Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][CH:20]5[CH2:25][C:24]([O:30][Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:32][CH3:33])([C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]5([CH:38]=[O:39])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:41].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4[CH2:17][CH2:18][CH2:19][CH:20]5[CH2:25][C:24]([O:30][Si:31]([CH2:36][CH3:37])([CH2:32][CH3:33])[CH2:34][CH3:35])([C:26]([F:29])([F:27])[F:28])[CH2:23][CH2:22][C:21]5([C:38]([OH:41])=[O:39])[C:13]4=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C=O)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC[Si](CC)(CC)OC1(C(F)(F)F)CCC2(C(=O)O)c3cc4cnn(-c5ccc(F)cc5)c4cc3CCCC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
t-Butanol (20 mL) and water (4 mL) were added to rac-(3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carb aldehyde (40, R1=4-Fluorophenyl, R3=Trifluoromethyl) (0.360 g, 0.642 mmol). After cooling to about 0° C., sodium dihydrogenphosphate (0.770 g, 6.42 mmol), 2-methyl-but-2-ene (0.270 g, 3.85 mmol), and sodium chlorite (0.348 g, 3.85 mmol) were added sequentially. After about 30 min, the ice bath was removed and the reaction was allowed to warm to rt. After about 3 h, a 1:1 solution of sat. aq. Na2SO3 and sat. aq. NaCl (50 mL) was added. Water (30 mL) was added. The mixture was extracted with EtOAc (3×50 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (40 g) using a gradient of 0-20% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(3R,4aR,12bS)-9-(4-fluorophenyl)-3-((triethylsilyl)oxy)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carboxylic acid (43, R1=4-Fluorophenyl, R3=Trifluoromethyl) (0.267 g, 72% yield); LC/MS, method 4, Rt=2.39 min.; MS m/z: 577 (M+H)+. 1H NMR (400 MHz, DMSO) δ 12.57 (s, 1H), 8.26 (d, J=0.7 Hz, 1H), 7.90 (s, 1H), 7.82-7.75 (m, 2H), 7.54 (s, 1H), 7.45-7.35 (m, 2H), 2.95-2.71 (m, 2H), 2.60-2.48 (m, 1H), 2.42-2.15 (m, 4H), 2.03-1.78 (m, 3H), 1.73-1.52 (m, 2H), 1.34-1.20 (m, 1H), 0.99-0.90 (m, 9H), 0.69-0.59 (m, 6H).
Reaction SMILES: [OH-:1].[K+].C(N[C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([C:13]([Cl:17])=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11])(=O)C>O>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[C:9]([C:10]([OH:12])=[O:11])=[C:8]([N+:18]([O-:20])=[O:19])[C:7]=1[OH:1]
Reactant: CC(=O)Nc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 130 °C
Yield: 94.6 %

Procedure:
A solution of KOH (73.4 g) in H2O (330 mL) was added to 3-acetamido-4,6-dichloro-2-nitrobenzoic acid 1-5 (38.1 g, 0.130 mol). The resulting brown solution was heated to reflux for 18 h (bath temp 130° C.). The reaction was cooled and extracted with ether. The aqueous layer was then acidified to pH 2 with concentrated HCl and extracted into EtOAc (×4). The combined organic layers were washed with brine (×3), dried over Na2SO4, filtered and concentrated to provide 4,6-dichloro-3-hydroxy-2-nitrobenzoic acid 1-6 as a brown solid (31.0 g, 95%). 1H NMR (400 MHz, d6-DMSO) δ7.88 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](O)=[O:6].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]([CH3:22])[C:16]=2[CH:23]=1.N1C(=O)CC[C@H]1C([O-])=O>>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:8]([OH:10])=[O:9].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]([CH3:22])[C:16]=2[CH:23]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: C[C@H]1CNCCc2ccc(Cl)cc21
Agent: O=C1CC[C@@H](C(=O)[O-])N1
Product: O=C1CC[C@@H](C(=O)O)N1

Procedure:
The aqueous solubility of Compound 1 pyroglutamate was determined to be >161.5 mg/mL at pH 3.94.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:17]Br>C(Cl)Cl>[NH2:1][C:2]1[C:14]([Br:17])=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc(N)c(CN2CCCCC2)c1
Reactant: BrBr
Solvent: ClCCl
Product: COc1cc(Br)c(N)c(CN2CCCCC2)c1

Procedure:
N-(2-Amino-3-bromo-5-methoxy-benzyl)-piperidine was prepared from N-(2-amino-5-methoxy-benzyl)-piperidine and bromine analogous to Example 9. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [C:1]([CH:5]1[CH2:9][S:8][CH:7]([CH3:10])[C:6]1=[N:11]O)([O:3][CH3:4])=[O:2].[ClH:13]>CCOCC>[ClH:13].[NH2:11][C:6]1[C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:9][S:8][C:7]=1[CH3:10]
Reactant: COC(=O)C1CSC(C)C1=NO
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1csc(C)c1N
Reaction time: 8 h

