Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.CS(O[CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)=O>>[C:28]1([CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:26][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1Cc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 37 %

Procedure:
Using ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 2,2-diphenylethyl methanesulfonate, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 37%.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>O>[F:23][C:24]([F:35])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of toluene (70 mL) and water (10 mL) was degassed with nitrogen for 30 min. A mixture of sodium carbonate (3.2 g, 30.43 mmol), 4-bromobenzaldehyde (2.0 g, 10.6 mmol), 4-trifluoromethoxyphenylboronic acid (2.86 g, 13.95 mmol) and tetrakis triphenyl phosphene palladium(0) (1.0 g, 1.562 mmol) were added to the above degassed water/toluene mixture. The reaction mixture refluxed overnight. After the reaction is completed, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ (ppm)=7.2-8.0 (m, 8H), 10.0 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([C:21]4[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH:4]=[N:3]1.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33].N1CCOCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:20]([C:21]4[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:32](=[O:33])[CH2:31][O:30][CH3:29])=[CH:27][CH:28]=4)=[N:19][CH:18]=[CH:17][N:16]=3)[CH2:13][CH2:14]2)[CH:4]=[N:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1c(CN2CCN(c3nccnc3-c3ccc(CN)cc3)CC2)cnn1C
Solvent: C1COCCN1
Solvent: ClCCl
Product: COCC(=O)NCc1ccc(-c2nccnc2N2CCN(Cc3cnn(C)c3C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
Dissolve 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzylamine (0.2 g, 0.53 mmol) in methylene chloride (5 mL). Add methoxy-acetyl chloride (1 eq., 0.058 g, 0.53 mmol). Add polymer bounded morpholine (1.1 eq., 0.234 g, 0.58 mmol). Stir at room temperature for 3 hr. Purify by SCX followed by reverse phase chromatography to give free base N-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-benzyl}-2-methoxy-acetamide, (0.051 g, 21%). MS (ES): m/z=450.3 [M+H].
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](NC3C=CC(OC4C=NC=CC=4)=CC=3)=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1OC.[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=O>>[N:31]1([CH:30]2[CH2:5][CH2:10][N:9]([C:8]3[C:7]([C:12]#[N:13])=[CH:6][C:5]4[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=4)[N:9]=3)[CH2:8][CH2:7]2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CN1CCCC1=O
Reactant: COc1cc2c(Nc3ccc(Oc4cccnc4)cc3)c(C#N)cnc2cc1F
Product: N#Cc1cc2ccccc2nc1N1CCC(N2CCCC2)CC1

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.39 mmol) of 7-fluoro-6-methoxy-4-[4-(pyridin-3-yloxy)phenylamino]-quinoline-3-carbonitrile and 299 my (1.94 mmol) of 4-(1-pyrrolidinylpiperidine) are refluxed in 1-methyl 2-pyrrolidinone (1 mL) at 105° C. for 12 hours to yield the crude product. Purification by silica gel chromatography (95:5 methylene chloride/methanol) gives 120 my of 6-methoxy-4-[4-(pyridin-3-yloxy)phenylamino]-7-(4-pyrrolidin-1-yl-piperidin-1-ylquinoline-3-carbonitrile as a yellow solid, mp 194-196° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N+]=[N-])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(OCC)(=O)C.O1CCCC1>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([O:14][CH:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC=O)n1

Procedure:
To a solution of 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (65.9 g) in ethyl acetate (300 ml) and tetrahydrofuran (200 ml) was dropwise added a solution of diphenyldiazomethane in ethyl acetate (1 m mol/ml, 200 ml) at ambient temperature and the mixture was stirred for an hour. The resultant mixture was washed with saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The solution was evaporated to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (99.3 g). To the solution of benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (99.0 g) in methanol (500 ml) was added conc. hydrochloric acid (41.6 g) at ambient temperature and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into a solution of sodium bicarbonate (33.6 g) in water (2.5 l) and extracted with ethyl acetate. The extracts were washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was pulverized with ether to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (72.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)[CH:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)[CH:19]([NH:21][S:42]([CH:39]4[CH2:41][CH2:40]4)(=[O:44])=[O:43])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CSc1ccc(C(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)N)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc(C(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)C(C)NS(=O)(=O)C2CC2)cc1
Temperature: 25 °C

