Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[OH-].[Na+].CCOCC>C1COCC1>[NH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1
Reactant: COc1ccc(C2(c3ccccc3)CCN(CCC#N)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2(c3ccccc3)CCN(CCCN)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a stirred solution of 3-[4-(4-methoxyphenyl)-4-phenylpiperidin-1-yl]propionitrile (1.41 g, 4.40 mmol, 1.0 equiv) in anhydrous THF (10 mL) under argon was added a solution of BH3 in THF (1.0 M, 11.0 mL, 2.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 15 mL) was added and stirring was continued for 2 hours at 55-60° C. The mixture was basified to pH 9 by addition of 6 N aq. NaOH and extracted with CH2Cl2 (3×75 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (10 mL) and treated with HCl in ether (1.0 M, 9.0 mL, 2.0 equiv). The solvents wore removed, ether (30 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×10 mL). Water (20 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1 M NaOH, and the aqueous phase was extracted with CH2Cl2 (3×40 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 610 mg (43%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[F:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2F)ccc1[N+](=O)[O-]
Reactant: COC(=O)CBr
Product: CCP(=O)(OCC(=O)OC)c1cc(Oc2ccc(C(F)(F)F)cc2F)ccc1[N+](=O)[O-]

Procedure:
In the same way, P-ethyl-2-nitro-5-(2-fluoro-4-trifluoromethylphenoxy)phenylphosphinic acid is reacted with methyl bromoacetate to give methoxycarbonylmethyl P-ethyl-2-nitro-5-(2-fluoro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.CO.[OH-].[NH4+]>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)C)cn3COCC[Si](C)(C)C)nc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)C)c3n2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To a solution of N-isopropyl-2-(5-methylpyridin-2-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 204 μmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (466 mg, 315 μL, 4.09 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo then the residue obtained was dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.45 mL). After 3 h at room temperature, the mixture was concentrated in vacuo then triturated with water and ether. The solid was collected by filtration to give N-isopropyl-2-(5-methylpyridin-2-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (23 mg, 74.1 μmol, 36%) as an off white solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.40 (s, 1H), 9.92 (s, 1H), 8.43 (s, 1H), 8.14 (s, 1H), 8.09 (d, J=3.2, 1 H), 7.86 (s, 1H), 7.85 (d, J=15.1 Hz, 1H), 7.55 (dd, J=8.5, 2.3 Hz, 1H), 4.16 (m, 1H), 2.26 (s, 3H), 1.25 (d, J=6.5, 6 H); MS (EI/CI) m/z: 311.1 [M+H].
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH2:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](OC(OCC)CBr)[CH3:19]>CN(C=O)C.O>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[O:16][CH:18]=[CH:19][N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: NC(=O)Cc1ccccc1Oc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccccc2Cc2ncco2)cc1
Yield: 41 %

Procedure:
A mixture of (2-phenoxyphenyl)acetamide (3.9 g) and bromoacetaldehyde diethyl acetal (3.1 ml) in DMF (100 ml) was heated for 2 hours. After cooling, the resulting mixture was diluted with water and extracted with ether. The extracts were washed with water then dried, concentrated and chromatographed using ethyl acetate: hexane (50:50) as eluant to give 2-(2-phenoxyphenylmethyl)oxazole (1.77 g, 41%) as a brown oil, 1H NMR (CDCl3): delta 4.20 (2H,s), 7.01 (1H,s) and 7.54 (1H,s) ppm.
Reaction SMILES: [C@H:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C[Si]([Br:14])(C)C.CS(C)=O.C(N(CC)C(C)C)(C)C.C1C=C(NS(C2C=CC(N/N=C3/C=CC(C(C(O)=O)=C/3)=O)=CC=2)(=O)=O)N=CC=1>C(Cl)(Cl)Cl>[Br:14][C@H:4]1[C@@H:5]2[CH2:6][C@@H:1]([C:7](=[O:9])[O:8]2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)Br
Reactant: O=C(O)[C@@H]1CC=CCC1
Agent: O=C(O)C1=C/C(=N\Nc2ccc(S(=O)(=O)Nc3ccccn3)cc2)C=CC1=O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1O[C@H]2C[C@@H]1CC[C@H]2Br

