Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[OH-].[Na+].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9]>O>[C:4]([CH2:3][NH:2][S:17]([C:14]1[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1)(=[O:18])=[O:19])#[N:5]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a stirred solution of 27.8 g (0.3 moles) aminoacetonitrile hydrochloride in 200 ml water, 24 g (0.3 moles) sodium hydroxide (50% aqueous) were added. The resulting mixture was cooled to about 20° C. with an ice bath. The ice bath was removed; then 22.2 g (0.1 mole) 4-nitrobenzenesulfonyl chloride were added. The reaction mixture was stirred 18 hours at ambient temperature. The solids were filtered. The resulting wet cake was crystallized from 50 ml ethanol. The solids were dried in vacuo to give 17.5 g of the above-identified product as a dark-yellow solid, melting point 115°-120° C.
Reaction SMILES: [Br:1]Br.[OH-].[Na+].C([C:8]1[C:9]([Br:20])=[N:10][S:11][C:12]=1[NH:13][C:14]([C@@H:16]1[CH2:18][C@H:17]1[CH3:19])=[O:15])(=O)C.S(=O)(O)[O-].[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[Br:20][C:9]1[C:8]([Br:1])=[C:12]([NH:13][C:14]([C@@H:16]2[CH2:18][C@H:17]2[CH3:19])=[O:15])[S:11][N:10]=1
Reactant: BrBr
Reactant: CC(=O)c1c(Br)nsc1NC(=O)[C@@H]1C[C@H]1C
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Add bromine (114; mL, 2.2; mol) dropwise over 45; min to a cooled aqueous solution of sodium hydroxide (4.6M, 3.84; L, 17.8; mol) at −10° C. and stir for 0.5; hour to give a yellow solution. Add this solution dropwise to a pre-cooled −5° C. solution of (1R,2R)-2-methyl-cyclopropanecarboxylic acid (4-acetyl-3-bromo-isothiazol-5-yl)-amide (150; g, 495; mmol) in 1,4-dioxane (2; L) and stir 45; min at 5-10° C. Maintain cooling at 10° C. whilst adding a 40% (wt/wt) aqueous solution of sodium bisulfite (47.5; mL) over 5 min, stir 5; min and add slowly 12; M hydrochloric acid (approximately 500; mL) over 15 min until acidic (pH=2). Dilute with ethyl acetate (2; L) and separate the layers. Extract the aqueous layer twice with ethyl acetate (1; L). Combine the organic phases, dry over magnesium sulfate, filter and concentrate. Dissolve the residue in dichloromethane (600 mL), dilute with n-hexane (3; L), and cool to 5° C. overnight. Filter and wash the recovered solid with four portions of n-hexane (125; mL) to give the title compound as a white solid (92.6; g, 55%). If desired a second crop of the title compound (50.97; g, 30%) can be harvested from the mother liquors. MS (m/z): 339, 341, 343; (M+1).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH2:11]([O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)[CH2:12][CH3:13]>>[F:10][C:4]1[CH:3]=[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH2:11][CH2:12][CH3:13])[CH:20]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CCCOc1cccc(B(O)O)c1
Product: CCCOc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 47.5 %

Procedure:
The title compound (0.3 g) was prepared from 4-Bromo-2,6-difluoro aniline (0.5 g, 2.4 mmol) and 3-propoxyphenylboronic acid (0.337 g, 3.1 mmol) as a red liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.30-7.24 (m, 3H), 7.18-7.10 (m, 2H), 6.86-6.80 (m, 1H), 5.31 (s, 2H), 3.97 (t, J 6.5, 2H), 1.75-1.65 (m, 2H), 0.98 (t, J 7.4, 3H).
Reaction SMILES: [CH2:1]1[CH2:7][O:6][CH2:5][CH2:4][NH:3][CH2:2]1.Cl.Cl[C:10]1[N:14]([CH3:15])[N:13]=[C:12]([CH3:16])[C:11]=1[CH:17]=[O:18].CN(P(N(C)C)(N(C)C)=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:15][N:14]1[C:10]([N:3]2[CH2:2][CH2:1][CH2:7][O:6][CH2:5][CH2:4]2)=[C:11]([CH:17]=[O:18])[C:12]([CH3:16])=[N:13]1
Reactant: C1CNCCOC1
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Cc1nn(C)c(N2CCCOCC2)c1C=O
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Homomorpholine hydrochloride (28.2 g, 200 mol) was added to a mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (21.68 g, 0.1368 mol, Example B(45), Step 2), HMPA (30 mL), water (50 mL), and potassium carbonate (59 g, 0.6 mol) at constant stirring and room temperature. The reaction mixture was heated at 80° C. for 50 h, diluted with water, and extracted with ethyl acetate (3×100 mL). The organic extracts were washed with water to weakly alkaline pH and dried with sodium sulfate. The product was purified chromatographically using hexane/ethyl acetate mixture as eluent to afford the title product (18.7 g, 61%). Satisfactory C,H,N-analysis was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[C:4](OS(C(F)(F)F)(=O)=O)=[CH:3]1.[Cl-].[Li+].[C:26]1([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.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].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=CC2(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(c1ccccc1)=CC2(C)C
Yield: 83.1 %