Procedure:
The racemic mixture of (1RS,2SR)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine (27a, 11 mg, 0.02 mmol) was dissolved in THF (1.5 mL). Excess N-ethyldiisopropylamine (0.185 mL, 1.1 mmol) and cyclopropanesulfonyl chloride (0.063 mL, 0.62 mmol) was added in portions over a period of 3 hours. The reaction mixture was stirred over night at room temperature, quenched by addition of water and purified by HPLC. Fractions with product was freeze dried to give the title compound as a colourless solid. Chiral HPLC was made using an Chiralpak IB™, 150×0.46 mm column, 15% EtOH in iso-Hexane, 0.5 mL/min, UV=254 nm. two peaks was seen in 1:1 ratio.
Reaction SMILES: [C:1]([CH2:5][O:6][CH:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[CH3:8])([O:3][CH3:4])=[O:2].Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([CH2:5][O:6][CH:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:22][CH2:21]1)=[O:19])[CH3:8])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COC(C)n1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: N#CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COC(C)n1c(C(=O)C2CCN(CCCCC#N)CC2)nc2ccccc21
Temperature: 90 °C

Procedure:
Mix 1-[(1-carbomethoxy methoxy ethyl)-1H-benzimidazol-2-yl][1-(4-piperidinyl)]methanone (4.45 g, 12.91 mmol), 5-bromovaleronitrile (2.5 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C.C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-nitro-1H-pyrazole (500 mg, 4.42 mmol; Bionet Research, Cornwall, UK) in DMF (5 mL) was treated with potassium carbonate (400 μL, 6.63 mmol) and 4-methoxybenzyl chloride (600 μL, 4.42 mmol). The reaction was stirred at room temperature for 2 h, then diluted with DCM (200 mL) and washed with water (4×40 mL). The organic layer was then dried (MgSO4), filtered and concentrated in vacuo to give the crude product, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[O:12][CH:11]([CH3:14])[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:7]=3[S:6][CH:5]=2)[CH2:3][CH2:2]1>C(OCC)(=O)C.Cl>[CH:1]1([C:4]2[C:13]3[O:12][CH:11]([CH3:14])[CH2:10][NH:9][CH2:8][C:7]=3[S:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(C3CC3)c2O1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1CNCc2scc(C3CC3)c2O1

Procedure:
tert-Butyl 8-cyclopropyl-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (254 mg) was stirred in 4N hydrogen chloride-ethyl acetate solution (5 ml,) for 20 min.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18](=O)[CH2:19]Br.CN(C)C=O>O>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:19]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3C(F)(F)F)cs2)cc1
Temperature: 125 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
A mixture of methyl 4-thiocarbamoylbenzoate (1.00 g), 2-trifluoromethyphenacyl bromide (1.50 g) and N,N-dimethylformamide (3 ml) was stirred at 120 to 130° C. for 3 hours. The reaction mixture was poured into water, and precipitated crystals were collected by filtration and then subjected to a silica gel column chromatography. From a fraction eluted with ethyl acetate-hexane (1:4, v/v), methyl 4-[4-(2-trifluoromethylphenyl)-2-thiazolyl]benzoate (1.01 g, yield: 54%) was obtained. The product was recrystallized from hexane-toluene to obtain colorless prisms. Melting point: 122 to 123° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=3)=[CH:31][NH:32]2)=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([C:35]3[CH2:36][CH2:37][N:38]([CH2:12][CH:13]4[O:18][C:17]5[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:16]=5[O:15][CH2:14]4)[CH2:39][CH:40]=3)=[CH:31][NH:32]2)=[CH:28][CH:27]=1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc2c1OC(CN1CC=C(c3c[nH]c4cc(F)ccc34)CC1)CO2

