Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)nn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-[3-(6-methoxy-pyridazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K7) (246 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (317 mg).
Reaction SMILES: Br[CH:2]([C:4]1[C:5]([F:27])=[CH:6][C:7]2[O:16][CH2:15][CH2:14][N:13]3[C:9](=[N:10][C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)=[CH:12]3)[C:8]=2[CH:26]=1)[CH3:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:27][C:5]1[C:4]([CH:2]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH3:3])=[CH:26][C:8]2[C:9]3[N:13]([CH:12]=[C:11]([C:17]4[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=4)[N:10]=3)[CH2:14][CH2:15][O:16][C:7]=2[CH:6]=1
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(C(C)Br)c(F)cc2OCC3)n(C(C)C)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2cc(C(C)N4CCN(C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Yield: 63.3 %

Procedure:
A solution of 9-(1-bromoethyl)-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 374 (99 mg, 0.23 mmol), N-methylpiperazine (28 μL, 0.25 mmol) and DIPEA (60 μL, 0.35 mmol) in dioxane (1 mL) was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (Si-PPC, gradient 0-8% 2 M NH3/MeOH in DCM) to give 66 mg of a pale yellow oil. The compound was further purified by reverse phase column chromatography (C18, gradient 2-50% MeOH in 1% TFA/H2O) and then loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2 M NH3 in MeOH. The basic fraction was concentrated in vacuo to afford 373 (47 mg, 40% over 2 steps) as a white solid. LCMS (Method K): RT 2.70 min [M+H]+ 454.2. 1H NMR (CD3OD, 400 MHz): δ 8.54 (1H, d, J=8.6 Hz), 7.68 (1H, s), 6.76 (1H, d, J=11.0 Hz), 5.83 (1H, sept., J=6.7 Hz), 4.49 (4H, br s), 3.84 (1H, q, J=6.8 Hz), 2.47 (8H, br s), 2.33 (3H, s), 2.22 (3H, s), 1.53 (3H, d, J=6.7 Hz), 1.52 (3H, d, J=6.7 Hz), 1.40 (3H, d, J=6.8 Hz)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:12]3[S:13][C:14]([Br:22])=[CH:15][C:16]=3[CH2:17][C:18]([O:20]C)=[O:19])=[CH:10][CH:11]=2)=[C:4]([CH2:23][C:24]([O:26]C)=[O:25])[CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1>[Br:22][C:14]1[S:13][C:12]([C:9]2[S:8][C:7]([C:5]3[S:6][C:2]([Br:1])=[CH:3][C:4]=3[CH2:23][C:24]([OH:26])=[O:25])=[CH:11][CH:10]=2)=[C:16]([CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1
Reactant: COC(=O)Cc1cc(Br)sc1-c1ccc(-c2sc(Br)cc2CC(=O)OC)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cc1cc(Br)sc1-c1ccc(-c2sc(Br)cc2CC(=O)O)s1
Temperature: 80 °C

Procedure:
Intermediate D (1.10 g, 2.00 mmol) was dissolved in dioxane (5 ml) and 2 M NaOH (5 ml) was added. The mixture was heated at 80° C. for 1 h. 6 M HCl was added and the aqueous mixture extracted with EtOAc. Combined organic layers were dried (MgSO4) and evaporated. Yield: 982 mg (94%); pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 3.77 (s, 4H), 7.30 (s, 2H), 7.31 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:22]([O-])=O)=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C:15]([CH3:17])([CH3:16])[N:8]3[CH:7]=[C:6]([C:18]([NH2:20])=[O:19])[C:5]2=[O:21])[C:11]=1[F:12].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.CO>[NH2:22][C:3]1[C:2]([F:1])=[C:11]([F:12])[C:10]2[O:13][CH2:14][C:15]([CH3:17])([CH3:16])[N:8]3[C:9]=2[C:4]=1[C:5](=[O:21])[C:6]([C:18]([NH2:20])=[O:19])=[CH:7]3
Reactant: CC1(C)COc2c(F)c(F)c([N+](=O)[O-])c3c(=O)c(C(N)=O)cn1c23
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)COc2c(F)c(F)c(N)c3c(=O)c(C(N)=O)cn1c23
Yield: 50.8 %

Procedure:
To a suspension of 10 (6.3 g, 18.6 mmol) in a mixture of water/methanol 1/1 v/v (160 mL), sodium hydrosulfite (19.4 g, 116 mmol) was added and the suspension was refluxed for 5 h until all starting material was consumed. The product was collected by filtration while the mixture was still hot and washed with warm water. The solid was dried under vacuum to give 11 (2.92 g, 51% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]O)[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(O)cc1
Reactant: OCc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCc2cccnc2)cc1
Temperature: 25 °C