Procedure:
(S)-Cyclohex-3-enecarboxylic acid (1.98 g, 15.7 mmol) ([α]D=−92.7° (c=1, CHCl3)=97.5% e.e., resolved by the method of Schwartz et al, J. Am. Chem. Soc., 100, 5199, (1978)) was reacted with trimethylsilyl bromide (4.10 mL, 31.3 mmol), DMSO (2.23 mL, 31.3 mmol), and N,N-diisopropylethylamine (4.45 mL, 31.3 mmol) (by a modification of the method of Iwata et al, Heterocycles., 31, 987 (1990)) to give a white solid, (2.91 g, 14.2 mmol, 90%);
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN1C(=O)CCC1.O>[N:12]1([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
5-Fluoro-2-nitrophenylamine (1.0 eq) and morpholine (3.0 eq) were dissolved in NMP and heated at 100° C. for 1 hour. The solution was cooled to room temperature and diluted with water. The resulting precipitate was filtered and dried under vacuum to yield 5-morpholin-4-yl-2-nitrophenylamine. The resulting solid was recrystallized from EtOH to afford pure product as a bright yellow solid. LC/MS m/z 224.1 (MH+), Rt 1.89 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[CH3:18][N:19]([CH3:26])[CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(Cl)Cl.CO.[NH4+].[OH-]>[CH3:22][C:21]([CH3:25])([CH2:24][O:17][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)[CH2:20][N:19]([CH3:26])[CH3:18]
Reactant: CN(C)CC(C)(C)CO
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N2CCCC2)c2ccc(OCC(C)(C)CN(C)C)cc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.1 %

Procedure:
A suspension of 114 mg (0.5 mmol) of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 2, 71 mg (0.53 mmol) of 3-dimethylamino-2,2-dimethyl-1-propanol, 196.7 mg (0.75 mmol) of triphenyl phosphine in THF (4 ml) was treated at RT with 123 μl (0.75 mmol) of diethyl azodicarboxylate and stirred at RT for 48 h. The precipitate that had formed was removed by filtration, the filtrate was concentrated in vacuo and the oily residue obtained was applied to silica gel column with CH2Cl2/MeOH/NH4OH (90:10:1) as eluent. The purified fractions were combined and concentrated in vacuo. The residue was taken up in ether, the crystalline solid that formed was filtered off by suction and dried in a high vacuum to give 24 mg (23%) of the desired [2,2-dimethyl-3-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxy)-propyl]-dimethyl-amine as an off-white solid. ISP mass spectrum, m/e: 342.4 (M+1 calculated for C21H31N3O: 342). (Further material, 30 mg, 29%, was obtained on concentration of the mother liquid and collection of the product as hydrochloride salt).
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[CH:9]=O.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO.C1COCC1>[CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[CH2:9][NH:21][CH:18]1[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: COC/C=C/c1cc(C=O)cc(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COC/C=C/c1cc(CNC2CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-[(1E)-3-Methoxyprop-1-en-1-yl]-5-(trifluoromethyl)benzaldehyde (1 eq.) from the previous step and cyclopropylamine (2 eq.) were combined in CH2Cl2 (0.2 M). To this was then added MgSO4 (1.5 eq.) and the resulting suspension was stirred at RT for 18 h. The insolubles were then removed via filtration through a pad of celite and the filtrate was concentrated in vacuo. The crude imine thus obtained was then re-taken up in a 2:1 (v/v) mixture of THF:MeOH (0.2 M). To this solution was added sodium borohydride (5 eq.) portionwise and the resulting mixture was stirred at RT for 18 h. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were then washed with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]#[N:11].[S:12]([OH:16])(=[O:15])(=[O:14])[CH3:13].[CH2:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[CH3:18]>ClC1C=CC=CC=1>[S:12]([OH:16])(=[O:15])(=[O:14])[CH3:13].[CH2:17]([C:19]1[CH:20]=[C:21]([NH:22][C:10]([NH:9][C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])=[NH:11])[CH:23]=[CH:24][CH:25]=1)[CH3:18]
Reactant: N#CNc1cc(Cl)ccc1Cl
Reactant: CCc1cccc(N)c1
Agent: CS(=O)(=O)O
Solvent: Clc1ccccc1
Product: CCc1cccc(NC(=N)Nc2cc(Cl)ccc2Cl)c1

