Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11].[CH2:12](Br)[CH:13]=[CH2:14].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:14]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][OH:11])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: OCc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1c(CO)nc2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
To a solution of (1H-benzoimidazol-2-yl)-methanol (501 mg, 3.38 mmol) and allyl bromide (0.29 mL, 3.38 mmol) in DMF (15 mL) was added N,N-diisopropylethylamine (0.71 mL, 4.06 mmol). The reaction mixture was stirred at 60° C. overnight. Then the mixture was cooled to room temperature and quenched with saturated NaHCO3 (25 mL). Then it was extracted with CH2Cl2 (3×25 mL). The combined organic layer was washed with brine (2×25 mL), dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a brown oil. Purification by flash column chromatography on silica gel using 2% CH3OH/CH2Cl2 afforded the product as a yellow oil (180 mg, 28%). 1H NMR (CDCl3) δ 4.85 (br s, 5H), 4.98 (d, 1H, J=17.1 Hz), 5.17 (d, 1H, J=10.5 Hz), 5.88-6.01 (m, 1H), 7.20-7.26 (m, 3H), 7.66 (t, 1H, J=3.9 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:4]([Cl:19])[N:3]=1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([CH2:30][NH2:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>CC#N.CCN(CC)CC>[Cl:19][C:4]1[N:3]=[C:2]([NH:31][CH2:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:20]=[CH:21][CH:22]=[CH:23]3)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=1
Reactant: NCc1ccc2ncccc2c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(NCc2ccc3ncccc3c2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of tert-butyl 2,6-dichloro-3-nitropyridin-4-ylcarbamate (1.2 g, 3.9 mmol) and quinolin-6-ylmethanamine (616 mg, 3.9 mmol) in CH3CN (15 mL) and Et3N (1 mL) was stirred at 80° C. for 1 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by chromatography to afford the title compound (1.60 g). MS (m/z): 430 (M+1)+.
Reaction SMILES: [CH:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH2:3][CH3:4])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH:8]3[CH2:7][CH2:6][CH:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CCC(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C)C1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 85.5 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-sec-Butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol) and 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 152 mg of the desired product as a white solid (50%). ESI-MS: 339 (M-16)+. 1H NMR (400 MHz, DMSO-d6) δ=8.30 (s, 1 H), 7.88 (s, 1 H), 7.75 (d, J=8.8 Hz, 1 H), 7.71-7.56 (m, 1 H), 7.24 (d, J=2.0 Hz, 1 H), 7.12 (dd, J=2.3, 8.8 Hz, 1 H), 4.70 (d, J=5.8 Hz, 1 H), 4.40-4.28 (m, 1 H), 3.55-3.41 (m, 2 H), 2.26-1.07 (m, 12 H), 0.94-0.79 (m, 3 H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][CH:10]([SH:12])[CH3:11].[H-].[Na+]>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:12][CH:10]([CH3:11])[CH3:9])=[N:3][CH:4]=1
Reactant: CC(C)S
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,5-dibromopyridine (2.07 g, 8.73 mmol) and 2-propanethiol (0.97 ml, 10.4 mmol) in N,N-dimethylformamide (20 ml) at 0° C. was added portionwise sodium hydride 60% dispersed in oil (450 mg, 11.3 mmol). The resulting mixture was stirred at room temperature for 1 hour, then partitioned between ether and water. The crude product from the organic phase was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to afford the 5-Bromo-2-isopropylthiopyridine compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(Nc3ccc(F)cc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 39.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-4-fluorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (115 mg, 0.23 mmol) obtained in step 2 and ethanesulfonamide (123 mg, 1.17 mmol), the title compound (53 mg, 39%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][C:8]#[N:9])([O-])=O.[H][H]>S(=O)(=O)(O)O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][C:8]#[N:9]
Reactant: [H][H]
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: N#CCc1cccc(N)c1

Procedure:
A correspondingly substituted benzyl cyanide of the formula Ve is nitrated in concentrated sulfuric acid. The formed 3-nitrobenzyl cyanide of the formula Vf is subsequently hydrogenated in the presence of a catalyst with hydrogen to obtain 3-aminobenzyl cyanide of the formula Vg. By treatment with isopentyl nitrite in the presence of sodium and ethanol, there is formed the Na salt of 3-aminobenzoyl cyanide oxime of the formula Vh, which is reacted with an ester of the formula VIII to obtain 3-aminophenoxime ether of the formula Va. This can be subjected to a condensation reaction, as described above, with the 3,4,5,6-tetrahydrophthalic anhydride of the formula II.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:21]=2[N:20]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:21]=3[N:20]=2)[CH2:11][CH2:10]1
Reactant: CC(=O)c1cnc(N2CCNCC2)c(Cl)c1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Agent: Cl
Product: CC(=O)c1cnc(N2CCN(c3nc4ccc(C(F)(F)F)cc4[nH]3)CC2)c(Cl)c1

