Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:15]([OH:17])=O)=[CH:5][N:6]=[C:7]2[O:12][CH2:13][CH3:14].CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1.O>C(O)(=O)C>[CH2:13]([O:12][C:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]3[N:1]4[C:20]([C:15](=[O:17])[C:4]([C:3]=23)=[CH:5][N:6]=1)=[CH:24][CH:23]=[CH:22]4)[CH3:14]
Reactant: CCOc1ncc(C(=O)O)c2c(N)cccc12
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ncc2c(=O)c3cccn3c3cccc1c23
Temperature: 20 °C

Procedure:
A solution of 5-amino-4-carboxy-1-ethoxyisoquinoline (50.8 g) and 2,5-dimethoxytetrahydrofuran (32 cc) in acetic acid (250 cc) is kept at a temperature between 90° and 95° C. for 35 minutes, whilst stirring. The solution is cooled to about 20° C. and then poured into water (1250 cc). The yellow crystals which precipitate are filtered off and washed with water (5 × 50 cc). After drying under reduced pressure (1 mm Hg) at 20° C., crude 4-ethoxy-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (52.7 g) is obtained. After recrystallisation from ethanol, the pure product melts at 188° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]1([Si:22]2([CH2:35][CH2:36][CH3:37])[CH2:27][CH2:26][CH:25]([CH:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([Si:22]2([CH2:35][CH2:36][CH3:37])[CH2:27][CH2:26][CH:25]([CH:28]3[CH2:33][CH2:32][CH:31]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Reactant: Fc1ccc(-c2ccc([Mg]Br)cc2)cc1
Product: CCC[Si]1(c2ccccc2)CCC(C2CCC(c3ccccc3-c3ccc(F)cc3)CC2)CC1

Procedure:
In the same manner as in Example 6, 25 g of 4-(4-fluorophenyl)phenylmagnesium bromide was reacted with 31.5 g of 4-(4-phenyl-4-n-propyl-4-silacyclohexyl)cyclohexanone and the resultant alcohol was dehydrated, followed by catalytic reduction to obtain 4-(4-phenyl-4-n-propyl-4-silacyclohexyl)cyclohexyl-4'-fluorobiphenyl. The biphenyl product was then reacted with iodine monochloride, followed by reduction with lithium aluminohydride to obtain 14.4 g (yield: 36%) of the intended product. The product was subjected to NMR and IR analyses with the results shown below.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([N:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][CH3:18])[N:3]=1
Reactant: CCNc1cccnc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CCN(c1cccnc1)c1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(3-pyridyl)-2-ethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-(ethylamino)pyridine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[NH2:17][C:18]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][NH:20][N:19]=1>C(#N)C>[NH2:17][C:18]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:20]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[N:19]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1N
Temperature: 60 °C
Yield: 53.5 %

Procedure:
According to Scheme 15 Step 1: 1-(Chloromethyl)-4-methoxybenzene (12.9 mmol, 2.02 g) followed by K2CO3 (25.8 mmol, 3.56 g) were added to a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (12.9 mmol, 2.00 g) in acetonitrile (10 mL) and then the reaction mixture was heated at 60° C. for 3 hours. After evaporation of the solvent, a saturated solution of Na2CO3 was added and the aqueous phase was extracted with AcOEt. The organic phase was dried over Na2SO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (100:0 to 20:80) as eluent to afford ethyl 3-amino-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (6.90 mmol, 1.90 g, 53%) as a white powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:22]([O-])([OH:24])=[O:23].O>C(O)(=O)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][C:16]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCCOC)c(OCCOC)c1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of ethyl 3,4-bis(2-methoxyethoxy)benzoate (23.23 g, 77.87 mmol) in acetic acid (80 mL) was added dropwise to concentrated nitric acid (21 mL) cooled with an ice bath at such a rate as to keep the internal temperature below 5° C. After 30 min, the solution was allowed to warm to room temperature and stirred for 48 h. The solution was poured onto iced water (400 mL) and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed cautiously with saturated aqueous sodium bicarbonate (3×200 mL) and brine (2×100 mL). The organic phase was dried (Na2SO4) and concentrated to give the title compound as a solid (24.82 g, 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](=[O:19])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)Cl)CC1)OCc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: O=C(N[C@H]1CC[C@H](C(=O)c2ccccc2)CC1)OCc1ccccc1

