Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23]([NH:25][C@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:13]([C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][CH2:9][N:10]([C:27](=[O:28])[C@H:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH2:11][CH2:12]1)(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCCC(=O)C1(C2CCCCC2)CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
0.44 g (1.9 mmol) of 1-(4-cyclohexylpiperidin-4-yl)butan-1-one, 0.56 g of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid (1.9 mmol), 0.4 g (2.1 mmol) of EDC and 0.282 g (2.1 mmol) of HOBt are dissolved in 4 ml of DMF. The mixture is stirred at room temperature for 2 hours. The solution is washed with aqueous 2.5% citric acid solution and extracted with ethyl acetate, and the organic phase is then washed with aqueous 10N sodium hydroxide solution. It is dried over sodium sulfate, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 7/3 heptane/ethyl acetate). 0.43 g is obtained in the form of a colourless oil in a yield of 44%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH2:14][OH:15])[CH:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH:10]([OH:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([C:43]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)Cl)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH2:14][O:15][C:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH:10]([OH:36])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1COCCCOc1ccc(C2C(O)CN(C(=O)OC(C)(C)C)CC2CO)cc1
Product: COc1ccccc1COCCCOc1ccc(C2C(O)CN(C(=O)OC(C)(C)C)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 13 (f), by reacting (3RS,4RS,5SR)-3-hydroxy-5-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester with triphenylchloromethane there was obtained (3RS,4RS,5SR)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]5-trityloxymethyl-piperidine-1-carboxylic acid tert-butyl ester as a colorless foam; MS: 761 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1.C(O)(=O)C.BrBr>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(Cl)cn2)=NN1
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc(-c2ccc(Cl)cn2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a dry 100 mL flask equipped with magnetic stirrer and reflux condenser was charged 2.0 g of 6-(5-chloropyridin-2-yl)-4,5-dihydropyridazin-3(2H)-one (0.00955 mol), and about 25 mL of glacial acetic acid (some solid did not dissolve). Bromine (0.5 mL; 0.00955 mol) was added in one portion, and the reaction was slowly heated to reflux. After about 15 minutes at reflux, the color discharged. An aliquot was analyzed by TLC which revealed no starting material remained, and one major product was formed. The reaction was cooled and stirred at ambient temperature overnight. The reaction mixture was poured into about 300 mL of water, and stirred to afford a tan solid which was collected by vacuum filtration, washed with water, hexane, and dried in vacuo at 40° C. overnight. Isolated 1.9 g of a tan solid was isolated. The NMR data is as follows: 300 MHz 1H NMR (DMSO d-6, TMS=0 ppm) 7.10 (d, AH); 7.75 (d, AH); 8.11 (d, 1H) 8.70 (d, AH); 13.4 (bs, 1H). The sample had 96% isolated yield.
Reaction SMILES: C([S:4][CH2:5][CH:6]([O:16][CH3:17])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C.C[O-].[Na+].CS(O)(=O)=[O:23].O>CO.C(OCC)(=O)C>[CH2:9]([O:8][CH2:7][CH:6]([O:16][CH3:17])[CH2:5][S:4][OH:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(COCc1ccccc1)CSC(C)=O
Reactant: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(COCc1ccccc1)CSO
Reaction time: 2 h

Procedure:
To a solution of 14.028 g (55 mM) of acetylthio-3-benzyloxy-2-methoxypropane VII 6 in 300 ml of methanol is added dropwise 11.24 ml (58.3 mM) of 28 weight % solution of sodium methoxide in methanol at -10° C. After the mixture is stirred at -10° C. to 0° C. for 2 hours, 3.58 ml of methanesulfonic acid is added. The reaction mixture is poured into water and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with water, dried, and evaporated. The oily residue is purified by column chromatography on silica gel using an ether-n-hexane (3:97) mixture as an eluent to give 8.85 g (41.7 mM) of the titled compound, 3-benzyloxy-2-methoxypropylthioalcohol VII 6 as an oil.
Reaction SMILES: [NH:1]([C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:20][CH:19]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1>C(O)C.[Pd]>[NH2:14][C:13]1[C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:20][CH:19]=2)=[N:11][CH:12]=1
Reactant: CN(C)CC(O)COc1ccc(Nc2ncc([N+](=O)[O-])c(Nc3ccccc3)n2)cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CN(C)CC(O)COc1ccc(Nc2ncc(N)c(Nc3ccccc3)n2)cc1
Reaction time: 18 h
Yield: 84.5 %