Procedure:
A mixture of 2,5-dichlorophenylcyanamide (1.02 g, 5.5 mmol), 3-ethylaniline mesylate (1.1 g, 5 mmol), and chlorobenzene (15 mL) were combined in a dry round bottom flask equipped with a water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 2 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., 15 hours) to yield the title compound, N-(3-ethylphenyl)-N'-(2,5-dichlorophenyl)guanidine mesylate, as a white solid (1.5 g, 75% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([OH:17])=O)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:39]1([CH3:48])[CH:44]=[CH:43][C:42]([C@@H:45]([NH2:47])[CH3:46])=[CH:41][CH:40]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:47][C@H:45]([C:42]2[CH:43]=[CH:44][C:39]([CH3:48])=[CH:40][CH:41]=2)[CH3:46])=[O:17])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(O)C1COCCN1c1nc(Cl)ncc1Br
Reactant: Cc1ccc([C@H](C)N)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc([C@H](C)NC(=O)C2COCCN2c2nc(Cl)ncc2Br)cc1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x31 using 4-(5-bromo-2-chloropyrimidin-4-yl)morpholine-3-carboxylic acid (PREPARATION x30, 1 g, 3.10 mmol), EDC (0.892 g, 4.65 mmol), HOBt (0.712 g, 4.65 mmol), triethylamine (1.296 mL, 9.30 mmol) and (S)-1-p-tolylethanamine (0.629 g, 4.65 mmol) in DMF (15 mL). 1H NMR (400 MHz, DMSO-d6) δ 1.37 (dd, J=6.95, 3.66 Hz, 3 H), 2.27 (s, 3 H), 3.55 (d, J=9.35 Hz, 2 H), 3.66-3.77 (m, 1 H), 3.82-3.92 (m, 1 H), 4.21-4.39 (m, 2 H), 4.83-5.01 (m, 2 H), 7.12 (d, J=7.83 Hz, 2 H), 7.16-7.28 (m, 2 H), 8.45 (d, J=10.86 Hz, 2 H). ESI-MS m/z [M+H]+ calc'd for C18H20BrClN4O2, 439.05; found 439.2.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:16])[N:7]([CH2:8][CH2:9][OH:10])[C:6](=[O:11])[C:5]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:4]12.Cl[CH2:18][C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][C:19]([CH2:18][O:10][CH2:9][CH2:8][N:7]1[C:6](=[O:11])[C:5]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:4]2[C:3]1=[O:16])=[O:26])[CH3:25]
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a slurry of sodium hydride (57% dispersion in oil, 66.1 g; 1.57M), in tetrahydrofuran (500 ml) cooled to 0° under nitrogen was added 2-phthalimidoethanol (150 g; 0.785M) followed by ethyl 4-chloroacetoacetate (129 g; 0.785M) in tetrahydrofuran (250 ml) over 1 hour. The mixture was stirred at room temperature overnight then poured into a mixture of 1M hydrochloric acid (800 ml) and ethyl acetate (750 ml). The organic phase was separated and the solvent was evaporated at reduced pressure. The residue separated into two layers and the upper layer of mineral oil was removed to leave the title compound (243 g) as a crude product which was used without further purification.
Reaction SMILES: C(C1CCC(C)CC1[O:11][C:12]([CH:14]1[CH2:18][CH:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH2:16][N:15]1C(OC(C)(C)C)=O)=[O:13])(C)C.[ClH:34]>C1(C)C=CC=CC=1>[ClH:34].[F:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][C@@H:17]1[CH2:16][NH:15][C@H:14]([C:12]([OH:13])=[O:11])[CH2:18]1
Reactant: CC1CCC(C(C)C)C(OC(=O)C2CC(Cc3cccc(F)c3)CN2C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1C[C@H](Cc2cccc(F)c2)CN1
Temperature: 25 °C
Yield: 81 %

