Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21](S(O)(=O)=O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:10]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:28][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6])[OH:3])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CC(O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 105 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
Dibenzyl-DL-malate was prepared using the method of Lee et al, J. Chem. Soc. Perkin Trans. I, 1995, 2877. To a three-neck 1 L round-bottomed flask equipped with a reflux condenser, Dean-Stark trap, thermocouple and mechanical stirrer, were added DL-malic acid (81.96 g), benzyl alcohol (132.0 g), toluene (620 mL) and p-toluene-sulfonic acid (1.165 g). The mixture was placed under nitrogen and heated to reflux. At 100° C., two phases started to collect in the Dean-Stark trap. After 2 hr, the reaction temperature was increased to 105° C. for 1.5 hr. The crude product was neutralized with saturated sodium bicarbonate and poured into a separatory funnel. The organic layer was washed with saturated sodium bicarbonate twice, washed once with water, and dried over magnesium sulfate. The toluene was removed via rotary evaporation. Two-thirds of the crude product were purified via column chromatography (20% ethyl acetate in hexane eluent). Residual benzyl alcohol was removed via vacuum distillation to give a low viscosity, clear, colorless oil with no detectable odor (49.9 g, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][NH2:11])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([N:15]=[C:16]=[O:17])[CH:13]=[CH2:14].C(OCC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][NH:11][C:16]([NH:15][CH2:12][CH:13]=[CH2:14])=[O:17])=[O:9])=[CH:6][CH:7]=1
Reactant: C=CCN=C=O
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
An amount of 5.00 g (29.3 mmol) of 4-chlorobenzenecarbohydrazide was suspended in dry tetrahydrofuran (150 ml) at 50° C. and then 2.63 ml (29.9 mmol) of allyl isocyanate in solution in 110 ml of dry tetrahydrofuran were added dropwise. The starting material underwent temporary complete dissolution, and then a fine precipitate was produced. The mixture was stirred at 50° C. for 2 hours. After cooling to room temperature it was admixed with diethyl ether. The colourless solid was isolated by suction filtration, washed with diethyl ether and dried in a high vacuum. This gave 7.42 g (100% of theory) of the target compound.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NCC[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[CH3:31][N:32](C)C=O>>[N:28]1[CH:29]=[CH:30][C:25]([N:22]2[CH2:21][CH2:20][N:19]([C:16]3[CH:15]=[CH:14][CH:13]=[C:18]([C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:17]=3[CH2:31][NH2:32])[CH2:24][CH2:23]2)=[CH:26][CH:27]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccccc1
Reactant: NCCc1ccc(N2CCN(c3ccncc3)CC2)cc1
Product: NCc1c(C(=O)c2ccccc2)cccc1N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzoic acid (22 mg) in dimethylformamide (2 ml), was added 1,1-carbonyldiimidazole (188 mg) in dimethylformamide (2 ml) and the solution stirred at ambient temperature for 1 hour. A solution of 1-[4-(2-aminoethyl)phenyl]-4-(4-pyridyl)piperazine (268 mg) in dimethylformamide (4 ml) was then added in one portion and the resulting solution stirred at ambient temperature for twelve hours. The solution was evaporated to dryness and aqueous sodium bicarbonate (8 ml, 1M) added. The mixture was d stirred vigorously at ambient temperature for thirty minutes. The solid was collected by filtration, washed with water to give 1-(4-pyridyl)-4-(benzoyl-aminomethyl-phenyl)piperazine (389 mg), retention time 11.49 mins (same HPLC conditions as in Example 57).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([O:18]CCCC)=O)[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].[CH3:25][NH2:26]>CO>[CH3:25][NH:26][C:16]([C@@H:14]1[O:13][C:12](=[O:23])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:24])[S:4][C:5]=3[CH:10]=2)[CH2:15]1)=[O:18]
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The butyl(5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 29, Step 2, 300 mg, 0.856 mmol) is treated with 2N methylamine in MeOH (8.6 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (10 mL) and stirred at ambient temperature for 1 h. The resulting slurry is filtered to give the title compound, mp 264-267° C.; MS (ESI+) for C13H13N3O4S m/z 308 (M+H)+; [α]25D−44 (c 0.92, DMSO).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1)[C:4]1[C:5]2[CH2:26][NH:25][CH2:24][CH2:23][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[CH:13][CH:12]=2)[N:9]=1)[CH3:2].[C:33](O)(=[O:35])[CH3:34].C(O)C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:3]([CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1)[C:4]1[C:5]2[CH2:26][N:25]([CH2:34][CH2:33][OH:35])[CH2:24][CH2:23][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[CH:15][CH:16]=2)[N:9]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCN(CC1CCCO1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1CNCC2
Agent: O=CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1CN(CCO)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.8 %