Procedure:
Under argon atmosphere, a mixture comprising 1.0 g trans-4-(benzyloxycarbonylamino)cyclohexanecarbonyl chloride, 1.92 g of tributylphenyltin, 61 mg of dichlorobis-(triphenylphosphine)palladium and 10 mL of dioxane was stirred at 110° C. for 12 hours. After cooling, the reaction mixture was concentrated by a centrifugal concentrator, and then, the residue was dissolved in tetrahydrofuran and evaporated to dryness with 5 g of silica gel. The resulting residue was purified by silica gel flash chromatography (solvent: ethyl acetate-hexane (1:2) to (1:1) to obtain 883 mg of N-benzyloxycarbonyl-trans-4-benzoylcylohexylamine.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.Cl>O.C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:16]([OH:17])[OH:15])=[CH:3][C:4]=1[O:10][CH3:11])#[N:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)ccc1C#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(B(O)O)ccc1C#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A 3-necked 1 L round-bottomed flask was equipped with an overhead stirrer, and a nitrogen line. The flask was charged with 45.56 g (215 mmol) of 4-bromo-2-methoxybenzonitrile, 64 mL (277 mmol) of tri-isopropylborate and 500 mL of THF. The solution was cooled to −78° C. in a dry-ice/acetone bath. n-Butyllithium (2.5M, 110 mL, 275 mmol) was added dropwise via addition funnel. The mixture was stirred for 30 minutes and 2N HCl was added. The mixture was stirred for an hour and poured into water. The mixture was extracted with Et2O. The organic solution was backextracted with 1N NaOH. The aqueous layer was washed with Et2O and acidified with conc. HCl. The mixture was extracted with Et2O. The organic extract was dried (MgSO4) and evaporated in vacuo to afford 20.77 g (55%) of the product as a white solid. 1H NMR (500 MHz, d6-DMSO) δ 7.68 (d, 1H), 7.59 (s, 1H), 7.47 (d, 1H), 3.95 (s, 3H).
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.CC1C=CN=C(N)C=1C>CN(C)C=O.C(OC)(C)(C)C>[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: Cc1ccnc(N)c1C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
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 are, together with 15 ml of tert-butyl-diphenylsilyl chloride, 5 g of imidazole and 200 mg of dimethyl-aminopyridine, dissolved in 100 ml of dimethylformamide, and the mixture is stirred at room temperature for 12 h. 400 ml of methyl tert-butyl ether are added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 20.5 g of (cis-3-allylcyclohexyloxy)-tert-butyl-diphenyl-silane as an oil. C25H340Si (378.64), MS(ESI): 379 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.93.
Reaction SMILES: [NH2:1][N:2]1[C@H:6]([CH2:7][O:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][C:3]1=O.[CH:29]([NH2:31])=O>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:9]([O:8][CH2:7][C@H:6]1[N:2]2[N:1]=[CH:29][N:31]=[C:3]2[CH2:4][CH2:5]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC=O
Reactant: NN1C(=O)CC[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(C(OC[C@@H]2CCc3ncnn32)(c2ccccc2)c2ccccc2)cc1
Temperature: 160 °C
Yield: 48.8 %

