Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:14]2[C:6](=[CH:7][C:8]3[O:12][CH2:11][O:10][C:9]=3[CH:13]=2)[C@@H:5]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([OH:23])=[C:17]([O:24][CH3:25])[CH:16]=2)[C@H:4]2[C:26](=[O:29])[O:27][CH2:28][C@H:3]12.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].N1C=CN=C1>CN(C)C=O>[NH2:1][C@@H:2]1[C:14]2[C:6](=[CH:7][C:8]3[O:12][CH2:11][O:10][C:9]=3[CH:13]=2)[C@@H:5]([C:15]2[CH:16]=[C:17]([O:24][CH3:25])[C:18]([O:23][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[C:19]([O:21][CH3:22])[CH:20]=2)[C@H:4]2[C:26](=[O:29])[O:27][CH2:28][C@H:3]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](N)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O[Si](C)(C)C(C)(C)C

Procedure:
A 63.4 mmol solution of (5R,5aR,8aS,9S)-9-amino-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one, 111.8 mmol of tert-butyldimethylsilyl chloride and 510 mmol of imidazole in 1.6 l of anhydrous dimethylformamide is stirred for 20 hours at ambient temperature. The reaction mixture is then washed with 2 l of water then 1 l of ether. The ether phase is then decanted and the aqueous phase extracted with ether. The organic phases are then dried on magnesium sulfate, are filtered and concentrated under reduced pressure. The expected product is obtained by recrystallization in a benzene/heptane mixture.
Reaction SMILES: [N:1]1C=CC=CC=1.[C:7](Cl)([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8]>C(Cl)Cl>[C:7](=[O:8])([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])[NH2:1]
Reactant: c1ccncc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Product: NC(=O)OCC(Cl)(Cl)Cl

Procedure:
To a stirring solution of amine (2 mmol, 1.00 eq) and pyridine (4 mmol, 2.00 eq) in CH2Cl2 (18 ml) at RT was added Troc-Cl (1.87 mmol, 1.05 eq). After 4 hours the reaction was washed with 3M HCl (1×), satd. NaHCO3 (1×), dried (Na2SO4), filtered and evaporated to afford the target 2,2,2-trichloroethyl carbamate. The material was used as is in the next reaction.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][S:7]([C:10]1[CH:29]=[CH:28][C:13]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:25]([CH3:26])[C:24]([CH3:27])=[N:23][CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:5])[CH3:4].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N1C=CC=CC=1.O>[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36]([O:1][CH2:2][C:3]([NH:6][S:7]([C:10]2[CH:29]=[CH:28][C:13]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH3:26])[C:24]([CH3:27])=[N:23][CH:22]=4)[CH:18]=[CH:17][N:16]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])([CH3:5])[CH3:4])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NC(C)(C)CO)cc3)n2)n1C
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)NS(=O)(=O)c2ccc(Nc3nccc(-c4cnc(C)n4C)n3)cc2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
2-{4-[N-(1-Hydroxy-2-methylprop-2-yl)sulphamoyl]anilino}-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Example 59; 2.36 g, 5.66 mmol) was dissolved in dry pyridine (55 ml) and the solution stirred and cooled to 0° C. under inert gas. Solid p-toluenesulphonyl chloride (5.61 g, 29.4 mmol) was added portionwise over 2 minutes. The reaction was stirred at 0° C. for 10 minutes and then at room temperature for 18 hr. The reaction mixture was diluted with water (200 ml) and the precipitated oil allowed to settle out. The supernatant water layer was decanted off and the residual oil was washed with more water and this was decanted off. This process was repeated and then the oil partitioned between EtOAc (100 ml) and water (50 ml). The layers were separated and the organic layer washed with water (50 ml), dried and the solvent evaporated in vacuo to yield the title compound as a gum (1.94 g, 60%) NMR 1.0 (s, 6H), 2.36 (s, 3H), 2.38 (s, 3H), 3.77 (s, 2H), 3.93 (s, 3H), 7.20 (d, 1H), 7.43 (d, 2H), 7.55 (s, 1H), 7.65 (m, 5H), 7.87 (d, 2H), 8.45 (d, 1H), 9.9 (s, 1H); m/z 571.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br.O>CN1CCCC1=O.C1(C)C=CC=CC=1>[C:8]1([CH3:7])[CH:13]=[CH:12][C:11]([S:14][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Br:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S)cc1