Procedure:
1-(5-Chloro-6-piperazin-1-yl-pyridin-3-yl)-ethanone, hydrochloride from step (d) above (0.6 g, 1.92 mmol) reacted with 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.423 g, 1.92 mmol, Example 1c) under the conditions of Example 94d to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 424 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].Br[CH2:12][CH:13]1[O:17][CH2:16][CH2:15][O:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][CH2:12][CH:13]1[O:17][CH2:16][CH2:15][O:14]1)[CH3:2]
Reactant: BrCC1OCCO1
Reactant: CCOC(CCN)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CCNCC1OCCO1)OCC
Temperature: 25 °C

Procedure:
3,3-Diethoxypropylamine (0.11 mole), 2-bromomethyl-1,3-dioxolane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(1,3-dioxolan-2-ylmethyl)amine.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C>C1COCC1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([B:24]([OH:25])[OH:23])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(Oc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To a solution of 4-phenoxybromobenzene (98.2 g, 0.39 mol) in dry THF (800 mL) under nitrogen at −78° C. was added n-BuLi (2.5M solution in hexanes) (172 mL, 0.43 mol) dropwise. A temperature rise to −65° C. was observed. On complete addition, the mixture was allowed to stir at −78° C. for 15 min. Triisopropylborate (109.2 mL, 0.473 mol) was added dropwise over 30 min. On complete addition, a suspension was observed. The mixture was allowed to warm to 0° C. over 1 hr, stirred at 0° C. for 4 hrs. The reaction was quenched by the dropwise addition of water (300 mL) such that the internal temperature<20° C. (ice-cooling required). The mixture was allowed to warm to room temperature overnight then evaporated to dryness. The residue was suspended in water (600 mL) and acidified by the cautious addition of conc. HCl. The resulting precipitate was collected by filtration and dried in vacuo at 45° C. The solid was ground to a fine powder and triturated with petroleum ether (40-60° C.). The pale solid was filtered and dried to give 4-phenoxyphenylboronic acid (68.8 g, 83%). 1H NMR (250 MHz, d6-DMSO):7.99 (1H, m), 7.91 (1H, t), 7.83 (1H, d), 7.4 (2H, m), 7.14 (1H, m), 6.92-7.07 (5H, m). Microanalysis:Req. C(71.4%), H(5.45%), Found C(70.25%), H(4.7%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH2:23])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1.[C:28]1([C:34]2[S:35][CH:36]=[C:37]([C:39](O)=[O:40])[N:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[NH:23][C:39]([C:37]4[N:38]=[C:34]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[S:35][CH:36]=4)=[O:40])[S:18][C:15]3=[N:16][CH:17]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Reactant: COCCN1CCN(Cc2cnc3sc(-c4ccccc4N)nc3c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCN(Cc2cnc3sc(-c4ccccc4NC(=O)c4csc(-c5ccccc5)n4)nc3c2)CC1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 2-phenylthiazole-4-carboxylic acid (3 eq), HATU (3 eq) and DIPEA (5 eq). The product was isolated by precipitation by the addition of water, triturated with hot methanol and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C30H30N6O2S2: 570.19. Found (M+H)+ m/z=571.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:19])[NH:16][N:17]([CH3:18])[C:13]=3[NH:12][C:11]3[CH2:20][CH2:21][C:22](=[O:23])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:25]([O:27][CH3:28])=[O:26].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[C:15](=[O:19])[N:16]([C:25]([O:27][CH3:28])=[O:26])[N:17]([CH3:18])[C:13]=3[NH:12][C:11]3[CH2:20][CH2:21][C:22](=[O:23])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(F)c(Br)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)n1c(=O)c2c(n1C)NC1=C(C(=O)CC1)C2c1ccc(F)c(Br)c1