Procedure:
A solution of 41.1 g. (0.217 mole) of 4-carbomethoxy-3-keto-2-methyltetrahydrothiophene oxime in 600 ml. anhydrous ether, previously saturated with gaseous hydrogen chloride at 0°, was allowed to stir at 25° overnight. The separated solid was collected, washed well with ether, and dried to afford 33.2 g. Evaporation of the filtrate yielded after recrystallization of the residue an additional 4.2 g. to afford a total yield of pure 3-amino-4-carbomethoxy-2-methylthiophene hydrochloride of 37.4 g. (84%). The compound melts 191°-192°.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1C(C1C=CC(Cl)=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CC(O)=O.[CH:47]([C:50]1[CH:51]=[C:52]([OH:56])[CH:53]=[CH:54][CH:55]=1)([CH3:49])[CH3:48]>O1CCOCC1.[Cu]I>[CH:47]([C:50]1[CH:51]=[C:52]([CH:53]=[CH:54][CH:55]=1)[O:56][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1)([CH3:49])[CH3:48]
Reactant: CC(C)c1cccc(O)c1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)c1cccc(Oc2cnc3c(c2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To a solution of 6-bromo-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 4, 400 mg, 1 mmol), CuI (24.7 mg, 0.13 mmol), Cs2CO3 (650 mg, 2 mmol) and 2-(dimethylamino)acetic acid (51.5 mg, 0.5 mmol) in dioxane (6 mL) was added 3-isopropylphenol (204 mg, 1.5 mmol). The reaction was heated at 140° C. (MW) for 1.5 h then cooled to RT and filtered. The filtrate was diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1) to give 6-(3-isopropylphenoxy)-1-methyl-3-(3-(tetra hydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (250 mg, 55% yield) as a solid. LCMS: MH+ 454 and TR=2.156 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C@@:17]12[C@H:25](O)[CH2:24][C@@H:20]([C:21]1([CH3:23])[CH3:22])[CH2:19][CH2:18]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.O1CCCC1>[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[CH2:10][CH2:11][C:12]([O:14][C@@H:18]1[CH2:19][C@H:20]2[C:21]([CH3:23])([CH3:22])[C@:17]1([CH3:16])[CH2:25][CH2:24]2)=[O:13]
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: CC1(C)[C@H]2CC[C@]1(C)[C@H](O)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)[C@H]2CC[C@]1(C)[C@H](OC(=O)CCC(=O)OCc1ccccc1)C2
Temperature: 50 °C
Yield: 61.5 %

Procedure:
In a 300 mL round bottom flask, fitted with reflux condenser, 4-(benzyloxy)-4-oxobutanoic acid (1.80 g, 1 eq., of Example 1) and anhydrous tetrahydrofuran (85 mL) were added. The reaction mixture was stirred under inert atmosphere and L-borneol (1.34 g, 1 eq.) was added, followed by the addition of HOBT (1.28 g, 1.1 eq.), EDC-HCl (1.81 g, 1.1 eq.) and DMAP (1.12 g, 1.1 eq). The reaction was heated in an oil bath at 50° C. for several hours until monitoring showed a substantial amount of product formation. The reaction mixture was filtered, concentrated and extracted with MTBE versus 1N HCl. The organic layer was washed with 1N HCl and brine, dried over MgSO4 and concentrated. The crude product was purified using column chromatography to give 1.83 g of a colorless oil (62%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:47][CH2:46][CH:45]([N:48](C)[C:49](=O)OC(C)(C)C)[CH2:44][CH2:43]3)=[N:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:32](=[O:33])[N:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[N:30]=[CH:29][CH:28]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([N:42]3[CH2:47][CH2:46][CH:45]([NH:48][CH3:49])[CH2:44][CH2:43]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(N3CCC(N(C)C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2n[nH]c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A round-bottomed flask was charged with tert-butyl 1-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidin-4-yl(methyl)carbamate (98.5 mg, 0.124 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at 80° C. overnight. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give the product, which was not pure enough. The impure product was further purified by preparative HPLC to afford product (17.3 mg, 24.3%). LRMS (APCI pos) m/e 573 (M+1). 1H NMR (400 MHz, CD3OD δ 11.97 (s, 1H), 8.38 (d, 1H), 8.33 (d, 1H), 8.25 (d, 1H), 8.08 (m, 1H), 7.65 (m, 2H), 7.48 (d, 1H), 7.40 (m, 1H), 7.28 (m, 2H), 6.28 (d, 1H), 4.10 (m, 2H), 3.32 (m, 1H), 3.01 (m, 2H), 2.72 (s, 3H), 2.18 (m, 2H), 2.81 (m, 2H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C.N1(C(C)CO)CCOCC1>>[C:12]([N:9]1[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(CO)N1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1