Procedure:
Methyl 1,1-dimethyl-3-(trifluoromethanesulfonyloxy)-1H-indene-5-carboxylate (580 mg, 1.86 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd2 dba3, 17 mg, 0.02 mmol), triphenylarsine (46 mg, 0.15 mmol), lithium chloride (240 mg, 5.59 mmol) and phenyltributyltin (680 mg, 1.86 mmol) in 5 mL of 2-methyl pyrrolidinone were stirred at 55° C. for 1.5 days. The mixture was diluted with water (30 mL), and extracted with ethyl ether (30 mL×3). The combined extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (EtOAc:hexane=1:20 to 1:5) to give 0.43 g (83% yield) of the title compound as a white solid; 1H-NMR (CDCl3) δ 1.41 (s, 6H), 3.91 (s, 3H), 6.48 (s, 1H), 7.39-7.62 (m, 6H), 7.99 (d, J=6.8 Hz, 1H), 8.14 (s, 1H); MS m/e 279 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][NH:12][C:4]=2[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.S(C1C=CC(C)=CC=1)(O)(=O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[C:11]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[NH:12][C:4]=2[CH:3]=1
Reactant: N#Cc1nc(Cl)cc2[nH]cnc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1nc(Cl)cc2[nH]c(C3CCCCO3)nc12
Temperature: 60 °C

Procedure:
6-Chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1 g) was dissolved in ethyl acetate (20 ml). To above solution was added 3,4-dihydro-2H-pyran (1 ml) and tosylic acid hydrate (50 mg). The mixture was heated at 60° C. for 10 hours, than washed with sodium bicarbonate (5%, 10 mL). The organic layer dried over sodium sulphate, solvent removed to give the title compound. 1H NMR (DMSO) □ 8.92 (s, 1H), 8.30 s, 1H), 5.81 (d, 1H), 4.00 (m, 1H), 3.78 (m, 1H), 2.18 (m, 1H), 2.07 (m, 1H), 1.67 (m, 4H).
Reaction SMILES: CN1C(=O)N(C)[CH2:5][CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[CH3:18][C:19]1([CH3:25])[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].IC(C)C>C1COCC1>[CH:4]([CH:21]1[C:20](=[O:24])[C:19]([CH3:25])([CH3:18])[CH2:23][CH2:22]1)([CH3:5])[CH3:3]
Reactant: CN1CCCN(C)C1=O
Reactant: CC1(C)CCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)I
Product: CC(C)C1CCC(C)(C)C1=O
Temperature: -20 °C
Yield: 78 %