Procedure:
To a solution of [3-(4-hydroxy-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (100 mg, 0.362 mmol), 3-pyridylmethanol (40 μL, 0.42 mmol)) and triphenylphosphine (200 mg, 0.76 mmol) in THF (2.1 mL) at 0° C. was added diethylazodicarboxylate (155 μL, 0.85 mmol) over 1.5 h. The reaction mixture was warmed rt for 24 h. Volatiles were removed under reduced pressure and the crude product was dry-loaded onto silica gel. Chromatography (1-2.5% CH3OH in CH2Cl2) provided {3-[4-(pyridin-3-ylmethoxy)-phenyl]isoxazol-4-yl}-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][N+:13]([O-])=C(C)[CH:11]=1>C(Cl)(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[CH:11]=[C:10]([O:9][CH3:8])[C:15]([CH3:16])=[CH:14][N:13]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C)[n+]([O-])cc1C
Solvent: ClC(Cl)Cl
Product: COc1cc(COC(C)=O)ncc1C

Procedure:
55 ml of acetic anhydride were added dropwise at room temperature to a solution of 19.9 g of 4-methoxy-2,5-dimethylpyridine 1-oxide in 75 ml of chloroform. After boiling under reflux for 2 hours the solution was evaporated, the residue was dissolved in 100 ml of toluene and again evaporated. The residue was taken up in 100 ml of ethyl acetate and the solution was extracted three times with 50 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The product was chromatographed on 100 g of silica gel with ether and there was obtained (4-methoxy-5-methyl-2-pyridyl)methyl acetate in the form of an oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([NH2:10])=[CH:8][N:7]=[CH:6][N:5]=1.[CH3:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=O.P(Cl)(Cl)(Cl)=O>C(O)C>[CH3:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][CH:8]=2)[N:3]=1
Reactant: Nc1cncnc1N
Reactant: COc1cc(SC)ccc1C(=O)Cl
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: COc1cc(SC)ccc1-c1nc2ncncc2[nH]1

Procedure:
A mixture of 4.1 g of 4,5-diamino-pyrimidine dihydrochloride, 7.1 g of 2-methoxy-4-methylmercapto-benzoylchloride, and 50 ml of phosphorus oxychloride was refluxed for three hours. The reaction mixture was evaporated until one-half of the original volume remained, and then the remaining mixture was poured into water. The precipitate that formed was dissolved in boiling ethanol, precipitated by addition of ether, and purified by chromatography on silicagel (eluate: methylene chloride/ethanol in a volume ratio of 19:1).
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.Cl.N1CCNCC1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>CO>[N:7]1([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
A mixtue of 38 g. (0.2 mole) piperazine hexahydrate, 28 g. (0.2 mole) piperazine dihydrochloride and 150 ml. methanol is mixed, while stirring at ambient temperature, with 45 g. (0.2 mole) methyl 4-bromomethylbenzoate. The reaction mixture is left to stand for 2 days and suction filtered from the precipitate. The clear solution is evaporated and the residue is recrystallised from ethanol to give 39 g. (64%) of the desired compound as a monohydrochloride; m.p. 226°-227° C.
Reaction SMILES: C(O)=O.CC(C)(C)C([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[N:10]=1)=O.[ClH:32]>CO>[ClH:32].[ClH:32].[ClH:32].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2cccc(NC(=O)C(C)(C)C)n2)CC1
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: Nc1cccc(CN2CCC(N)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 2-(trimethylacetylamino)-6-[(4-t-butoxycarbonylamino-1-piperidinyl)methyl]pyridine formic acid salt (0.74 g, 3.0 mmol) in methanol (6 mL) was added 6 N HCl (2 mL) at room temperature. The resulting mixture was heated to reflux for 10 h. Then, the reaction was cooled to room temperature and concentrated under rotary evaporator. After azeotropic removal of water with 1-propanol twice (20 mL each), the resulting solid was treated with methanol (5 mL). After being stirred for 1 h in methanol, ethanol (12 mL) was added slowly and stirred for additional 1 h. After filtration, drying of the resulting crystalline solid gave the desired title compound (491 mg, 80% yield, 98 A % purity).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:9]([O:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCC(=O)O
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)CCCCC(=O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 65.1 %