Reactant: Brc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Sc2ccccc2Br)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of potassium tert-butoxide (75 g, 0.668 mol, 1.1 eq) in N-methyl-2-pyrrolidone (225 mL) a solution of 4-methylthiophenol (78 g, 0.628 mol, 1.0 eq) dissolved in N-methyl-2-pyrrolidone (225 mL) was added. To the reaction mixture was then added to 1,2-dibromobenzene (73 mL, 605 mol, 1.0 eq); once the addition was complete the reaction mixture was warmed to 100° C. and maintained at this temperature for approximately 22 hrs. (The reaction is monitored by HPLC). After cooling to room temperature water (750 mL) and toluene (375 mL) were added, the phases separated, and the water phase extracted with toluene (250 mL). The organic phases were combined and the organic phase was concentrated by vacuum distillation. Once the distillation was complete, the residue was cooled and methanol (750 mL) added. The solvents were removed from the organic phase by vacuum distillation and further methanol (250 mL) added. Stirring over night at room temperature precipitated 2-(4-tolylsulfanyl)-phenyl bromide which was isolated by filtration, washed with methanol (260 mL) and dried in vacuum. Yield=120.8 g.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:11]=1.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[OH:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[CH:9]=[C:8]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)[CH:7]=1
Reactant: COC(=O)CCc1cc(-c2ccc(O)cc2)cc(-c2ccc(O)cc2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCCCc1cc(-c2ccc(O)cc2)cc(-c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.90 g (8.32 mmol) 3-(4,4″-dihydroxy-[1,1′;3′,1″]terphenyl-5′-yl)-propionic acid methyl ester are dissolved in THF, and 55 ml (55 mmol) of a 1 M solution of DIBAL-H in toluene are added dropwise under cooling. The cooling is removed and the mixture is stirred overnight at RT. After addition of 3 ml isopropanol the mixture is poured onto ice/water, acidified with 2 M hydrochloric acid and extracted three times with MTB ether. The combined organic layers are washed with sat. aq. sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue is filtered through silica gel with toluene/ethylacetate (2:1). 5′-(3-hydroxy-propyl)-[1,1′;3′,1″]terphenyl-4,4″-diol is obtained as colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1O.CCN=C=NCCCN(C)C.CS(O)(=O)=O>O.C(Cl)(Cl)Cl>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]2[O:8][C:6]([C:5]3[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=3)=[N:14][C:15]=2[CH:20]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(-c2nc3cc(Cl)ccc3o2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (25.0 g, 135 mmol), 2-amino-4-chlorophenol (21.3 g, 149 mmol), CHCl3 (500 mL), and WSC (28.5 g, 149 mmol) were added together and stirred at room temperature for 2 hours. The reaction mass was concentrated, and then the residue was washed with water and ethanol. To a dioxane (500 mL) solution of the solid obtained was added methanesulfonic acid (81.9 g, 811 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (31.0 g, 78% yield) as reddish-brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[C:11]1(/[CH:17]=[CH:18]/[C:19]2[O:20][C:21]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][C:22]=3[N:28]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][C:21]3[O:20][C:19](/[CH:18]=[CH:17]/[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:28][C:22]=3[CH2:23][CH2:24]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C(=C/c1nc2c(o1)CCNCC2)\c1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCc2nc(/C=C/c3ccccc3)oc2CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