Procedure:
[(2R)-8-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl 4-methylbenzenesulfonate (0.30 g, 0.86 mmole), 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.60 g, 2.7 mmole) and sodium bicarbonate (0.80 g) were added to a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 20 mL) and the reaction mixture was refluxed under nitrogen for 18 hours. The solvent was evaporated and the residue partitioned between 400 mL each of water and methylene chloride. The layers were separated and the methylene chloride solution was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous potassium carbonate and filtered. The filtrate was evaporated in vacuum and the residue crystallized from chloroform containing 3% methanol, giving 0.23 g (68%) of the (S)-enantiomer of the title compound as an off-white solid, m.p. 184–185° C.
Reaction SMILES: Cl.[CH:2]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=1.C(N(CC)CC)C>C(#N)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:2]2[CH2:3][CH2:4]3)=[CH:11][C:12]=1[C:19]([F:20])([F:21])[F:22])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: C1CC2CCC1N2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Temperature: 80 °C
Yield: 88 %

Procedure:
To a flask containing 7-azabicyclo[2.2.1]heptane hydrochloride 7a (4.6 g, 34.43 mmol, obtained from Tyger Scientific Inc., 324 Stokes Avenue, Ewing, N.J., 08638 USA under a nitrogen atmosphere was added a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene 18 (6.0 g, 28.69 mmol) and triethylamine (8.7 g, 12.00 mL, 86.07 mmol) in acetonitrile (50 mL). The reaction flask was heated at 80° C. under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool and then was partitioned between water and dichloromethane. The organic layer was washed with 1 M HCl, dried over Na2SO4, filtered, and concentrated to dryness. Purification by silica gel chromatography (0-10% ethyl acetate in hexanes) yielded 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane 19 (7.2 g, 88% yield) as a yellow solid. 1H NMR (400.0 MHz, DMSO-d6) δ 8.03 (d, J=9.1 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.25 (dd, J=2.6, 9.1 Hz, 1H), 4.59 (s, 2H), 1.69-1.67 (m, 4H), 1.50 (d, J=7.0 Hz, 4H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl>[Cl-].C[N+](C)(C)CC1C=CC=CC=1>[CH3:7][Si:8]([CH3:11])([CH3:10])[O:1][CH2:2][CH:3]([O:4][Si:8]([CH3:11])([CH3:10])[CH3:7])[CH2:5][O:6][Si:8]([CH3:11])([CH3:10])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: OCC(O)CO
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: C[Si](C)(C)OCC(CO[Si](C)(C)C)O[Si](C)(C)C

Procedure:
1 mole of glycerol, 4 moles of trimethylchlorosilane and 0.003 moles of trimethylbenzyl ammonium chloride were reacted at the reflux temperature (54°-102° C.) as in Example 1. Excess silylating agent was distilled off after termination of the reaction. The catalyst was filtered off when the reaction mixture was cold.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1>[OH-].[Na+]>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(C(O)C(O)c2ccc(O)cc2)cc1
Temperature: 15 °C
Yield: 77.2 %

Procedure:
A solution containing 20.0 grams (0.16 mole) of 4-hydroxybenzaldehyde and 200 milliliters of 1.0 molar aqueous sodium hydroxide was charged to the reservoir. Also charged to the reservoir was a small amount of Union Carbide SAG 470 silicone antifoam agent. The solution was circulated through the cell at a flow rate of about 1500 milliliters per minute. The electrolysis was conducted at a constant current of 5.0 amperes and a temperature of 30° C over a 1.36-hour (4900-second) period. After the electrolysis had been completed, the solution was removed from the apparatus, which was then washed with water. The combined solution and washings were reduced in volume to 100 milliliters by evaporation in vacuo. The remaining solution was acidified to about pH 6.3 by the dropwise addition of dilute (approximately 6 molar) hydrochloric acid and cooled to 15° C in an ice-water bath. The precipitate was collected by suction filtration, washed with cold water, and dried to yield 15.2 grams of 1,2-bis(4-hydroxyphenyl)ethane-1,2-diol.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6](O)=[O:7])[CH3:3].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[CH3:1][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6]([Cl:17])=[O:7])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(C)C)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C(C)C)c1C(=O)Cl
Reaction time: 15 h