Procedure:
1-Boc-4-Hydroxymethyl-piperidine was prepared from 1-Boc-piperidine-4-carboxylic acid ethyl ester by a procedure similar to that described in the preparation of 2-morpholin-4-yl-propanol.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].[C:7]([C:9]1[C:10](F)=[CH:11][C:12]([NH:15][C:16]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[N:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:17])=[N:13][CH:14]=1)#[N:8]>CC(N(C)C)=O.CCOC(C)=O>[C:7]([C:9]1[C:10]([O:4][CH:2]([CH3:3])[CH3:1])=[CH:11][C:12]([NH:15][C:16]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[N:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:17])=[N:13][CH:14]=1)#[N:8]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(F)c(C#N)cn1)CCC2
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(OC(C)C)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Propanol (16.2 mg, 0.269 mmol) was diluted in DMA (1 ml) under argon and treated with NaH (60% dispersion in mineral oil, 10.77 mg, 0.269 mmol). The reaction mixture was stirred for 30 min at room temperature. This mixture was added to a solution of N-(5-cyano-4-fluoropyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 33, 25 mg, 0.054 mmol) in DMA (1 ml). The reaction mixture was then stirred at room temperature for 1 h and the at 110° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with sat. aq. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated to give the title compound as a white solid. (UPLC-MS 3) tR 1.27 min; ESI-MS 412.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][S:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:31])[F:32])[CH:22]=4)(=[O:29])=[O:28])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=c1[nH]c2nccc(Oc3cccc(NS(=O)(=O)c4cccc(C(F)(F)F)c4)c3)c2[nH]1
Yield: 72 %

Procedure:
Method K was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-(trifluoromethyl)benzenesulfonyl chloride to afford the title compound as an off-white solid (42 mg, 72%). 1H-NMR (δ, ppm, DMSO-d6): 6.19 (d, 1H, HPy,5, J=5.5 Hz), 6.78 (s, 1H, Harom), 6.86 (d, 1H, Harom, J=8.0 Hz), 6.98 (d, 1H, Harom, J=7.5 Hz), 7.31-7.35 (m, 1H, Harom), 7.74 (d, 1H, HPy,6, J=5.5 Hz), 7.82-7.85 (m, 1H, Harom), 7.96-8.06 (m, 4H, Harom), 10.57 (s, 1H, NHSO2), 11.13 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.21, 110.98, 113.74, 115.45, 116.59, 123.09, 123.24, 129.88, 130.68, 131.02, 131.08, 138.71, 138.72, 140.20, 141.16, 144.09, 147.21, 154.15, 155.04. HRMS (EI): m/z [M+H] calcd for C19H14F3N4O4S: 451.0688; found: 451.0687.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C1COCC1.CN(C=O)C.CCOC(C)=O>[C:22]([O:21][C:19](=[O:20])[CH2:18][O:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(CCO)c1ccc([N+](=O)[O-])cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CCOCC(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Reaction time: 8 h

Procedure:
(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (350 mg, 1.77 mmol) in THF (15 mL) and DMF (2 mL) was stirred with 60% NaH in oil (142 mg, 4.44 mmol) for 1 hr. The mixture was cooled and to this was added tert-butyl bromoacetate (1.31 mL, 8.88 mmol). The reaction mixture was allowed to stir overnight. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness and yielded 262 mg following flash chromatography. ES-MS calcd for C14H21N3O5 (m/e) 311.34, obsd 312 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][NH2:10])=[O:8])=[N:4][N:3]=1.[C:11](Cl)(Cl)=[S:12]>O1CCOCC1>[SH:12][C:11]1[O:8][C:7]([C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)=[N:9][N:10]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1nnc(C(=O)NN)o1
Solvent: C1COCCO1
Product: Cc1nnc(-c2nnc(S)o2)o1
Reaction time: 5 h

Procedure:
3.6 g of 5-methyl-1,3,4-oxadiazole-2-carboxylic acid hydrazide of melting point 150°-151° C., prepared in the customary manner from the corresponding ethyl ester [Canad.J.Chem. 65, 166 (1987)], are stirred in 100 ml of dioxane with 2.9 g of thiophosgene at room temperature overnight and then at 55° C. for 5 hours. After cooling, undissolved solids are filtered off and 200 ml of hexane are added to the filtrate, the desired product (4 g of decomposition point 225°) crystallizing out.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=[C:21]([Br:23])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl.O1CCOCC1>[Br:23][C:21]1[CH:22]=[C:17]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)=[CH:14][N:13]=2)[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CCN1CCN(c2ccc(N)nc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Temperature: 100 °C