4-Fluorobenzoyl chloride (0.016 mL, 0.14 mmol) was added dropwise to a stirred solution of 5,6,7,8-tetrahydro-2-[(E)-2-phenylethenyl]-4H-oxazolo[4,5-d]azepine (95 mg, 0.13 mmol) and TEA (0.026 mL, 0.19 mmol) in DCM (1 mL) at 0° C. The reaction mixture was stirred at room temperature for 15 minutes and then diluted with a saturated solution of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was triturated with DIPE to yield 6-(4-fluorobenzoyl)-5,6,7,8-tetrahydro-2-[(E)-2-phenylethenyl]-4H-oxazolo[4,5-d]azepine (37 mg, 80% yield) as a white solid. C22H19FN2O2.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)#[N:3].ClC1C=C(N2[C:24]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:23][C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=N2)C=CC=1F>>[Cl:32][C:27]1[CH:26]=[C:25]([C:24]2[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:2]#[N:3])[CH:5]=3)[N:11]=[C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=2)[CH:30]=[C:29]([F:31])[CH:28]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: N#Cc1cccc(NN)c1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(C#N)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 1A and 3-cyanophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 1.96 g of the title compound with 55% purity (86% of theory) are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:51]=[CH:52][C:53]=1[O:54][CH3:55])[CH2:32][O:33][C:34]([NH:36][C:37]1[NH:38][C:39](=[O:50])[C:40]2[N:41]=[CH:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=2[N:45]=1)=[O:35]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:47](=[O:48])[CH2:46][N:43]2[CH:42]=[N:41][C:40]3[C:39](=[O:50])[NH:38][C:37]([NH:36][C:34]([O:33][CH2:32][C:31]4[CH:51]=[CH:52][C:53]([O:54][CH3:55])=[C:29]([O:28][CH3:27])[CH:30]=4)=[O:35])=[N:45][C:44]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)O)c(=O)[nH]2)cc1OC
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)N3CCN(S(=O)(=O)c4nc5ccccc5s4)C(=O)C3)c(=O)[nH]2)cc1OC

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(3,4-dimethoxybenzyloxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.41 (s, 1H), 11.37 (s, 1H), 8.34 (m, 1H), 8.24 (m, 1H), 7.81 (s, 0.6H), 7.77 (s, 0.4H), 7.71 (m, 2H), 7.04 (s, 1H), 6.95 (d, 1H), 6.94 (d, 1H), 5.15 (s, 2H), 5.13 (s, 1.2H), 5.02 (s, 0.8H), 4.51 (s, 0.8H), 4.27 (s, 1.2H), 4.24 (t, 1.2H), 4.07 (t, 0.8H), 4.03 (t, 1.2H), 3.84 (t, 0.8H), 3.75 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][O:20][CH2:21][CH3:22]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) in N,N-dimethylformamide (4.5 mL) was added cesium carbonate (1324 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. 1-Bromo-2-ethoxyethane (1016 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 14 hrs. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (120 mL×3). The organic layer was washed with saturated brine (100 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (697 mg) as a pale-yellow oil.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](=[O:27])[N:11]([C:18]1([CH3:26])[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[C:12]2=[O:17])=[O:6])=[N+]=[N-].O.[ClH:29]>CO.[Pd]>[ClH:29].[NH2:1][CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10](=[O:27])[N:11]([C:18]1([CH3:26])[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[C:12]2=[O:17])=[O:6]
Reactant: CC1(N2C(=O)c3cccc(NC(=O)CN=[N+]=[N-])c3C2=O)CCC(=O)NC1=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC1(N2C(=O)c3cccc(NC(=O)CN)c3C2=O)CCC(=O)NC1=O
Reaction time: 5 h