Procedure:
A solution of DMPU (9.86 g, 77.0 mmol) in THF (100 ml) was added at −70° C. within 5 min to a stirred solution of lithium diisopropylamide (2 M in THF, 38.5 ml, 77.0 mmol). After 10 min stirring at −70° C. a solution of 2,2-dimethylcyclopentanone (7.80 g, 70.0 mmol) in THF (50 ml) was added over a period of 30 min. The reaction mixture was warmed up to −20° C. and treated dropwise with 2-iodopropane (18.7 g, 105 mmol). The reaction mixture was warmed up slowly to room temp., stirred over night at room temp., and quenched with satd. aq. NH4Cl solution (300 ml) and extracted with Et2O (3×300 ml). The combined organic extracts were dried (Na2SO4), and concentrated under the reduced pressure. The resulting residue was purified by silica gel FC (pentane/Et2O, 98:2, Rf 0.25) to furnish 5-isopropyl-2,2-dimethylcyclopentanone (8.42 g, 78%). IR (neat): v=1731 (s, vC═O), 1462 [m, δas(CH3)], 1367 [m, δs(CH3)] cm−1. 1H NMR (CDCl3): δ=0.80/0.99 (2d, J=7.0 Hz, 6 H, 1′-Me2), 0.94/1.06 (2s, 6 H, 2-Me2), 1.62-1.69 (m, 2 H, 3-Hax, 4-Hax), 1.76-1.81 (m, 1 H, 5-H), 1.89-1.94 (m, 1 H, 1′-H), 2.11-2.17 (m, 2 H, 3-Heq, 4-Heq) ppm. 13C NMR (CDCl3): δ=18.4/21.1 (2q, 1′-Me2), 20.6 (t, C-4), 23.1/24.7 (2q, 2-Me2), 27.4 (d, C-1′), 36.4 (t, C-3), 45.3 (s, C-2), 224.1 (s, C-1) ppm. MS (EI): m/z (%)=154 (15) [M]+, 139 (7) [M-CH3]+, 112 (36) [M-C3H6]+, 97 (18) [M-C4H9]+, 56 (100) [C3H4O]+.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]([OH:25])=[O:24])[CH:19]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O.C(OCC)C>[CH2:1]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:23]([OH:25])=[O:24])[CH:19]=2)[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCBr
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Yield: 68.8 %

Procedure:
After a solution of decylmonobromide (7 g), 2-hydroxy-6-carboxynaphthalene (2 g) and anhydrous potassium carbonate (4 g) in dimethylformamide (100 ml) was stirred at 130° C. for two hours, it was poured in water. Dilute aqueous hydrochloric acid solution was added thereto until the solution was neutral. To the solution was added diethylether in order to effect extraction. The extracted layer was distilled to remove the solvent. The residue was added to a solution of sodium hydroxide (3.3 g) in water (10 ml) and ethanol (50 ml). The mixture was refluxed for about one day. Thereto was added dilute aqueous hydrochloric acid solution until the solution was neutral. The solution was distilled to remove the solvent and concentrated. Solid precipitate was collected and recrystallized from water-ethanol mixture to obtain the titled compound (2.4 g).
Reaction SMILES: C([O:4][C:5]1[CH:41]=[CH:40][C:8]([C:9]([N:11]([CH:37]([CH3:39])[CH3:38])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[O:10])=[CH:7][C:6]=1[F:42])(=O)C.O.C(=O)([O-])[O-].[K+].[K+]>CO>[F:42][C:6]1[CH:7]=[C:8]([CH:40]=[CH:41][C:5]=1[OH:4])[C:9]([N:11]([CH:37]([CH3:39])[CH3:38])[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[CH:20]1[CH2:29][CH2:28][C:27]2[CH:26]=[C:25]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[CH:24]=[CH:23][C:22]=2[CH2:21]1)=[O:10]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(OC(C)=O)c(F)c2)C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a solution of pivalic acid 6-{2-[(4-acetoxy-3-fluorobenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (1.1 g) in methanol (18 ml) were sequentially added water (2 ml) and potassium carbonate (321 mg), and the solution was stirred for 1 hour at room temperature. Water was added thereto, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (637 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH:14]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2>CCO.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3=CCC4(CC3)OCCO4)ccc(N)c2C1=O
Agent: [Pd]
Solvent: CCO
Product: CN1Cc2c(C3CCC4(CC3)OCCO4)ccc(N)c2C1=O
Temperature: 25 °C