Procedure:
To a round-bottomed flask equipped with a stirring bar, 138b (2.52 g, 12.22 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (4.89 g, 18.32 mmol), Pd2(dba)3 (1.12 g, 1.22 mmol), XantPhos (1.13 mg, 1.96 mmol), Cs2CO3 (13.14 g, 40.33 mmol) and dioxane (50 mL) were added. The reaction mixture was heated at 100° C. overnight. CH2Cl2 (200 mL) was added to the resulting mixture was washed with water (30 mL×3). CH2Cl2 (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. CH2Cl2/ether (1:2, 5 mL) was added followed by sonication, the precipitation was filtered as 138c, a yellow solid, 2.718 g (57%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:22][CH2:23]1
Reactant: ICCC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CCC4CCCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 2-(iodoethyl)cyclohexane.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([N:26]=O)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[OH-].[Na+]>O.C1C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH2:22][N:23]([NH2:26])[CH2:24][CH2:25]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(N2CCN(N=O)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(N)CC2)cc1
Reaction time: 20 h

Procedure:
To a stirred suspension of 10 parts of lithium aluminium hydride in 900 parts of tetrahydrofuran is added dropwise, during a 20 hours period, a solution of 40 parts of 1-(4-methoxyphenyl)-4-nitrosopiperazine in 720 parts of benzene. Upon completion, stirring is continued for 20 hours at room temperature. The reaction mixture is decomposed by the successive dropwise additions of 10 parts of water, 7.5 parts of a sodium hydroxide solution 50% and 30 parts of water. The whole is filtered and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 1,1'-oxybisbutane. The product is filtered off and dried, yielding 18.56 parts of 4-(4-methoxyphenyl)-1-piperazinamine; mp. 107° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.C(N(CC)CC)C.[CH2:30]([O:32][CH2:33][C:34](Cl)=O)[CH3:31]>[Pt].C1(C)C=CC=CC=1.C(O)C>[CH2:30]([O:32][CH2:33][C:34]1[N:14]([CH2:15][C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=1)[CH3:31]
Reactant: CCOCC(=O)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCCCC1
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanol prepared above (87%, 7.00 g, 20.3 mmol) and 5% platinum on carbon (0.60 g) in toluene (160 mL) and ethanol (20 mL) was hydrogenated at 20-30 psi (1.4×105 to 2.1×105 Pa) on a Parr apparatus for 2 h. The mixture was filtered through CELITE filter agent, which was rinsed with toluene. The filtrate was concentrated to a golden oil. The oil was concentrated twice from toluene. To the oil was added CH2Cl2 (200 mL) and the resulting solution was cooled in an ice bath. Triethylamine (3.11 mL, 22.3 mmol) was added followed by dropwise addition of ethoxyacetyl chloride (88%, 2.96 g, 21.3 mmol). The solution was allowed to warm to rt and stir for 1 h, during which time a precipitate formed. The reaction mixture was concentrated to a yellow foam to which ethanol (200 mL) and triethylamine (11 mL) were added. The resulting solution was heated at reflux for 13 h. The solution was concentrated to a yellow solid, which was dissolved in CH2Cl2 (150 mL) and washed with water (50 mL) and brine (75 mL). The organic layer was dried over MgSO4, filtered, and concentrated to a solid that was crystallized from CDCl3/CH2Cl2 to yield 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol as pale orange crystals after drying (1.94 g, 28%).
Reaction SMILES: FC(F)(F)[C:3]([N:5]([C:7]1[CH:8]=[C:9]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:30])[NH:23][C:24]3[C:29]\2=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][CH:12]=1)C)=O.[OH-].[Na+]>CO>[CH3:3][NH:5][C:7]1[CH:8]=[C:9]([NH:13]/[C:14](=[C:21]2\[C:22](=[O:30])[NH:23][C:24]3[C:29]\2=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C(=O)C(F)(F)F)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 8 from (Z)-3-{1-[3-(N-trifluoroacetyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-2-indolinone and sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([OH:23])[C:10]=1[C:24](=[O:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=2)[C:10]=1[C:24](=[O:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)c1c(O)cc(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 110 °C
Yield: 73 %

Procedure:
A stirred suspension of 1-[2,4-bis(benzyloxy)-6-hydroxyphenyl]ethanone (Bulletin of the Chemical Society of Japan (1985), 58(1), 136-41) (5.2 g, 15 mmol), potassium carbonate (3.1 g, 22 mmol) and 1-fluoro-4-nitrobenzene (2.1 g, 15 mmol) in DMF (10 mL) was heated at 110° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and thoroughly washed with brine (4×50 mL). The organic phase was dried over Na2SO4 and then evaporated to dryness. The crude was chromatographed on a small pad of silica gel eluting with hexane/ethyl acetate 5/1, to provide the title compound (5 g, 73% yield).