Procedure:
To a stirred solution of 0.540 g (1.45 mmol) of (5S)-1-amino-5-[(trityloxy)methyl]pyrrolidin-2-one from step A above in 5 mL of anhydrous DMF was added 0.327 g (7.25 mmol) of formamide followed by 0.050 g (0.36 mmol) of zinc(II) chloride. The resulting mixture was heated to 160° C. for 48 h, cooled to ambient temperature and diluted with 25 mL of ethyl acetate. The solution was washed sequentially with an aqueous sodium bicarbonate solution, water and then brine and the organic layer dried over magnesium sulfate. The mixture was then filtered, evaporated to dryness in vacuo and purified by silica gel chromatography eluting with a 0-100% ethyl acetatae in hexanes gradient to afford the title compound (0.27 g, 49%). LC-MS: m/z (ES) 382 (MH)+.
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[CH3:38][NH:39][CH3:40]>CN(C=O)C>[CH3:38][N:39]([CH3:40])[C:32]1[S:33][C:29]([C:2]2([OH:1])[CH2:3][CH2:4][CH:5]([N:8]3[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=4)=[O:14])[CH2:11]3)[CH2:6][CH2:7]2)=[CH:30][N:31]=1
Reactant: CNC
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Solvent: CN(C)C=O
Product: CN(C)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
A solution of N-({1-[4-Hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a, 100 mg, 0.18 mmol) and dimethylamine (Aldrich, 40% in water, 2 mL) in DMF (1 mL) was heated to 120° C. in a sealed tube overnight. The crude solution was directly purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:24])=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc([N+](=O)[O-])cc1
Product: CCCCCCCCCCCCNC(=O)c1ccc(N)cc1
Yield: 98 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step c) using N-dodecyl-4-nitrobenzamide and hydrogen at a pressure of 20 bar at 50° C. gave the title compound (98%). 1H NMR (DMSO-d6, 300 MHz) δ 7.93 (t, 1H, J=5.6 Hz), 7.53 (d, 2H, J=8.7 Hz), 6.50 (d, 2H, J=8.7 Hz), 8.30 (s, 2H), 3.16 (m, 2H), 1.36-1.52 (m, 2H), 1.12-1.33 (m, 18H), 0.83 (t, 3H, J=6.7 Hz). HPLC (Condition A), Rt: 4.87 min (HPLC purity 99.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[N:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccncc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cnccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,7]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: [C:1]12([C:11]3[CH:23]=[CH:22][C:14]([O:15][CH2:16][CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(C3C=CC(OC=CCC(O)=O)=CC=3)CC3CC(CC(C3)C1)C2.[H][H]>CO.[Pd]>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:22][CH:23]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: [H][H]
Reactant: O=C(O)C=CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Pd]
Agent: O=C(O)CC=COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Solvent: CO
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 24 h

Procedure:
A solution of 0.9 g of the mixture of 4-[4-(1-adamantyl)-phenoxy]-2-butenoic acid and 4-[4-(1-adamantyl)-phenoxy]-3-butenoic acid in 30 ml of absolute methanol is hydrogenated with 0.3 g of palladium (5% strength on charcoal) until 1 equivalent of hydrogen has been taken up (normal pressure, about 25° C). The catalyst is then filtered off, and the filtrate is mixed with 10 ml of 2 N sodium hydroxide solution and left to stand for 24 hours at about 25° C. It is then evaporated in vacuo to half its volume. The evaporation residue is partitioned between 50 ml of 2 N hydrochloric acid and 3 times 50 ml of methylene chloride. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Crystallisation of the evaporation residue from ethanol gives 4-[4-(1-adamantyl)-phenoxy]butyric acid of melting point 170°-172° C.
Reaction SMILES: [Mg].[Si:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[C:17]1([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].CN([CH:27]=[O:28])C>BrC(Br)C.O>[Si:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:27]=[O:28])=[CH:12][C:11]=1[C:17]1([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC1(c2cc(Br)ccc2O[Si](C)(C)C(C)(C)C)CCCCC1
Reactant: CN(C)C=O
Agent: CC(Br)Br
Agent: [Mg]
Solvent: O
Product: CC1(c2cc(C=O)ccc2O[Si](C)(C)C(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.54 g of magnesium are placed in a 500 ml three-necked round-bottomed flask and then a solution containing 22.09 g (57.7 mmol) of 4-tert-butyldimethylsilyloxy-3-(1-methylcyclohexyl)bromobenzene is added through a dropping funnel. The reaction is activated by a few drops of dibromoethane. 4.45 ml (57 mmol) of DMF are then added and the mixture is left stirring for 30 min at room temperature. The reaction medium is poured into water and then extracted with ethyl acetate. After rinsing the organic phase with water, drying over magnesium sulphate, evaporation and chromatography on silica in the dichloromethane/hexane eluent (50/50), 16 g (84%) of the expected derivative are isolated.
Reaction SMILES: [CH2:1]([C:3]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].C([Li])CCC.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)C>[C:17]([O:11][C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: C=C(C)C(=O)Cl
Reactant: CCC1(O)CCCCCCC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(CC)CCCCCCC1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a 500-mL 3-necked round bottom flask equipped with a 250-mL pressure equalizing addition funnel, a nitrogen inlet with thermocouple and an overhead stirrer was added 32.5 g (0.208 mol) of 1-ethyl-1-cyclooctanol and 100 mL of anhydrous tetrahydrofuran. The addition funnel was charged with 150 mL (0.239 mol, 15% excess) of n-butyllithium (1.6M in hexane) which was then added to the cooled alcohol over 2 hours. The addition funnel was then charged with a solution of 25 g (0.239 mol) of freshly distilled methacryloyl chloride in 50 mL of dry tetrahydrofuran which was then added slowly with cooling over 1.5 hours. The reaction mixture was allowed to warm to room temperature with stirring overnight after which 100 mL of saturated sodium bicarbonate was carefully added with stirring. The mixture was stirred for 1 hour at which time it was diluted with 500 mL of diethyl ether and the organics washed with water, brine and dried for 1 hour over anhydrous magnesium sulfate. Filtration and removal of the solvent at reduced pressure resulted in a light-colored oil which was distilled twice from Na2CO3 and phenothiazine through a based-washed 15-cm Vigreux to yield 24 g (51%) of the title compound (bp 84° C.@ 1 mmHg) as a clear, colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:29])(=[O:28])[N:26]([CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[N:23]1[S:27](=[O:28])(=[O:29])[N:26]([CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:25](=[O:36])[CH2:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(O)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 5-[2-benzyloxy-4-(tert-butyldimethylsilanyloxy)phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (100 mg, 0.18 mmol) in THF (4.5 mL) is added 0.5 mL of 4N HCl in dioxane and the mixture is stirred at RT for 5 days. The solution is concentrated, dissolved in EtOAc and the aqueous phase separated. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to afford the title compound: 1H NMR (CDCl3δ7.29 (m, 5H), 7.16 (d, J=8.3 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 6.27 (dd, J=8.3, 2.5 Hz, 1H), 4.92 (s, 2H), 4.24 (s, 2H), 3.52 (m, 2H), 0.99 (m. 2H), 0.00 (s, 9H): (M+1)+=435.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(C1C=CC(C)=CC=1)(O[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])(=O)=O.[BH4-].[Na+]>CO.O>[CH2:19]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: c1cnc2ccncc2c1
Reactant: C=CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCCCN1CCc2ncccc2C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1,6-naphthyridine (6.5 g, 0.05 mol) and 4-pentenyl tosylate was heated at 80° C. for 6 hours. The reaction mixture was dissolved in methanol (300 ml) and water (100 ml). To the mixture, sodium borohydride (9.5 g, 0.25 mol) was added portionwise over the internal temperature range 0° to 20° C. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with ether. The organic layer was dried over anhydrous potassium carbonate and evaporated in vacuo. The resulting residue was purified by alumina column chromatography (eluted successively with petroleum ether and ether) and distilled, bp. 110°-112° C./0.35 mmHg, to afford the Compound No. 15 (6.9 g, 68.6%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CC(=O)CC>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)OC)c(O)c1
Yield: 73.5 %