Procedure:
To a solution of 7-amino-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.7 g, 5.7 mmol) in EtOH (100 mL) was added palladium 10% wt on activated carbon (0.60 g, 0.57 mmol). The reaction mixture was evacuated and purged with hydrogen (3×) and stirred over night at rt. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.04 (d, J=8.34 Hz, 1H), 6.52 (d, J=8.08 Hz, 1H), 5.85 (s, 2H), 4.34 (s, 2H), 3.86-3.89 (m, 4H), 2.98 (s, 3H), 2.42-2.48 (m, 1H), 1.52-1.80 (m, 8H); MS (ES+): m/z: 303.1516 [MH+]. HPLC: tR=1.21 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]=[N:10][NH:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20].[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[K+].[CH2:30](Br)[CH:31]=[CH2:32].ClOC(C)(C)C>ClCCl>[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[CH3:21][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH+:9]1[CH:30]=[C:31]([CH3:32])[N:11]([C:12]2[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=2[CH3:18])[NH:10]1
Reactant: Cc1cc(C)c(N=NNc2c(C)cc(C)cc2C)c(C)c1
Reactant: C=CCBr
Agent: CC(C)(C)OCl
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: CC1=C[NH+](c2c(C)cc(C)cc2C)NN1c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of triazene 8b (1.70 g, 6 mmol) and anhydrous potassium hexafluorophosphate (1.10 g, 6 mmol) and allyl bromide 12 (1.04 mL, 12 mmol) in dry dichloromethane (20 mL) in the dark at −78° C. is added tert-butyl hypochlorite (1.0 mL, 9 mmol), upon which the mixture instantly darkens. The mixture is stirred overnight as it is slowly allowed to warm to room temperature. The contents are then filtered, and the solid residue is washed with dichloromethane. The filtrate is collected, and volatiles are evaporated under reduced pressure. Diethyl ether is then added, and the mixture is vigorously triturated for ca. 1 hour, with occasional scratching of the glass surfaces to ensure efficient mixing. Filtration and washing with copious quantities of diethyl ether affords the crude dihydrotriazolium salt 13 as a beige solid (3.02 g, ˜92%), which is contaminated by ca. 30% of the aromatized triazolium salt 10bi. 1H-NMR (CDCl3, 300 MHz): δ=7.07 (s, 2H), 7.06 (s, 2H), 6.03 (t, J=12.7 Hz), 5.20 (t, J=14.9 Hz, 1H), 4.85 (t, J=12.5 Hz, 1H), 3.91 (dd, J=12.8, 2.5 Hz, 1H), 3.68 (d, J=12.6 Hz, 1H), 2.45-2.36 (m, 18H). 13C-NMR (CDCl3, 75 MHz): δ=142.8, 142.6, 135.9, 134.8, 134.3, 134.1, 132.2, 131.2, 130.5, 128.8, 68.3, 59.1, 30.1, 21.3, 21.2, 19.0, 18.7, 17.8. Calcd. for C21H27BrN3 [M+]: 400.1383. found 400.1400.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([OH:10])[CH2:5]1)[CH:2]=[CH2:3].[Si:11](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CN=C1.CN(C1C=CC=CN=1)C>CN(C)C=O>[CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1CCC[C@H](O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC[C@@H]1CCC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6.8 g of cis-3-allylcyclohexanol and 15 ml of tert-butyldiphenylsilyl chloride, 5 g of imidazole and 200 mg of dimethylaminopyridine are dissolved in 100 ml of dimethylformamide and stirred at room temperature for 12 hours. 400 ml of methyl tert-buthyl ether are added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 20.5 g of (cis-3-allylcyclohexyloxy)tert-butyl-diphenylsilane as an oil. C25H34OSi (378.64), MS(ESI): 379 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.93.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][CH3:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][CH3:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1)=[O:1]
Reactant: CCCc1c[nH]c2cc(CO)ccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCc1c[nH]c2cc(C=O)ccc12
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Manganese dioxide (5.05 g) was added in one portion to a sirred solution of 6-hydroxymethyl-3-propylindole (1.1 g) in methylene chloride (50 ml) under an atmosphere of nitrogen. The mixture was vigorously stirred for 60 min, filtered through a pad of diatomaceous earth, washing the pad several times with methylene chloride (5×30 ml). The filtrate was evaporated to give 6-formyl-3-propylindole (1.03 g, 95%) as a pale yellow oil; partial NMR (250 MHz, DMSO-d6): 0.93 (t, 3H, CH2CH3), 1.65(m, 2H, CH2CH3), 2.65(t, 2H, CH2CH2CH3), 9.98(s, 1H, CHO).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([C@H:21]([CH3:25])[C:22]([OH:24])=[O:23])=[CH:14]2.Br[CH2:27][CH2:28][CH2:29][CH2:30][O:31][N+:32]([O-:34])=[O:33]>CN(C=O)C>[Br:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([C@H:21]([CH3:25])[C:22]([O:24][CH2:27][CH2:28][CH2:29][CH2:30][O:31][N+:32]([O-:34])=[O:33])=[O:23])=[CH:14]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1Br
Reactant: O=[N+]([O-])OCCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2cc([C@H](C)C(=O)OCCCCO[N+](=O)[O-])ccc2c1Br