Procedure:
To a mixture of fluorobenzene (37.3 g) and adipic acid monoethyl ester chloride (18.0 g) was added gradually aluminum chloride (26.6 g) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (500 ml) and extracted with diethyl ether (200 ml×2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (200 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 6-(4-fluorophenyl)-6-oxohexanoate as an oil (14.1 g, 57%).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([S:15][CH3:16])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:17]([O:19]CC)=O)=[N:3]1.C[N:23](C)C=O.O.[NH4+]>CO>[CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([S:15][CH3:16])[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:17]([NH2:23])=[O:19])=[N:3]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(SC)nc1-2
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CSc1ncc2c(n1)-c1c(c(C(N)=O)nn1C)CC2
Temperature: 65 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
13.00 g (0.043 mol) of ethyl 1-methyl-8-(methylthio)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate were suspended in a mixture of 200 mL of methanol, 200 mL of dimethylformamide and 200 mL of ammonium hydrate 30%. The mixture was stirred at 65° C. in a closed bottle for about 8 hours. The solvent was then evaporated to dryness, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude was purified by chromatography on a silica gel column eluted by a mixture cyclohexane/ethyl acetate, giving 6.16 g (52% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]([C:10]2[C:15]([F:16])=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)=O)[CH:7]=1.Cl.[NH2:27][OH:28]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6](/[C:8](/[C:10]2[C:15]([F:16])=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)=[N:27]/[OH:28])[CH:7]=1
Reactant: COc1ccc(F)cc1C(=O)c1nccc(-c2cnccc2C)c1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(F)cc1/C(=N/O)c1nccc(-c2cnccc2C)c1F
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of (5-fluoro-2-methoxyphenyl)(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)methanone (0.024 g, 0.071 mmol) and hydroxylamine hydrochloride (0.033 g, 0.480 mmol) in pyridine (Volume: 0.353 ml) was refluxed for 3 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 0-95% EtOAc in hexanes over 15 min, tr=0.5, 1.5, 2.5 min) gave the title compound (22 mg, 0.061 mmol, 87% yield) as a yellow residue. ESI MS (M+H)+=356.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.[NH4+].[Cl-]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[CH:17]3)[CH:10]([NH:12][S:39]([CH:36]2[CH2:38][CH2:37]2)(=[O:41])=[O:40])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)N)cn1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(Oc2ccc3c(cnn3-c3cccnc3)c2)C(C)NS(=O)(=O)C2CC2)cn1
Reaction time: 20 h

Procedure:
To a stirred solution of 1-[6-methoxypyridin-3-yl]-1-[1-(pyridin-3-yl)indazol-5-yl]oxypropan-2-amine (45 mg, 120 μmol) in dichloromethane (4.5 mL) was added triethylamine (40 μl), followed by cyclopropane sulfonic acid chloride (25 mg, 180 μmol) and DMAP (1.5 mg, 12 μmol). The stirring was continued for 20 hours at room temp. The reaction mixture was poured into sat. NH4Cl solution and extracted with dichloromethane, then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 4 mg as a racemic mixture of two diastereomeres (7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH2:15]([O:22][C:23]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:24]=1[CH:25]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:24]=1/[CH:25]=[CH:10]/[C:8]([C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=1[OH:11])=[O:9])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Product: Cc1cc(C(=O)/C=C/c2ccc(OCc3ccccc3)cc2OCc2ccccc2)c(O)c([N+](=O)[O-])c1
Yield: 42.6 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (500 mg, 2.56 mmol) and 2,4-dibenzyloxybenzaldehyde (900 mg, 2.83 mmol) were reacted according to the same procedure as Preparation 22 to give 540 mg (Yield 43%) of the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([S:19][CH2:20][CH2:21][CH2:22]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12>O1CCCC1>[C:13]1([S:19][CH2:20][CH2:21][CH2:22][N:47]2[C:43](=[O:53])[C:44]3[C:45](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:46]2=[O:48])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCSc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCSc1ccccc1
Reaction time: 15 h
Yield: 85 %