Yield: 35 %

Procedure:
A mixture of 2-azido-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-acetamide (1.4 g, 3.8 mmol) and 10% Pd/C (0.2 g) in methanol (100 mL) and 4N HCl (20 mL) was hydrogenated in Parr Shaker for 5 hours. H2O (10 mL) was added, and the mixture was filtered through celite. The filtrate was concentrated, and the residue was evaporated with ethanol (3×20 mL). The solid was slurried with hot methanol (30 mL) to give 2-amino-N-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-acetamide hydrochloride (0.5 g, 35%) as a yellow solid: mp 111-113° C.; 1H NMR (DMSO-d6) δ 1.90 (s, 3H, CH3), 2.04-2.09 (m, 1H), 2.50-2.72 (m, 3H), 3.97 (s, 2H, CH2), 7.64 (d, J=7.2 Hz, 1H, Ar), 7.86 (t, J=7.7 Hz, 1H, Ar), 8.32 (d, J=8.2 Hz, 1H, Ar), 8.40 (s, 3H, NH3), 10.30 (s, 1H, NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.05, 28.55, 29.10, 41.11, 58.83, 117.98, 118.92, 127.13, 131.76, 134.74, 135.99, 166.18, 167.22, 167.75, 172.04, 172.18; Anal. calcd. for C16H17N4O5Cl: C, 50.47; H, 4.50; N, 14.71; Cl, 9.31. Found: C, 50.35; H, 4.40; N, 14.54; Cl, 9.01.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:29](=[O:30])[C:26]2[C:27]3[C:28]4[C:23](=[CH:24][CH:25]=2)[C:22]2[C:31]5[C:18]([CH:19]=[CH:20][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=5[C:13]=4[CH:12]=[CH:11][C:10]=3[C:8]1=[O:9].[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>N1C=CC=CC=1.O1CCOCC1.C(Cl)Cl>[C:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8](=[O:9])[C:10]2[C:27]3[C:28]4[C:13](=[CH:12][CH:11]=2)[C:14]2[C:31]5[C:18]([CH:17]=[CH:16][CH:15]=2)=[CH:19][CH:20]=[CH:21][C:22]=5[C:23]=4[CH:24]=[CH:25][C:26]=3[C:29]1=[O:30])(=[O:35])[CH:33]=[CH2:34]
Reactant: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1CCCCCO)c54
Reactant: C=CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
2 g (5 mmol) of N-(5-hydroxypentyl)perylene-3,4-dicarboximide from 1. were dissolved under nitrogen in 60 ml of pyridine, with heating at 80° C., cooled to 65° C. and admixed dropwise at this temperature with a solution of 0.81 ml (10 mmol) of acryloyl chloride in 30 ml of anhydrous dioxane. The mixture was stirred at 65° C. for a further 1.5 h, the solvent was removed by distillation, the residue was taken up in 20 ml of chloroform, a filtration was conducted, the filtrate was admixed with 100 ml of hexane, and the precipitated product was isolated by filtration. Chromatography on a short silica gel column using methylene chloride as eluent gave 1.5 g (65%) of the desired product as a brownish red powder with a strong tendency to polymerize on heating.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:12]3[N:17]=[CH:16][C:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: C1CN(CC2CC2)CCN1
Reactant: N#Cc1ccc(-c2ccc(Cl)nc2)cc1
Product: N#Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Temperature: 140 °C
Yield: 36.9 %

Procedure:
1-Cyclopropylmethyl-piperazine (13 g, 94 mmol) was mixed with 4-(6-cloro-pyridin-3-yl)benzonitrile (5 g, 23 mmol). The mixture was heated at 140° C. for 1.5 hours. The mixture was cooled to rt and purified by column chromatography (EtOAc:petrolether=1:1) on silica gel to give 2.7 g (43%) of 4-[6-(4-cylopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzonitrile.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].CO[Na].[Br:8][C:9]1[CH:10]=[C:11]2C(=[CH:17][C:18]=1[F:19])O[CH:14]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][C:12]2=[N:26][C:27]#[N:28].[CH3:29][OH:30]>>[Br:8][C:9]1[CH:10]=[C:11]2[C:12]3([O:4][N:3]([CH3:2])[C:27]([NH2:28])=[N:26]3)[CH2:13][CH:14]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:30][C:29]2=[CH:17][C:18]=1[F:19]
Reactant: CO
Reactant: CNO
Reactant: N#CN=C1CC(c2ccccc2)Oc2cc(F)c(Br)cc21
Agent: CO[Na]
Agent: Cl