Procedure:
A solution of 2-(1-methylethyl)-6-methylbenzoic acid (64 mg, 0.35 mmol) in dichloromethane (3 mL) containing DMF (2 drops) was treated with oxalyl chloride (0.16 mL, 1.8 mmol) and the mixture was stirred for 15 h. The mixture was concentrated, azeotroping with toluene to remove traces of oxalyl chloride and the residue was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:30]1([CH2:33][O:34][CH2:35][C:36]([OH:38])=O)[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][O:34][CH2:35][C:36]([N:14]([CH:13]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[O:38])[CH2:31][CH2:32]1
Reactant: O=C(O)COCC1CC1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)COCC1CC1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 177, the title compound 2-cyclopropylmethoxy-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-acetamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using Cyclopropylmethoxy-acetic acid instead of 4,4,4-trifluorobutyric acid and was obtained as an off-white foam. MS m/e: 550.2 [M]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH:8]2[CH2:20][NH2:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][S:23]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:21][CH2:20][CH:8]2[CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:12][N:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:32])=[CH:29][CH:28]=1)(=[O:25])=[O:24]
Reactant: NCC1CN(Cc2ccccc2)CCN1c1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Product: CS(=O)(=O)Nc1ccc(C(=O)NCC2CN(Cc3ccccc3)CCN2c2ccccc2)cc1

Procedure:
In a manner similar to Preparation 3, react 1-phenyl-4-(phenylmethyl)-2-piperazinemethanamine (11.1 g, 40 mmol) with 4-[(methylsulfonyl)amino]benzoyl chloride (10.1 g, 43 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:42]=[C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:44]=1[OH:45])[CH2:8][C:9]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([OH:37])=[C:29]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:28]=1)([C:23]([CH3:25])=[O:24])[C:10]([O:12][CH:13]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[C:50](OC(=O)C)(=[O:52])[CH3:51]>>[C:33]([C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:30]=1[OH:37])[CH2:26][C:9]([CH2:8][C:7]1[CH:42]=[C:43]([C:46]([CH3:49])([CH3:48])[CH3:47])[C:44]([OH:45])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)([C:23]([CH3:25])=[O:24])[C:10]([O:12][CH:13]1[CH2:14][C:15]([CH3:22])([CH3:21])[N:16]([C:50](=[O:52])[CH3:51])[C:17]([CH3:20])([CH3:19])[CH2:18]1)=[O:11])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(=O)C(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OC1CC(C)(C)NC(C)(C)C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(C)(C)CC(OC(=O)C(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(C)=O)CC1(C)C

Procedure:
A solution of 2,2,6,6-tetramethyl-4-piperidinyl 2,2-bis-(3,5-di-tert-butyl-4-hydroxybenzyl)-acetoacetate (Example 1, 10.0 g; 0.015 mol) in 100 ml of acetic anhydride is stirred for 20 hours at 100°. The mixture is concentrated in vacuo. After recrystallisation from hexane/toluene, the product is filtered off and 8.41 g of 1-acetyl-2,2,6,6-tetramethyl-4-piperidinyl 2,2-bis-(3,5-di-tert-butyl-4-hydroxybenzyl)-acetoacetate, melting point 165°-166° C. (compound 22), are obtained.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[CH:30]([NH:33][CH2:3][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH3:1])([CH3:32])[CH3:31]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Reactant: CC(C)N
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CNC(C)C)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with isopropylamine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 23.3, 26.5, 35.9, 43.2, 49.3, 53.2, 57.7, 59.0, 102.6, 102.9, 103.1, 105.1, 112.4, 112.4, 112.5, 112.6, 131.7, 137.7, 138.7, 161.9, 162.1, 164.4, 164.5, 169.1; MS m/z 450.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:17])([CH2:15][CH3:16])[CH:13]=[O:14]>Cl.O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][CH:13]([OH:14])[C:12]([Cl:17])([Cl:11])[CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCC(Cl)(Cl)C=O
Reactant: NC(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(Cl)(Cl)C(O)NC(=O)c1ccc(Br)cc1
Yield: 51 %

Procedure:
4-Bromobenzamide 118 (1.0 g, 4.85 mmol), 2,2-dichlorobutanal (2 mL) and HCl (3 drops) in dioxane (4 mL) were heated to 120° C. (bath temperature) for 18 hours. The mixture was concentrated, and absorbed onto silica gel. Chromatography (CH2Cl2) produced an off-white solid as 4-bromo-N-(2,2-dichloro-1-hydroxybutyl)benzamide 119 (0.84 g, 51%).