Procedure:
N4-Ethyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (95 mg, 0.22 mmol) was dissolved in methanol (3 mL). Acetic acid (0.013 mL, 0.22 mmol) was added followed by glycoaldehyde (13.16 mg, 0.22 mmol). The reaction was stirred at room temperature for 15 minutes and sodium cyanoborohydride (13.77 mg, 0.22 mmol) was added. The reaction was stirred for 1 h, the solvent was evaporated under reduced pressure, the crude redissolved in methanol, filtered and purified twice by preparative HPLC yielding 2-(4-(ethyl((tetrahydrofuran-2-yl)methyl)amino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (7.10 mg, 6.6%).
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([O-:5])=O.[CH:8]([Mg]Cl)(C)[CH3:9].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22](C(N2C=CN=C2)=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22]([C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)n2ccnc2)C1
Reactant: CC(C)[Mg]Cl
Reactant: O=C([O-])CC(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A solution of the malonate (0.92 g, 6.97 mmol) in THF (5 mL) was cooled to 0° C. under N2. Isopropylmagnesium chloride (6.97 mL, 2.0 M) was added and the reaction was stirred for 30 min at 0° C., 30 min at room temperature and 30 min at 40° C. The solution was then cooled to 0° C. and the crude solution of (R)-3-(imidazole-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was added via cannula. A thick precipitate formed. The reaction was warmed to room temperature and stirred under N2 for 12 h. The reaction mixture was cooled to 0° C. and ice-cold 1.0 M H3PO4 (20 mL) was added to the mixture. After 5 min, the reaction was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with sat. NaHCO3 (15 mL) and brine (15 mL), dried over MgSO4 and concentrated to afford crude (R)-3-(2-ethoxycarbonyl-acetyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.91 g, crude 69%). The material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][O:11][CH:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Yield: 95.5 %

Procedure:
In a 500-mL round-bottom flask, the 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (5.0 g, 22 mmol) was dissolved in DMF (75 mL). Benzyl bromide (3.6 ml, 30 mmol) was added via syringe, followed by potassium carbonate (4.8 g, 35 mmol). The sides of the glass were rinsed down with dmf (25 mL), and an air condenser was affixed, and the reaction mixture was heated at 80° C. in an oil bath for 14 h. The reaction was cooled to ambient temperature and concentrated. The residue was transferred to a separatory funnel with 60% ether-hexane (300 mL), and the organic layer was extracted with water (75 mL), half-saturated brine (30 mL), and saturated brine (30 mL), then was dried over sodium sulfate and concentrated. The residue was purified through silica gel (500 mL) using 20% to 30% EtOAc-hexane to afford the title compound (6.81 g, 21 mmol). MS m/z 266 (M+1-isobutylene).
Reaction SMILES: [CH3:1][C:2]1([C@H:5]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]4[O:21][C:22](S(C)=O)=[N:23][N:24]=4)[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[CH3:6])[CH2:4][CH2:3]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CN(C=O)C>[CH3:1][C:2]1([C@H:5]([NH:7][C:8]2[C:9]3[N:10]([CH:17]=[C:18]([C:20]4[O:21][C:22]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[N:23][N:24]=4)[CH:19]=3)[N:11]=[CH:12][C:13]=2[C:14]([NH2:16])=[O:15])[CH3:6])[CH2:4][CH2:3]1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3nnc(S(C)=O)o3)cc12)C1(C)CC1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3nnc(N4CCN(C)CC4)o3)cc12)C1(C)CC1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 15.2 %