Procedure:
The product from Example 1 (0.1 g) in methylene chloride (10 mL) was stirred overnight with methyl chloroformate (0.04 mL) and pyridine (0.06 mL). The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with 5% ethanol/methylene chloride to provide 0.038 g of the title compound. 1H NMR (DMSO-d6) δ 2.32 (t, 2H), 2.72 (m, 2H), 3.65 (s, 3H), 3.7 (s, 3H), 4.72 (s, 1H), 7.11 (m, 1H), 7.22 (t, 1H), 7.32 (dd, 1H), 10.80 (s, 1H); MS (ESI+) m/z 438 (M+H)+; Anal. Calcd for C18H15N3BrFO4: C, 49.54; H, 3.44; N, 9.63. Found: C, 49.69; H, 3.27; N, 9.72.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[CH2:15]([O:17][CH2:18][CH2:19]O)[CH3:16].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:16][CH2:15][O:17][CH2:18][CH3:19])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: CCOCCO
Reactant: C=CCNc1cccc(CC(=O)O)c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCNc1cccc(CC(=O)OCCOCC)c1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 3-(allylamino)phenylacetic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 3-(allylamino)phenylacetate.
Reaction SMILES: C(=S)([O-])N.[NH4+].Br[CH:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.[C:26](=[S:29])([S-:28])[NH2:27].[NH4+]>C(O)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[CH:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[S:29][C:26](=[S:28])[N:27]=2)=[CH:11][CH:12]=1
Reactant: NC(=S)[S-]
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Agent: NC([O-])=S
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(C2=NC(=S)SC2c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4.92 g of ammonium thiocarbamate are suspended in 70 ml of 96% strength ethanol. The suspension is cooled to 5° and, while stirring, 15 g of 2-bromo-1,2-bis-(p-methoxyphenyl)-ethanone are added thereto in portions in the course of 10 minutes, the internal temperature being maintained at approximately 10° by cooling. The mixture is then stirred for 1 hour at 10°, a further 2.4 g of ammonium dithiocarbamate are added and stirring is carried out again for 3 hours at room temperature. The mixture is then poured into 500 ml of ice-water, the crude product is filtered off with suction and then washed with ice-water. For purification, the crude product is suspended in 50 ml of ethanol and heated under reflux, first of all dissolution occurring and, after 90 minutes, reprecipitation. The whole is allowed to cool, filtered with suction and the residue is then washed with cold ethanol. 4,5-bis-(p-methoxyphenyl)-thiazoline-2-thione having a melting point of 226°-230° is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH2:17][O:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][C@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C[C@@H](CO)C[C@@H](C)CCCCC)(C)(C)C>>[C:1]([O:5][C:6](=[O:29])[CH2:7][C@@H:8]([CH2:17][O:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:9][C@@H:10]([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Agent: CCCCC[C@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Product: CCCCC[C@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Yield: 64 %

Procedure:
A procedure similar to that used to prepare compound 159 was used except that (3S,5S)-3-Hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167 (4.164 g, 15.29 mmol) was used as a reactant to give 168 as an oil (4.17 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=8.30 Hz, 2H), 7.31 (d, J=8.30 Hz, 2H), 3.97 (dd, J=9.52, 4.15 Hz, 1H), 3.90 (dd, J=9.52, 5.13 Hz, 1H), 2.42 (s, 3H), 2.28, 2.19-2.13 (m, 2H), 1.37 (s, 9H), 1.27-1.01 (m, 11H), 0.85 (t, J=7.08 Hz, 3H), 0.76 (d, J=6.35 Hz, 3H).
Reaction SMILES: C[O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C:15]([CH2:28][CH3:29])=[C:14]2[CH2:30][C:31]([NH2:33])=[O:32])(=[O:6])[O:4]C.C[Si](Br)(C)C.CO>C(Cl)Cl>[NH2:33][C:31](=[O:32])[CH2:30][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][P:3](=[O:2])([OH:6])[OH:4])[CH:12]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:15]=1[CH2:28][CH3:29]
Reactant: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1cccc(Cl)c1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(O)O)ccc2n1Cc1cccc(Cl)c1
Reaction time: 0.75 h
Yield: 64.5 %