Procedure:
A mixture of triethylamine (5.25 g, 52 mmol), of 2-(S)-(5-bromo-6-methoxy-2-naphthyl)propanoic acid (Bromo-Naproxen) (13.3 g, 43 mmol); e.e.99%) and of 4-bromobutylnitrate (43 mmol) in DMF (120 ml) was stirred under nitrogen for 2 days at 25° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]2=[O:21].[CH2:22]([NH:25][C:26]1[CH:47]=[CH:46][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:28][CH:27]=1)[CH:23]=[CH2:24]>>[O:21]=[C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][N:25]([CH2:22][CH:23]=[CH2:24])[C:26]3[CH:47]=[CH:46][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:28][CH:27]=3)[CH:4]=2)[N:9]=[CH:8][N:7]1[CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)OCn1cnc2ccc(CBr)cc2c1=O
Reactant: C=CCNc1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1
Product: C=CCN(Cc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)cc1

Procedure:
This was synthesised by reaction of the compound (4) and diethyl N-(4-(prop-2-enylamino)benzoyl)-L-glutamate Lit. T. R. Jones, A. H. Jackman, S. J. Brown, M. Jones and K. R. Harrap: Europ. J. Cancer, 17 11 (1981). For characterisation a portion was dried at 70° C./P2 05 /1 mm/10 hours to give a brittle glass.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:19])[CH2:14][CH:13]3[CH2:26][OH:27])[CH2:9]2)C=CC=CC=1.Cl>CCO>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH:13]2[CH2:26][OH:27])[CH2:9]1
Reactant: O=C(c1ccccc1)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C(CO)C1
Agent: Cl
Solvent: CCO
Product: O=C(c1ccccc1)N1CCN(C2CNC2)C(CO)C1
Reaction time: 14 h
Yield: 152.4 %

Procedure:
Compound 37e (450 mg, 1.02 mmol) was added to a 500 mL-Parr hydrogenation bottle and dissolved in absolute EtOH (6 mL). A 12N conc. HCl solution (95 μL, 1.14 mmol) was added and the bottle was purged with N2. 10% Pd/C (264 mg) was added and the mixture was shaken under 60 psi of H2 for 14 h. An additional amount of 10% Pd/C (430 mg) was added and the mixture was returned to 60 psi of H2 and shaken 5 h more. The mixture was filtered through a pad of diatomaceous earth, and the solids were rinsed thoroughly with MeOH. The Titrate was concentrated to dryness under reduced pressure to afford crude compound 37f as a sticky oil (428 mg) which was used in the following step without further purification. LC/MS m/z (M+H+) 276.3.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[C:8]1[C:9]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH3:23])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31](=[N:33]O)[NH2:32])[CH:30]=1.CCN(C(C)C)C(C)C>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31]2[N:32]=[C:13]([C:12]3[CH:16]=[CH:8][C:9]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]4[CH3:23])=[N:10][CH:11]=3)[O:15][N:33]=2)[CH:30]=1
Reactant: Cc1cc(C(=O)O)cnc1N1CCCCC1C
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)nc2)n1

Procedure:
Oxalyl chloride (138 μL; 1.63 mmol; 3 eq.), Intermediate 39 (120 mg; 0.54 mmol; 1 eq.), Intermediate 23 (100 mg; 0.54 mmol, 1 eq.) and DIEA (282 μL; 1.54 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 50/50) afforded the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=[O:14])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17]Br>C(O)(=O)C>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[CH2:12][C:13]([CH2:15][Br:17])=[O:14])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)c1nnc(NC(=O)CC(=O)CBr)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A reaction flask was charged with 14.3 g (0.059 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)acetoacetamide dissolved in 230 ml of acetic acid. With efficient stirring, there was added dropwise 9.4 g (0.059 mole) of bromine dissolved in 55 ml of acetic acid while controlling the temperature at 20°-25°. The reaction solution was allowed to stir overnight at ambient temperature. On the following morning a sample of the precipitated solids was withdrawn. By N.M.R. analysis, the material was determined to be the corresponding 2-bromoacetoacetamide, m.p. 128°-30°. The reaction mixture was heated at 75°-80° for twelve hours. The solution was cooled at 20° and the precipitated solid was collected on a vacuum filter. After washing the filter cake with water, the material was stirred with aqueous sodium bicarbonate. The product was isolated and dried. There was obtained 8.8 g (46.6%) of authentic N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, m.p. 144°-46°. N.M.R. (CDCl3) ∂ 1.4 [C(CH3)3 ], 4.4 (CH2), 6.3 (CH, enol).