Procedure:
To a solution of 4-((R)-1-(1-methylcyclopropyl)ethylamino)-6-(5-(methylsulfinyl)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (16.00 mg, 0.041 mmol) in NMP (0.5 mL, 0.082M) was added 1-methylpiperazine (20.63 mg, 0.206 mmol) followed with DIPEA (0.029 mL, 0.165 mmol). The solution was stirred at 130° C. for 30 min in a Biotage Initiator microwave. The reaction mixture was dissolved in 1.5 mL of DMF and directly purified on Reverse Phase HPLC to yield desired product (2.65 mg, 15% yield). 1H NMR (599 MHz), δ 8.33 (s, 1H), 8.27 (s, 1H), 7.20 (s, 1H), 3.96-3.89 (m, 1H), 3.63-3.53 (m, 4H), 2.72-2.23 (m, 7H), 1.37 (d, J=6.4 Hz, 3H), 1.23 (s, 3H), 0.68-0.58 (m, 1H), 0.55-0.49 (m, 1H), 0.39 (m, 2H). MS (ES+) m/z: 424.90 (M+H); HPLC: 97%, retention time: 1.70 min (analytical HPLC Method B).
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][C@H:63]([C:68](O)=[O:69])[C@H:64]([CH2:66][CH3:67])[CH3:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:68]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:69])[C@H:64]([CH2:66][CH3:67])[CH3:65]
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)C(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.1 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (250 mg, 0.65 mmol), DCC (160 mg, 0.78 mmol) and DMAP (8 mg, 0.06 mmol) in ethyl acetate (10 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-isoleucine (228 mg, 0.65 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (275 mg) was dissolved in dry THF (8 mL) and cooled to 0° C. Dimethylamine (8 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 110 mg (31%) of the title compound as an off white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH3:21])=C([CH:18]=1)C(O)=O)(=[O:9])[CH3:8]>ClCCl.CN(C)C=O>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH3:21])=[C:1]([CH:18]=1)[C:2]([Cl:4])=[O:3])(=[O:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)=O)cc1C(=O)Cl

Procedure:
Oxalyl chloride (3.66 g, 0.029 mol) was added dropwise to a stirred solution of 5-acetyl-2-ethoxybenzoic acid (3.0 g, 0.014 mol) in dichloromethane (15 ml) and dimethylformamide (0.1 ml) After 3 hours at room temperature, the solvent was removed by evaporation under vacuum and the residue axeotroped with hexane (3×30 ml) to give the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6]S[CH2:4][CH2:3]1.O.O[O:33][S:34]([O-:36])=O.[K+]>C(#N)C.CO>[CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][S:34](=[O:36])(=[O:33])[CH2:4][CH2:3]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCSCC4)c3n2)cc(OC)c1OC
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCS(=O)(=O)CC4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
A suspension of (4-methyl-tetrahydro-thiopyran-4-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (9 mg, 0.02 mmol) in acetonitrile (0.4 ml), MeOH (0.4 ml), and water (0.2 ml) was treated with Oxone (26 mg, 0.04 mmol) and stirred overnight at room temperature. The reaction mixture was partitioned between EtOAc/water. The organic layers were collected, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography using 30% EtOAc in hexanes as eluant to provide 6 mg (62%) of (4-methyl-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as an off white solid. M+H=460.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[CH:22][C:23]([NH2:24])=[C:17]2[N:16]=1.C1N=CN([C:31]([N:33]2[CH:37]=N[CH:35]=[CH:34]2)=[O:32])C=1.N1CC[C@H:40]([OH:43])C1>C(Cl)Cl>[F:25][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[CH:22][C:23]([NH:24][C:31]([N:33]3[CH2:34][CH2:35][C@@H:40]([OH:43])[CH2:37]3)=[O:32])=[C:17]2[N:16]=1
Reactant: O[C@H]1CCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)F)nc12
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)F)nc12)N1CC[C@@H](O)C1
Reaction time: 2 h
Yield: 69 %