Product: CN1OC2(CC(c3ccccc3)Oc3cc(F)c(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a solution of N-methyl-hydroxylamine hydrochloride (35 mg, 0.355 mmol) in MeOH (5 mL) was added MeONa (0.07 mL, 25% (Wt.) in MeOH), followed by N-(6-bromo-7-fluoro-2-phenylchroman-4-ylidene)cyanamide (122 mg, 0.355 mmol). After stirred for 10 minutes, the solvent was removed in vacuo. The residue was purified by preparative TLC to give 6-bromo-7-fluoro-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (30 mg, 30%). 1H-NHR (MeOD): 2.18 (m, 1H), 2.33 (m, 1H), 3.08 (d, 3H), 5.28 (m, 1H), 6.75 (m, 1H), 7.38 (m, 5H), 7.61 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=O)[CH:17]([CH2:21][C:22]24[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]2)[CH2:29]4)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH:18]=[C:17]([CH2:21][C:22]24[CH2:23][CH:24]5[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]5)[CH2:31]2)[CH2:29]4)[CH2:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cccc3c2C(=O)C(CC24CC5CC(CC(C5)C2)C4)C3)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2cccc3c2C=C(CC24CC5CC(CC(C5)C2)C4)C3)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
94.0 g (228 mmole) 7-(4′-tert-Butyl-phenyl)-2-(1-adamantylmethyl)-indan-1-one were dissolved in 291 ml toluene in a 1 l-roundbottom flask equipped with a reflux condenser. 9.5 g (1:1 eq.) sodium borohydride were added. Then 40 ml (4.3 eq.) methanol were added at 50° C. and the mixture was stirred for 6 h at 50° C. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 350 ml of toluene. After addition of 0.7 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate, evaporation of the solvent and crystallization from 900 ml ethanol afforded 76.9 g (85%) of the desired indene as white crystals. 1H-NMR (400 MHz, CDCl3): δ=7.44, 7.32, 7.23, 7.12 (4×m, 7H, aromatic), 6.63 (s, 1H, ═CH), 3.32 (s, 2H, benzylic), 2.29 (d, 2H, aliphatic), 1.69-1.15 (m, 15H, aliphatic), 1.38 (s, 9H, C(CH3)3) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:35][C:36]1[CH:47]=[C:46]2[C:39]([NH:40][CH:41]=[C:42]2[CH2:43][CH2:44][NH2:45])=[CH:38][CH:37]=1.C(Cl)CCl.CO>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:12]([NH:45][CH2:44][CH2:43][C:42]1[C:46]2[C:39](=[CH:38][CH:37]=[C:36]([OH:35])[CH:47]=2)[NH:40][CH:41]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: O=C(NCCc1c[nH]c2ccc(O)cc12)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
2a was synthesized by the condensation of 3,4,5-tris(benzyloxy)benzoic acid (860 mg, 1.95 mmol) and 5-hydroxy tryptamine hydrochloride (496 mg, 2.34 mmol) according using standard EDC coupling method. The compound was isolated as white solid (874 mg, 75%) by elution with 2% methanol in chloroform. Rf: 0.470 (5% methanol in chloroform).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@:15]2(O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@H:16]2[O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][CH:10]=1.C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C>C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C@H:16]([O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@](O)(c2ccc(F)cc2)[C@H](OC(=O)C(C)(C)C)C1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@H](OC(=O)C(C)(C)C)C1
Yield: 93.4 %

Procedure:
To a toluene solution (40 mL) of tert-butyl (3R,4R)-4-(4-fluorophenyl)-4-hydroxy-3-(pivaloyloxy)piperidine-1-carboxylate (2.04 g, 5.16 mmol) synthesized in Reference Synthesis Example 135, methyl N-(triethylammoniosulfonyl)carbamate (1.72 g, 7.22 mmol) was added and the resultant mixture was stirred at 60° C. for 3 hours. After completion of the reaction, ethyl acetate was added to the reaction solution and the resultant mixture was washed with each of saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→3/1) to obtain the title compound (1.82 g, yield 93%).