Procedure:
4-(3-Fluoro-benzyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-(2-isopropyl-5-methyl -cyclohexyl) ester (Preparation 3, 0.91 g, 1.96 mmol) was dissolved in toluene (2 ml). 6N hydrochloric acid (50 ml) was added and stirred at reflux for 18 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×20 ml). The aqueous layer was concentrated by evaporated under reduced pressure to give the title compound (417 mg, 81%) as a white solid. 1H-NMR showed a 7:1 ratio of cis:trans diastereoisomers so the product was recrystallised from isopropyl alcohol to give the title compound (170 mg, 65%) in a ratio of 14:1 cis:trans as determined by NMR.
Reaction SMILES: [OH-].[Na+].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[C:15]([C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[CH2:22]Cl)([CH3:18])([CH3:17])[CH3:16].[CH:32](=[O:36])[CH:33]([CH3:35])[CH3:34].C(Cl)C1C=CC=CC=1.C(=O)C(C)C.Cl>C1C=CC=CC=1.O.C1C=CC=CC=1.O>[CH3:34][C:33]([CH3:35])([CH2:22][C:21]1[CH:20]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=1)[CH2:32][OH:36]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Reactant: CC(C)C=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: ClCc1ccccc1
Product: CC(C)(CO)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 103 %

Procedure:
A three-neck, three-liter flask equipped with a mechanical stirrer, thermometer and an addition funnel was charged with 80 grams of sodium hydroxide and 80 milliliters of water under a nitrogen atmosphere. The mixture was stirred until dissolved and a mixture of 450 milliliters of benzene and 12.5 milliliters of 40 percent methanolic benzyl trimethyl ammonium hydroxide was added forming a benzene-water mixture. A mixture of 383 grams of 3,5-di-t-butyl-4-hydroxy benzyl chloride and 144 grams of isobutyraldehyde was prepared and placed in the addition funnel. The benzyl chloride/isobutyraldehyde mixture was added to the mixture of benzene and water while the flask contents were vigorously stirred at a temperature of 50° C to 60° C over a two-hour period. After addition was complete, the mixture was stirred for an additional one-half hour at room temperature. The mixture was hydrolyzed with dilute hydrochloric acid until the benzene layer turned clear yellow-orange color. The benzene layer was separated and the benzene evaporated to obtain 453 grams of 2,2-di-methyl-3-(3,5-di-t-butyl-4-hydroxyphenyl)propanol. The melting point of the product was between 72° C and 74° C after recrystalization from hexane.
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[CH2:11]([O:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=O)=[CH:29][CH:28]=3)=[N:25][CH:26]=2)[CH2:17][CH2:16]1)[CH2:12][CH3:13].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:11]([O:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:31]#[N:33])=[CH:34][CH:35]=3)=[N:25][CH:26]=2)[CH2:17][CH2:16]1)[CH2:12][CH3:13]
Reactant: CCCO[C@H]1CC[C@H](c2cnc(-c3ccc(C(N)=O)cc3)nc2)CC1
Agent: Cl
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCO[C@H]1CC[C@H](c2cnc(-c3ccc(C#N)cc3)nc2)CC1
Temperature: 40 °C

