC(=O)N(c1ccccc1)S(=O)Cl
Yield: 61.1 %

Procedure:
Eighteen grams isopropyl phenylcarbamate (~0.1 mol) and 14.0 g thionyl chloride (0.12 mol) were dissolved in 50 ml dry tetrahydrofuran and protected from moisture by a calcium chloride tube. Eight grams pyridine (0.1 mol) were added dropwise while the mixture was stirring at a water bath temperature (15°-20° C.). After the addition of pyridine was completed, the mixture was stirred for 12 hours at room temperature. Pyridine hydrochloride was filtered and the solvent was removed under vacuum. The concentrated residue was diluted with hexane and filtered. The hexane was removed under vacuum and the residue was distilled, giving 16.0 g of product distilling at 113-115/0.08 mm. NMR spectrum of the product in chloroform-d-TMS gave the following absorptions: δ7.6-7.2 (m, 5H, phenyl protons), δ5.5-4.9 (m, 1H, CH) and δ1.4-1.3 (d, 6H, C(CH3)2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18](O)[CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[N:9]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]([N:25]2[C:21](=[O:31])[C:22]3[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24]2=[O:26])[CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[N:9]=1
Reactant: CC(O)c1cc2ncccc2nc1-c1ccccc1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cc2ncccc2nc1-c1ccccc1F)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.12 h

Procedure:
1-(2-(2-Fluorophenyl)-1,5-naphthyridin-3-yl)ethanol (550 mg, 2.04 mmol) and phthalimide (600 mg, 4.09 mmol) were dissolved in THF (20 mL) and the mixture was cooled to 0° C. To the cooled mixture was added PPh3 (1.07 g, 4.09 mmol) and the mixture was stirred for 5-10 min at 0° C. Then DIAD (800 mg, 4.09 mmol) was added dropwise to the above reaction mixture at 0° C., and the reaction mixture was slowly allowed to warm to rt and maintained at rt for 3 h. After completion of reaction, the reaction mixture was quenched with water and ethyl acetate. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-(1-(2-(2-fluorophenyl)-1,5-naphthyridin-3-yl)ethyl)-1H-isoindole-1,3(2H)-dione as a white solid: 1H-NMR (CDCl3) δ: 1.8 (s, 3H), 5.0 (brs, 1H), 6.4 (s, 2H), 7.7-7.2 (m, 7H), 8.4 (d, 1H), 9.0-8.8 (d, 2H).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[OH:21][N:20]1[C:14](=[O:13])[C:7]2[CH:6]=[CH:5][C:4]([N+:16]([O-:18])=[O:17])=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12]
Reactant: O=C1OC(=O)c2ccc([N+](=O)[O-])c3cccc1c23
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3c([N+](=O)[O-])ccc(c23)C(=O)N1O
Yield: 72.4 %

Procedure:
4-Nitro-1,8-naphthalic anhydride (2.61 g, 10.7 mmol) and hydroxylamine hydrochloride (1.5 g, 21.4 mmol) were reacted in pyridine (50 mL) following the procedure of Example 1. The crude product was recrystallized from ethanol to give 2.0 g of the title compound, mp 255-260° C.;
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](C(N)=O)=[C:6]2SC1C=CC=CC=1)=[O:2].[CH3:22]I>CO.C(Cl)Cl>[CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[CH:7]=[CH:6]2)=[O:2]
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: CI
Solvent: ClCCl
Solvent: CO
Product: Cn1ccc2cc(C=O)ccc21

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph; 400 mg, 1.35 mmol) with MeI (101 μl) as described in General Procedure XIV to provide the 5-formyl-1-methylindole the title compound 14 (280 mg, 67%), Rf (5% MeOH/CH2Cl2)=0.75.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:10][CH2:11][N:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[NH:9][CH2:8][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:10][CH2:11][N:12]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:32]
Reactant: CCOC(N)=O
Reactant: CCCCN(CCCC)CCC(CN)(c1ccccc1)c1ccccc1
Product: CCCCN(CCCC)CCC(CNC(=O)OCC)(c1ccccc1)c1ccccc1