Procedure:
[[3-[[3-(2-Amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester (99 mg, 0.2 mmol) and 0.21 mL (1.6 mmol) of trimethylsilyl bromide in 2 mL of methylene chloride was stirred for 16 hours, 5 mL of MeOH added, stirred 0.75 hours and concentrated at reduced pressure. The residue was crystallized from EtOAc/MeCN/HOAc/water to give 60 mg (65% yield) of [3-[[3-(2-amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-5-yl]oxy]propyl]phosphonic acid, mp, 203-205° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].N1C=CN=C1.[CH3:10][C:11]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])[CH3:12]>O1CCCC1>[Si:14]([O:3][CH2:2][CH2:1][OH:4])([C:11]([CH3:13])([CH3:12])[CH3:10])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCO
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCO)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
Into a 2-L 3-necked round-bottom flask was placed tetrahydrofuran (800 mL), ethane-1,2-diol (40 g, 644.46 mmol, 1.00 equiv) and imidazole (61.4 g, 901.92 mmol, 1.40 equiv). This was followed by the addition of TBDPSCl (186.3 g) dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred overnight at room temperature. The solids were filtered out, and the filtrate cake was washed with 200 mL of EA. The resulting mixture was washed with 200 mL of brine and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:25). Purification afforded 83 g (43%) of 2-[(tert-butyldiphenylsilyl)oxy]ethan-1-ol (85.2) as a colorless oil.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][CH2:16][O:17][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]=O)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][CH2:16][O:17][C:10]=3[CH:9]=2)[CH:28]([C:26]2[CH:25]=[CH:24][C:23]3[O:18][CH2:19][CH2:20][O:21][C:22]=3[CH:27]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCCO2
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)OCCO3)c2cc3c(cc21)OCCO3
Yield: 14 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(ethylenedioxy)-phenyl]urea (132 mg) and 1,4-benzodioxan-6-carboxaldehyde (113 mg) by the procedure described in example 10 in 14% yield, mp: 92-95° C. 1H NMR (CDCl3): 6.85-6.76 (m, 3H), 6.62 (s, 1H), 6.32 (s, 1H), 5.20 (s, 1H), 4.99 (s, 1H), 4.46 (m, 1H), 4.24 (s, 4H), 4.23-4.17 (m, 4H), 1.56 (d, J=6.9, 3H), 1.54 (d, J=6.9, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH2:14][CH2:15][Cl:16].[N:17]1([C:23]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH:26]=[CH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[ClH:16].[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[C:6]2[CH2:14][CH2:15][N:20]1[CH2:21][CH2:22][N:17]([C:23]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH:26]=[CH:25][N:24]=2)[CH2:18][CH2:19]1
Reactant: c1cc2sccc2c(N2CCNCC2)n1
Reactant: Nc1ccc2[nH]c(=O)cc(CCCl)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2[nH]c(=O)cc(CCN3CCN(c4nccc5sccc45)CC3)c2c1
Temperature: 60 °C

Procedure:
A mixture of 0.35 g (1.35 mmol) of 6-amino-4-(2-chloroethyl)-2(1H)-quinolone hydrochloride, 0.33 g (1.5 mmol) of 4-(1-piperazinyl)thieno[3,2-c]pyridine and 0.17 g (2 mmol) of sodium bicarbonate in 10 ml of dimethylformamide is heated to 60° C. for 24 hours. After cooling to room temperature, the reaction medium is diluted in 50 ml of water and the crude product is extracted with chloroform. The organic phase is dried over sodium sulpbate and concentrated. The crude product is purified by flash chromatography on silica, eluting first with a methanol/ethyl acetate (6.5:93.5) mixture containing traces of triethylamine and then with a methanol/dichloromethane (6.5:93.5) mixture comprising traces of aqueous ammonia.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:29][CH2:28][CH2:27][O:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[CH3:12])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:25])[C:22]2=[O:23]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O)cc2c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCCl)cc2c1=O

Procedure:
N-Cyclopropyl-3-(6-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (0.621 g), 1-bromo-2-chloroethane (0.772 ml) and potassium carbonate (2.56 g) were stirred in DMF (25 ml) at 50° C. for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water (5×), brine (2×), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 70-80% ethyl acetate/hexane gave 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (0.46 g) as a white solid; NMR Spectrum: DMSOd6) 0.55 (m, 2H), 0.70 (m, 2H), 2.12 (s, 3H), 2.35 (m, 1H), 3.98 (t, 2H), 4.41 (t, 2H), 7.52 (d, 1H), 7.55 (d, 1H), 7.61 (s, 1H), 7.75 (d, 1H), 7.85 (s, 1H), 7.91 (d, 1H), 8.20 (s, 1H), 8.44 (d, 1H); Mass Spectrum: M+H+ 398.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4]>C1CCCCC1.ClC(Cl)C.[Fe](Cl)Cl>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:2]([CH3:5])([CH3:3])[CH3:1])=[CH:8][CH:7]=1)[CH2:3][OH:4]
Reactant: CC(CO)Cc1ccccc1
Agent: Cl[Fe]Cl
Solvent: CC(Cl)Cl
Solvent: C1CCCCC1
Product: CC(CO)Cc1ccc(C(C)(C)C)cc1
Yield: 84 %

Procedure:
DE 29 52 719 likewise describes the iron chloride-catalyzed Friedel-Crafts alkylation of 2-methyl-3-phenylpropanol. In cyclohexane or dichloroethane as solvent, a yield of 84-86% of 2-methyl-3-(4-tert-butylphenyl)propanol was obtained. The formation of the m-isomeric compound (2-methyl-3-(3-tert-butylphenyl)propanol), was not demonstrated. A disadvantage of the described Friedel-Crafts alkylations is the small amount of the m-isomeric compound formed (m:p ratio is max. 1:5).