Procedure:
9.2 Ml. of benzenesulfonyl chloride are added dropwise while stirring to a suspension of 16.0 g. of trans-p-[5-(4-n-propyloxycyclohexyl)-2-pyrimidinyl]benzamide in 170 ml. of pyridine. The mixture is then warmed to 40° C. for 15 hours in an oil-bath. The clear mixture is poured into a mixture of 200 g. of ice and 24.1 ml. of concentrated hydrochloric acid and the product is taken up in methylene chloride. The extract is washed three times with 195 ml. of 3-N hydrochloric acid each time, then with 100 ml. of saturated sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated. The crude product is chromatographed on a column of 200 g. of silica gel with benzene and with benzene containing 1% and 2% acetone (v/v). The fractions which are pure according to thin-layer chromatography are recrystallized from acetone/hexane. There is obtained trans-p-[5-(4-n-propyloxycyclohexyl)-2-pyrimidinyl]benzonitrile; melting point 114.5° C., clearing point 223.5° C.
Reaction SMILES: [OH:1][CH:2](S([O-])(=O)=O)[CH2:3][CH2:4][CH:5]([N+:14]([O-:16])=[O:15])[CH2:6][CH2:7][CH:8]([OH:13])S([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[N+:14]([CH:5]([CH2:4][CH2:3][CH:2]=[O:1])[CH2:6][CH2:7][CH:8]=[O:13])([O-:16])=[O:15]
Reactant: O=[N+]([O-])C(CCC(O)S(=O)(=O)[O-])CCC(O)S(=O)(=O)[O-]
Agent: O=C([O-])O
Agent: O=CC(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=CCCC(CCC=O)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium 1,7-dihydroxy-4-nitro-heptane-1,7-disulfonate, 9, (219 g, 0.57 mol) in methylene chloride (1.6 L) was added a solution of glyoxylic acid (160 g, 1.7 mol) and sodium bicarbonate (150 g, 1.78 mol) in water (2 L). The resulting mixture was stirred at room temperature for 30 to 60 minutes until all solids were dissolved. The organic layer was split and the aqueous layer was extracted with methylene chloride twice (2×400 ml). Combined extracts were then concentrated to give a colorless oil. The product was carried to next step without further purification. Yield: 85 g, 86%. 1H NMR (400 MHz, CDCl3) δ 2.09-2.24 (m, 4H), 2.58 (m, 4H), 4.61 (m, 1H), 9.77 (s, 2H). 13C NMR δ 26.2, 39.9, 86.9, 200.0.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH:16]([CH3:18])[CH3:17])=[C:10]([CH:14]=1)[C:11]([OH:13])=O)(=[O:5])=[O:4])[CH3:2].Cl.[F:20][C:21]([F:34])([F:33])[C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH:16]([CH3:18])[CH3:17])=[C:10]([C:11]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:26][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:23][N:24]=3)[CH2:28][CH2:29]2)=[O:13])[CH:14]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CCS(=O)(=O)c1ccc(OC(C)C)c(C(=O)O)c1
Agent: Cl
Product: CCS(=O)(=O)c1ccc(OC(C)C)c(C(=O)N2CCN(c3ncc(C(F)(F)F)s3)CC2)c1
Yield: 21 %

Procedure:
Prepared in analogy to example 1 (b) from 5-ethanesulfonyl-2-isopropoxy-benzoic acid (Example A18) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by reversed phase HPLC (acetonitrile/water) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 21%). MS (m/e): 492.1 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:20])[C:12]2[N:13]([N:15]=[C:16]([CH2:18][OH:19])[CH:17]=2)[CH:14]=1.COCCOC.CN(C=O)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:20])[C:12]2[N:13]([N:15]=[C:16]([CH:18]=[O:19])[CH:17]=2)[CH:14]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cn2nc(CO)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: COCCOC
Product: O=Cc1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1.15 g (3.37 mmol) of 6-(2,4-dichlorophenyl)-2-(hydroxymethyl)pyrazolo[1,5-a]pyrazin-4(5H)-one (Example 17A) were suspended in 100 ml of dichloromethane, and 1 drop of water was added. 100 ml of 1,2-dimethoxyethane and 9.6 ml of DMF were then added, and the mixture was cooled to 0° C. 7.16 g (16.87 mmol) of Dess-Martin periodinane were added, ice-bath cooling was removed and the mixture was stirred at RT for 15 h. Ethyl acetate and then 200 ml of a 10% strength sodium thiosulfate solution were added to the mixture, and the organic phase was washed with saturated aqueous sodium bicarbonate solution. Drying of the organic phase with sodium sulfate and removal of the solvent under reduced pressure gave 660 mg (57% of theory) of the product as a solid which was reacted without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[Br:14][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1cccc(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(OC)c1
Reaction time: 2 h

Procedure:
A mixture of 15.7 g (87.1 mmol) of methyl (3-methoxyphenyl)acetate, 16.3 g (91.5 mmol) of N-bromosuccinimide and a catalytic amount of AIBN in tetrachloromethane (150 ml) was heated under reflux with stirring for 2 h. The cooled reaction solution was filtered and the solvent was removed in vacuo.