Procedure:
From 2,2-diphenyl-4-di-n-butylaminobutyl-amine in analogy to 3a. The crude urethane was further reacted in a crude state.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])#N.CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[O:34]1CCCC1>>[CH:13]1([NH:12][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:34])=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#Cc1ccc(NC2CCCC2)c(C(=O)O)c1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: O=Cc1ccc(NC2CCCC2)c(C(=O)O)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a solution of 5-cyano-2-(cyclopentylamino)benzoic acid (40.0 mg) in anhydrous tetrahydrofuran (2 mL) was added 1.5 M diisobutylaluminium hydride hexane solution (0.34 mL) under dry ice-acetone cooling, and the mixture was stirred for an hour at −78° C. and then for 4 hours at ambient temperature. The reaction was quenched by addition of methanol and an aqueous saturated ammonium chloride solution. After stirring at ambient temperature for a half hour, the mixture was partitioned with 5% sulfuric acid and chloroform. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a preparative silica gel chromatography with 10% methanol in chloroform to give 2-(cyclopentylamino)-5-formylbenzoic acid (25.0 mg) as pale orange powders.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6]3=[C:7]([CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][N:5]3[CH2:4][CH2:3]1)[CH:8]=[CH:9][CH:10]=2.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6]3=[C:7]([CH2:12][NH:13][CH2:14][CH2:15][N:5]3[CH2:4][CH2:3]1)[CH:8]=[CH:9][CH:10]=2
Reactant: CC(C)(C)OC(=O)N1CCN2CCC(C)(C)c3cccc(c32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCN2CCNCc3cccc1c32
Temperature: 25 °C
Yield: 72.4 %

Procedure:
287 mg (0.9 mmol) of tert-butyl 8,8-dimethyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate of step 1.3 were dissolved in 5 mL of dichloromethane and treated with 2.5 mL of trifluoroacetic acid. The mixture was stirred over night at room temperature and then extracted once with water (10 mL). The organic phase was then extracted twice with a diluted solution of sodium hydroxide (10 mL each), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica (eluent: 10-30% methanol in dichloromethane) to yield 141 mg of the title compound as a yellow oil.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][C:12]2([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:29][O:28][C:23]1[C:22]2[O:21][C:20]3[C:15]([C:12]4([CH2:13][CH2:14][NH:9][CH2:10][CH2:11]4)[C:27]=2[CH:26]=[CH:25][CH:24]=1)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: COc1cccc2c1Oc1ccccc1C21CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cccc2c1Oc1ccccc1C21CCNCC1

Procedure:
A solution of 1'-benzyl-4-methoxyxanthene-9-spiro-4'-piperidine hydrochloride (3.0 g.) in absolute ethanol (100 ml.) is hydrogenated using 5% palladium on carbon catalyst, at 4 atmospheres pressure and 50° C. The catalyst is filtered off and the solvent evaporated to dryness. The residue is crystallised from ethanol-ether to give 4-methoxyxanthene-9-spiro-4'-piperidine, m.p. 214°-216° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH3:15])[CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[N+:11]([O-])=O)[CH3:2].C(O)C>[C].[Pd].C(OCC)(=O)C>[CH2:14]([CH:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH2:11])[CH3:15]
Reactant: CCC(CC)CCn1ccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(CC)CCn1ccnc1N
Reaction time: 20 h
Yield: 96.1 %

Procedure:
A solution of the 1-(3-ethylpentyl)-2-nitro-1H-imidazole (370 mg) and 10% palladium-carbon (200 mg) in an ethanol (5 ml)-ethyl acetate (5 ml) mixture was stirred at room temperature and normal pressure for 20 hours under a hydrogen stream. After filtering the reaction mixture through celite, it was washed with ethyl acetate-methanol. The filtrate was distilled off under reduced pressure to yield a crude product of 1-(3-ethylpentyl)-1H-2-imidazoleamine (305 mg) as a light yellow solid. A solution of the 1-(3-ethylpentyl)-1H-2-imidazoleamine (305 mg, 1.68 mmol) and 2-bromo-1-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1-ethanone (660 mg, 2.02 mmol) in methanol (20 ml) was heated at 60° C. for 3 hours. The reaction mixture was distilled under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate. After washing the crystals with diethyl ether, they were dried to yield the target compound (700 mg) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][CH:7]=1.S(Br)([Br:16])=O>O1CCOCC1.C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Br:16])=[CH:8][CH:7]=1
Reactant: OCc1ccc(OCCCCl)cc1
Reactant: O=S(Br)Br
Solvent: C1COCCO1
Solvent: CCOCC
Product: ClCCCOc1ccc(CBr)cc1
Reaction time: 0.17 h

Procedure:
A solution consisting of 4-(3-chloropropoxy)-benzyl alcohol No. 162 (10.6 g, 52.8 mmol) in dioxane (0.125 l) was cooled to 0° C. and treated with a dropwise addition of thionyl bromide (12.0 g, 58.0 mmol). After 10 minutes the reaction was complete. The dioxane was diluted with ethyl ether and washed with water, brine, and then dried over MgSO4. The material was concentrated down to yield 15 g of an oil: 1H NMR (DMSO) 7.36 (d, 2 H, J=8.8 Hz), 6.92 (d, 2 H, J=8.6 Hz), 4.68 (s, 2 H), 4.08 (t, 2 H, J=5.9 Hz), 3.77 (t, 2 H, J=6.4 Hz); MS (FAB) 266 (M+H+).