Procedure:
To a solution of 33.0 g (196 mmol) of methyl 2,4-dihydroxybenzoate and 68.0 g (491 mmol) of potassium carbonate mixed in 500 ml of 2-butanone was added 50 ml (235 mmol) of octyl bromide and the whole was refluxed for 18 hours. Water was added to the solution and the whole was extracted with ethyl acetate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 40.4 g of methyl 2-hydroxy-4-octyloxybenzoate (29) as a colorless clear liquid (yield: 73.5%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:28])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:18][CH:19]=[C:20]([CH:22]=O)[CH:21]=3)[CH:15]=2)[N:10]([C:24](=[O:26])[CH3:25])[C@@H:9]([CH3:27])[CH2:8]1)[CH3:3].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[O:18][CH:19]=[C:20]([CH2:22][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:28])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:27])(=[O:26])[CH3:25]
Reactant: C1CCNCC1
Reactant: CC(=O)N1c2ccc(-c3cc(C=O)co3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3cc(CN4CCCCC4)co3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 0.5 h

Procedure:
1-Methylethyl[(cis)-1-acetyl-6-(4-formyl-2-furanyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 20) (28 mg, 0.073 mmol) was dissolved in dichloromethane (DCM) (1 mL), mixed with piperidine (8.65 μL, 0.087 mmol) and acetic acid (8.34 μL, 0.146 mmol) and stirred under nitrogen for 30 minutes. Sodium triacetoxyborohydride (20.07 mg, 0.095 mmol) was added and the mixture was stirred again under nitrogen. After 16 hours reaction time the mixture was loaded onto a 2 g Flash SCX-column, eluting with MeOH (60 mL) followed by 2M MeOH/NH3 (60 mL). The product-containing fraction was evaporated to dryness to give a light brown solid (19 mg).