Procedure:
4-Anilino-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}-5-nitropyrimidine (Example 20, 400 mg, 0.90 mmol) was dissolved in ethanol (20 ml). Under an atmosphere of nitrogen, cyclohexene (5 ml) was added followed by 10% palladium-on-carbon (100 mg). The mixture was heated under reflux for 5 hours, and then a further portion of 10% palladium on carbon (100 mg) was added and heating was continued for 18 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated by evaporation. The resulting oil was purified by column chromatography, eluting with 0-10% 2.0M methanolic ammonia in DCM to give the product as a white solid (300 mg, 80%). NMR: 2.15 (s, 6H), 2.3 (m, 2H), 3.8 (m, 3H), 4.3 (s, 2H), 4.7 (s, 1H), 6.8 (d, 2H), 7.0 (t, 1H), 7.3 (t, 2H), 7.5 (d, 2H), 7.6 (s, 1H), 7.8 (d, 2H), 8.1 (s, 1H), 8.4 (s, 1H); MS (MH+): 395.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[S:10][C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[S:10](=[O:34])[C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)c2sc3ccccc3c2-c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccccc3S2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 1 (8.2 g,; 0.0238 mole) dissolved in chloroform was cooled in an ice-ethanol bath, and 4.5 g. (0.026 mole) of m-chloroperbenzoic acid in chloroform were added dropwise. The mixture was stirred at room temperature overnight. The resulting mixture then was washed successively with aqueous sodium bicarbonate solution, aqueous sodium chloride solution, and water. The mixture then was dried over magnesium sulfate. The mixture was concentrated, and ethanol was added to the residue. The product crystallized upon scratching of the vessel wall. The solid was filtered and washed with a mixture of ethanol and ether. The solid was air dried to obtain 7.2 g. of product, m.p. 118°-120° C. Thin layer chromatography (TLC) showed the presence of a trace of starting material.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12](O)=[O:13])[C:6]=2[C:15]=1[CH3:16].B.CSC.CO>O1CCCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([CH2:12][OH:13])[C:6]=2[C:15]=1[CH3:16]
Reactant: Cc1c(C)c2c(c(C)c1O)C(C(=O)O)C(C)(C)O2
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)C(CO)C(C)(C)O2
Yield: 0.1 %

Procedure:
To a stirred solution of 58.82 g (0,235 mol) of 2,3-dihydro-5-hydroxy-2,2,4,6,7-pentamethyl-1-benzofuran-3-carboxylic acid (see Example 1) in 500 ml of dry tetrahydrofuran is added dropwise over 30 minutes 50 ml of 10M borane-methyl sulfide and the resulting mixture is stirred at reflux temperature for 7 hours. After cooling, 120 ml of methanol is added carefully and the resulting solution is evaporated to dryness. The residue is taken up in ethyl acetate and the solution is washed with 2N hydrochloric acid, water, a sodium bicarbonate solution, and brine, and is dried over anhydrous sodium sulfate. Filtration and evaporation of solvent gives an oil that crystallizes from ethyl acetate/heptane to give 37.85 g of the title compound, m.p. 89°-90° C. Elemental analysis, IR, UV, and 1H-NMR spectra confirm the structure. A second crop of 12.60 g is obtained, raising the yield to 91%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:24](=[O:25])[C:23]2[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:22]=2[F:21])=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1cc(F)c(F)cc1F)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 2,4,5-trifluorobenzoic acid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[S:25][C:24]([C:26]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)=[O:27])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cc1ccc(C(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)s1

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 5-methyl-2-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound, melting at 71°-73° C., was obtained in a yield.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH3:32])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C@H:12]2[CH2:13][C@@H:14]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:15][CH2:16][NH:11]2)=[C:26]([CH3:32])[CH:27]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(F)ccc1[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
In 350 ml of ethanol was dissolved 37.0 g of cis-1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidine, and 5.5 g of palladium-carbon (moisture content of 50.9%) was added thereto, and the mixture was stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite, and ethanol was removed by distillation, to give 25.8 g of cis-2-(4-fluoro-2-methylphenyl)-4-tert-butoxycarbonylaminopiperidine as shown in Table 132 below.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH:20]1([CH2:19][CH2:18][S:17][C:9]2[N:8]([CH2:7][C:6]([OH:26])=[O:5])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)Cn1c(SCCC2CCCCC2)nc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(SCCC2CCCCC2)nc2ccccc21
Yield: 29 %