Procedure:
Diethyl azodicarboxylate (14 ml, 89 mmol) was added over 3 minutes to a stirred solution of 3-phenylthiopropanol (14.91 g, 89 mmol), triphenylphosphine (23.25 g, 89 mmol) and phthalimide (13.05 g, 89 mmol) in tetrahydrofuran (350 ml) at room temperature. After 15 hours, the mixture was concentrated in vacuo. Flash chromatography of the residue, eluting with 1:1 ether/hexane, gave the title compound as a white solid (22.5 g 85%). NMR (200 MHz, CDCl3): δ 2.0 (q, 2H), 2.95 (t, 2H), 3.85 (t, 2H), 7.25 (m, 5H), 7.8 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:34]([C:35]#[N:36])=[N:33][C:5]2[CH:6]=[C:7]3[C:16](=[N:17][C:4]=2[CH:3]=1)[C:15]1[N:14]=[C:13]2[C:18](=CC4C=CC=CC=4)[CH2:19][CH2:20][CH2:21][C:12]2=[C:11]([CH2:29][CH2:30][CH2:31][CH3:32])[C:10]=1[CH2:9][CH2:8]3.N#N.[O:39]=[O+][O-].CSC>CO>[NH2:1][C:2]1[C:34]([C:35]#[N:36])=[N:33][C:5]2[CH:6]=[C:7]3[C:16](=[N:17][C:4]=2[CH:3]=1)[C:15]1[N:14]=[C:13]2[C:18](=[O:39])[CH2:19][CH2:20][CH2:21][C:12]2=[C:11]([CH2:29][CH2:30][CH2:31][CH3:32])[C:10]=1[CH2:9][CH2:8]3
Reactant: O=[O+][O-]
Reactant: CCCCc1c2c(nc3c1CCc1cc4nc(C#N)c(N)cc4nc1-3)C(=Cc1ccccc1)CCC2
Agent: N#N
Solvent: CO
Solvent: CSC
Product: CCCCc1c2c(nc3c1CCc1cc4nc(C#N)c(N)cc4nc1-3)C(=O)CCC2
Temperature: -78 °C
Yield: 35 %

Procedure:
To a 250 mL round bottomed flask were added 0.305 g (0.147 mmol) of crude 2-amino-12-benzylidene-8-n-butyl-3-cyano-6,7,9,10,11,12hexahydrobenzo[b]pyrido[2,3-j][1,10]phenanthroline, 40 mL of CH2CL2 and 115 mL of CH3OH. The solution was cooled to approximately -78° C. by means of a dry ice/acetone bath and N2 was passed through the solution for 5 min. A stream of O3 was passed through the solution until the color turned from dark orange-brown to dark green-brown. N2 was passed through the solution for an additional 5 min. then 0.6 mL of dimethyl sulfide was added via syringe. The solution was allowed to warm to room temperature overnight and the solvents removed by rotary evaporation. The crude product was washed with ether (3×50 mL) then recrystallized from CHCL3 /EtOH. Vacuum filtration gave 0.09 g (35%) of product as a yellow solid after drying at 0.5 mm Hg pressure and 61° C. for 48 hr. (mp>300° C.).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@@H:50]([OH:54])[CH2:51][O:52][CH3:53])[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:53][O:52][CH2:51][C@H:50]([OH:54])[CH2:49][O:48][C@H:10]1[C@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13][NH:8][CH2:9]1
Reactant: COC[C@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: Cl
Solvent: CO
Product: COC[C@H](O)CO[C@@H]1CNC[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
In analogy to the procedure described in example 1) (l) the (3S,4R,5R)-3-[(2S)-2-hydroxy-3-methoxy-propoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the (2S)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol as colorless oil; MS: 646.3 (M+H)+.
Reaction SMILES: Br[C:2](=[C:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][CH:39]=[CH:40][N:41]=1)CCC>C1COCC1.CCOC(C)=O>[C:3]1([C:2](=[C:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]3[C:26]4[C:21](=[C:22]([O:29][CH3:30])[N:23]=[CH:24][C:25]=4[O:27][CH3:28])[NH:20][CH:19]=3)=[O:17])[CH2:11][CH2:10]2)[C:37]2[S:38][CH:39]=[CH:40][N:41]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(Br)c4ccccc4)CC3)c[nH]c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4nccs4)CC3)c[nH]c12
Temperature: 90 °C
Yield: 34.1 %

Procedure:
A mixture of 1-[4-(1-bromo-1-phenyl-methylene)-piperidin-1-yl]-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione (0.032 g, 0.066 mmol), 2-(tri-n-butylstannyl)thiazole (0.025 g, 0.066 mmol) and bistriphenylphosphinepalladium dichloride (0.001 g, 1 mol %) in THF (4 mL) was heated at 90° C. in a sealed tube under Ar for 15 h. The cooled mixture was then diluted with EtOAc, washed (1M KF, brine), dried (Na2SO4) and evaporated to give a clear yellow oil. Purification by preparative HPLC afforded the product (0.011 g, 34%) as a white solid:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:37]([CH3:36])(=[O:39])=[O:38])=[C:5]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C(C#N)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (71.2 mg, 150 μmol) was initially charged in dry THF (3 ml), and sodium hydride (60% in mineral oil; 8.4 mg, 210 μmol; 1.4 eq.) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of methanesulfonyl chloride (24.1 mg, 210 μmol; 1.4 eq.) in THF (1 ml) was then slowly added dropwise. After a reaction time of 20 h, the reaction mixture was concentrated and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compound as a colorless solid (70 mg, 84% of theory).