Procedure:
To a DCM (0.6 mL) solution of (R)-5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (10 mg, 0.028 mmol, prepared as described in the following paragraph), was added CDI (9 mg, 0.056 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (8 mg, 0.084 mmol) was added in one portion. The reaction was stirred overnight, then concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a solid (9 mg, 69%). MS (apci) m/z=461.2 (M+H).
Reaction SMILES: C(C1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][CH:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:14][C:4]=1[C:5]=23)#N.[CH3:22][Mg]Br.[NH4+].[Cl-].C([O:29][CH2:30][CH3:31])C>C1C=CC=CC=1>[C:30]([C:31]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][CH:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:14][C:4]=1[C:5]=23)(=[O:29])[CH3:22]
Reactant: CCOCC
Reactant: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(CN3)C1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: CCCN(CCC)C1Cc2c(C(C)=O)ccc3c2C(CN3)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.5 g (1.8 mmol) of (±)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 75 mL of benzene was treated with 5 mL of 2.0M methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 2 days. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of a saturated NH4Cl solution. The benzene layer was separated and washed once with a saturated NaCl solution. The organic solution was evaporated to an oil. The oil was dissolved in 25 mL of 5N HCl and the solution was stirred at room temperature for 30 min. The acidic solution was made alkaline with the addition of excess concentrated NH4OH solution. The basic mixture was extracted twice with CH2Cl2. The combined organic solution was washed once with a saturated NaCl solution and dried over MgSO4. The CH2Cl2 solution was evaporated to yield 0.5 g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 0.4 g (75%) of product as an oil which upon standing solidified.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Cl:14])[CH:8]=1.[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1.Cl>CCCCCC.O1CCCC1>[Cl:14][C:9]1[CH:8]=[C:7]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH3:23])([CH3:15])[CH2:17][CH2:18]2)[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: CC1(C)CCC(=O)CC1
Reactant: Oc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(O)(c2ccc(O)c(Cl)c2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
100 ml of a 1.6 M solution of n-butyllithium in hexane are added at −78° C. to 15.1 g of 4-bromo-2-chlorophenol in 150 ml of tetrahydrofuran, and the reaction mixture is stirred at −78° C. for 1 hour. 10.1 g of 4,4-dimethylcyclohexanone (compound 3.1) are added and the reaction mixture is stirred at −78° C. for a further 30 minutes and then at room temperature for 12 hours. The reaction mixture is hydrolysed with 1 N hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The solid obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate mixture varying from 98/2 to 90/10 (v/v). 11.8 g of solid are obtained.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH:4]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH3:14])=[CH:7][CH:6]=1.[OH-].[K+].C(O)C.Cl>O>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([O:23][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH3:14])=[CH:7][CH:6]=2)[C:3]([OH:34])=[O:2])=[CH:25][CH:26]=1)([CH3:31])([CH3:32])[CH3:33]
Reactant: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCC(C)Oc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(COc1ccc(C(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1)Oc1ccc(Cl)cc1
Yield: 91.7 %

Procedure:
A mixture of 6.4 g of methyl(p-tert.-butylphenoxy){p-[2-(p-chlorophenoxy)propoxy]phenyl}acetate, 4 g of potassium hydroxide, 35 ml of ethanol and 35 ml of water is refluxed for 4 hours. The mixture is acidified with concentrated HCl, cooled, diluted with water and extracted with dichloromethane. The extract is washed with saturated NaCl solution, dried (MgSO4) and the solvent removed under reduced pressure to give 5.7 g of gum. Crystallization from hexane-ether gives 4.5 g of white crystals. Recrystallization from chloroform-hexane gives the product as white crystals, mp 135°-138° C.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:26][CH3:27])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC(C)=O.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:26][CH3:27])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(c3ccc(O)cc3)=C1c1ccc(OC)cc1C2
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCC12CCC(=O)C(c3ccc(OCCN4CCCCC4)cc3)=C1c1ccc(OC)cc1C2
Temperature: 60 °C
Yield: 96.3 %

Procedure:
A mixture of crude 9a-butyl-4-(4-hydroxyphenyl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (787 mg, approx. 2 mmol), cesium carbonate (1.564 g, 4.8 mmol), and 1-(2-chloroethyl)-piperidine monohydrochloride (442 mg, 2.4 mmol) in acetone (5 mL) was stirred and heated in an oil bath at 60° C. for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc and filtered to remove salts. The filtrate was washed with water and brine, dried over MgSO4, filtered, and evaporated under vacuum to a yellow gum (0.95 g). The crude product was purified by chromatography on EM silica gel 60 (230-400 mesh, 50 mL dry) using 2% MeOH+1% Et3N in EtOAc as eluting solvent. The product containing fractions were evaporated under vacuum and the residue stripped with toluene to provide 9a-butyl-7-methoxy-4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one (912 mg, 96% weight pure) as a pale yellow gum.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.[SH:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>C(O)(C)C>[ClH:1].[CH3:9][C:8]1[C:3]([CH2:2][S:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Reactant: Sc1ccncc1
Solvent: CC(C)O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CSc1ccncc1
Product: Cl
Yield: 87.1 %

Procedure:
0.53 g (1.3 mmol) of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitro-imidazo[1,2-b]pyridazine and 0.15 g (1.3 mmol) of 4-mercaptopyridine in 30 ml of isopropanol are reacted as described in Example 2. 0.59 g (87%) of the title compound of m.p. 174-178° C. is isolated.