Procedure:
A solution of tert-butyl[2-(2-cyclohexyl-ethylsulfanyl)-benzoimidazol-1-yl]-acetate (Precursor A-01b, 42 mg, 0.13 mmol) in TFA/dichloromethane (1:1, 0.5 ml) is stirred at rt for 4 h. The solvents are removed in vacuo. The crude residue is sonicated in Et2O/heptane (1:1, 1 ml) until a solid precipitates. It is rinsed with heptane and purified by flash chromatography on silica gel (AcOEt/heptane, 1:1 containing 1% of AcOH), yielding the title compound (12 mg) in 30% as a white solid: tR=6.44 min (LC-1), ESI-MS (pos.): m/z 319.12 [M+H]+, ESI-MS (neg.): m/z 317.37 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 0.82-0.94 (m, 2H), 1.09-1.23 (m, 3H), 1.37 (m, 1H), 1.54 (q, 2H, SCH2CH2), 1.68 (m, 5H), 3.34 (t, 2H, SCH2), 4.88 (s, 2H, CH2CO2), 7.22 (s, 3Harom), 7.65 (m, 1Harom).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[CH:12]=[N:13][OH:14]>CN(C=O)C>[Cl:1][O:14][N:13]=[CH:12][C:11]1[C:10]([Cl:9])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:19]
Reactant: ON=Cc1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ClON=Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Alternate Procedure: Add a solution of N-chlorosuccinimide (8.4 g, 62.8 mmol) in DMF (33 mL) to a 42° C. solution of 2,6-dichloro-benzaldehyde oxime (217 g, 1.14 mol) in DMF (700 mL). Stir for 30 minutes and then add a solution of N-chlorosuccinimide (159 g, 1.19 mol) in DMF (617 mL) while maintaining the temperature between 40° C. and 45° C. Stir for 1 hour. Cool to room temperature and stir for 2 h. The resulting solution of the title compound is used directly Step 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.B(O)(O)[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[N:15][CH:14]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[Br:19][C:16]1[N:15]=[CH:14][C:13]([NH:1][C:2]2[CH:3]=[N:4][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:7]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: OB(O)c1ccc(Br)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Nc2ccc(Br)nc2)cn1
Reaction time: 8 h

Procedure:
To a solution of 3-amino-6-trifluoromethyl pyridine (0.25 g, 1.2 mmol, 2.0 equiv) and 2-bromopyridyl-5-boronic acid (0.10 g, 0.62 mmol, 1.0 equiv) in 5 Ml dichloromethane was added pyridine (0.10 Ml, 1.2 mmol, 2.0 equiv), copper (II) acetate (0.17 g, 0.93 mmol, 1.5 equiv) and 4 Å molecular sieves. The heterogeneous reaction mixture was allowed to stir vigorously open to air overnight. The reaction was then filtered through Celite, concentrated in vacuo, and purified by silica gel chromatography to afford the title compound: (M+H)+319.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:20][CH:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH:13]2[C:21](O)=[O:22])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O=S(Cl)[Cl:26]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:20][CH:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH:13]2[C:21]([Cl:26])=[O:22])(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)C1C2CCCCC2CN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1C2CCCCC2CN1S(=O)(=O)c1cc(Cl)cc(Cl)c1

Procedure:
N-(3,5-Dichlorobenzenesulfonyl)-octahydroisoindole-1-carboxylic acid (1 gm, 2.64 mmol) was dissolved in CH2Cl2 (5 mL) containing DMF (1 drop) and SOCl2 (770 μL, 10.56 mmol). The reaction mixture was refluxed under nitrogen for ˜1 hr. The reaction mixture was monitored by TLC for the formation of the acid chloride. The reaction mixture was then concentrated in vacuo and azeotroped with toluene (1×5 mL) to afford N-(3,5-dichlorobenzenesulfonyl)-octahydroisoindole-1-carboxylic acid chloride which was used without further purification in the subsequent step.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([O:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1oc(Oc2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 140 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), phenol (0.94 g), potassium carbonate (2.10 g) and N,N-dimethylformamide (10 ml) was stirred at 140° C. for 3 hours. Water was added to the reaction mixture, which was then acidified with 6 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-phenoxy-5-oxazolepropionic acid (1.60 g, 93%). This was recrystallized from ethyl acetate to give colorless needles. mp 136-137° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]2[O:20][CH3:21])=[C:4]([F:22])[CH:3]=1.[C:23](Cl)(=[O:25])[CH3:24].N1C=CC=CC=1>C(Cl)Cl>[C:23]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]=[C:10]2[O:20][CH3:21])[C:4]([F:22])=[CH:3][C:2]=1[Cl:1])(=[O:25])[CH3:24]
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)=O)c(Cl)cc1F

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-trifluoromethyl-6(1H)-pyrimidinone and acetyl chloride with pyridine in methylene chloride there is obtained 2-chloro-4-fluoro-5-[2-methoxy -6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-phenyl acetate, m.p. 110°-112° C.;
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:26][O:27][Si](C(C)(C)C)(C)C)[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.F[Si-2](F)(F)(F)(F)F.[H+].[H+]>O1CCOCC1.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH2:26][OH:27])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3Cc4cc(Br)ccc4CC3CO[Si](C)(C)C(C)(C)C)nc(N)n2)CC1
Agent: [H+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2cc(N3Cc4cc(Br)ccc4CC3CO)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[7-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4-dihydroisoquinolin-2(1H)-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (150 mg, 0.27 mmol) in 1,4-dioxane (3 mL) was added 1.7 M of fluorosilicic acid in water (480 uL). The reaction mixture was stirred at r.t. for 2 h., and then concentrated to remove dioxane. The residue was dissolved in MeOH and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS(M+H)+: m/z=433.2.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[C:22]1([S:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:22]1([S:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:34])=[CH:31][CH:30]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(Sc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(Sc2ccccc2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To a solution of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 50 ml of dry methylene chloride, under nitrogen, and cooled to 0° C. is added 5.0 ml of triethylamine followed by a solution of 2.16 g of 4-(phenylthio)benzoyl chloride (Reference Example 34) in 30 ml of methylene chloride. The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with 50 ml of chloroform and washed with 50 ml each of water, 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 1.92 g of the desired product as a solid. M+H 397.1 M+Na 419.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]=[C:11](N)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)[Cl:26]>>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]=[C:11]([Cl:26])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1-c1ccc(Cl)cc1Cl
Reactant: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCc1cc(Cl)ncc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 62 %

Procedure:
A mixture of [2-amino-5-(2,4-dichloro-phenyl)-pyridin-4-ylmethyl]-carbamic acid tert-butyl ester (1.78 g, 4.82 mmol, prepared according to Example 6, Step 3.2), tBuONO (1.05 mL, 8.0 mmol), and CuCl2 (1.01 g, 7.51 mmol) in CHCl3 (6 mL) was stirred at RT for 3 days with exclusion of light. The reaction mixture was concentrated under vacuum, then the remaining residue was suspended in a 2.0 M aqueous Na2CO3 solution (200 mL) and extracted with AcOEt (2×100 mL). The combined organic fractions were dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→4:6) to yield the title compound (1.17 g, 3.0 mmol, 62%) as a colorless solid. MS: 388 [M+1]+; HPLC: AtRet=2.89; TLC: RF 0.36 ([hexane/DCM 1:1]/TBME 95:5).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(O)(=O)C.N1[CH2:18][CH2:17][CH2:16][CH2:15]C1>C1(C)C=CC=CC=1>[C:1]([C:3](=[CH:15][CH:16]1[CH2:18][CH2:17]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=CC1CC1
Yield: 43 %

Procedure:
A solution of 14 g (0.2 mol) of cyclopropylcarbaldehyde, 22.6 g (0.2 mol) of ethyl cyanoacetate, 1.4 ml of glacial acetic acid and 0.4 ml of piperidine in 200 ml of toluene was refluxed for 6 hours. After cooling, the mixture was washed with in each case 300 ml of 10% strength hydrochloric acid and water. The organic phase was dried and concentrated and the residue was subjected to distillation in vacuo. This gave 14.2 g (yield 43%) of ethyl 2-cyano-3-cyclopropyl-2-propenoate (b.p. 95° C./0.3 mbar).