Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[CH3:21][Si:22](Cl)([CH2:24][CH2:25][Si:26](Cl)([CH3:28])[CH3:27])[CH3:23]>O1CCCC1>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[Si:26]([CH3:28])([CH3:27])[CH2:25][CH2:24][Si:22]2([CH3:23])[CH3:21])[CH:18]=[CH:19][CH:20]=1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: Nc1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Temperature: 78 °C
Reaction time: 0.75 h

Procedure:
A solution of freshly distilled diisopropylamine (22.9 mL) in dry tetrahydrofuran (175 mL) at -78° C. under N2 is treated with n-butyllithium (1.6M in hexanes, 109 mL) dropwise over 15 minutes, and the resulting mixture is stirred at 78° C. for 45 minutes and is then added over ten minutes via cannula to a solution of 3-fluoroaniline (8.00 mL) in dry tetrahydrofuran (166 mL) at -78° C. under N2. The resulting reaction mixture is stirred at -78° C. for 50 minutes and is then treated wilt a solution of 1,1,4,4-tetramethyl-1,4-dichlorodisilethylene (18.3 g) in dry tetrahydrofuran (85 mL). The mixture is allowed to slowly warm to ambient temperature over four hours with stirring and is then washed with water (2×200 mL) and saline (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) 7.12, 6.65, 6.58, 0.86, 0.24 δ.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([NH2:11])[C@H:6]1[O:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[CH2:5]([N:11]=[C:1]=[O:2])[C@H:6]1[O:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(Cl)Cl
Reactant: NC[C@@H]1CCCO1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C=NC[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of phosgene (2 mL of a ˜20% in toluene, 4.44 mmol) in 5 mL of dichloromethane at 0° C. was added a solution of (S)-tetrahydrofurfurylamine (0.15 mL, 1.48 mmol) and triethylamine (0.45 mL, 3.26 mmol) in 4 mL of dichloromethane dropwise over 20 min. The reaction mixture was stirred for 2.5 h at room temperature. The solvent was removed under reduced pressure, and the resulting residue was dissolved in ether. The triethylamine hydrochloride salt was removed by filtration. Concentration afforded 46A as a clear oil in quantitative yield.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]([CH3:64])[C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1>CN(C=O)C>[CH3:49][N:50]([CH3:64])[C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:53][CH:52]=1
Reactant: CN(C)c1ccc(-c2cccc(N)c2)cn1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-dimethylamino-pyridin-3-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.011 g of product in 42% yield: LCMS (ESI) m/z 402 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])=[O:6])[CH3:2].P([O-])([O-])([O-])=O>>[CH2:1]([O:3][C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH2:1]([O:3][C@@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])=[O:6])[CH3:2]
Reactant: CCOCCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=P([O-])([O-])[O-]
Product: CCOCCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCO[C@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C

Procedure:
Ethoxyethyl (2RS) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.5 ml of a solution containing 2 mg/ml in a phosphate, pH 7, 0.1 M) was added followed by immobilised protease from Pseudomonas putida (L-aminopeptidase, available as Novozym 180 or SP 180 from Novo Nordisk) (5 mg) and phosphate buffer (0.1 M, pH 7, 0.5 ml); The reaction mixture was shaken at room temperature and analysed at different times (maximum 36 h). The reaction mixture was analysed without work up by the gradient HPLC method 1 and by the chiral HPLC method.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:21])[CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[N-:22]=[N+:23]=[N-:24].[Na+].CS(C)=O>O>[N:22]([CH2:9][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:21])=[N+:23]=[N-:24]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(Cl)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@@H](O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of toluene-4-sulfonic acid (S)-2-(3-chlorophenyl)-2-hydroxyethyl ester (16.34 g, 0.050 mol), sodium azide (6.50 g, 0.10 mol) and DMSO (50 ml) was stirred for 2 h at 80° C. Water (100 ml) was added, extracted with hexane-ether (1:1) mixture (2×150 ml). Combined extract was dried over Na2SO4, evaporated. The residue was separated on SiO2 (100 g), hexane-EtOAc, 0 to 20%. Colorless oil, 7.0 g, (0.035 mol, 71%). 1H NMR (300 MHz, DMSO) δ 7.46 (s, 1H), 7.36 (m, 3H), 5.95 (d, J=4.5 Hz, 1H), 4.82 (q, J=5.3 Hz, 1H), 3.35 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:19])([CH3:18])[CH2:10][CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1.CS(C)=O.C(N(CC)CC)C>ClCCl>[CH2:15]([O:14][C:12](=[O:13])[C:11](=[O:17])[CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:19])[CH3:18])[CH3:16]
Reactant: CCOC(=O)C(O)CC(C)(C)c1cccc(OC)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
2019 g (78.47 mmol) of ethyl 4-(3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate is dissolved in 820 ml of dichloromethane and mixed with 273 ml of dimethyl sulfoxide. After 39.7 g (392.36 mmol) of triethylamine is added, the batch is mixed in portions with 31.2 g (196.18 mmol) of SO3/pyridine complex and then stirred for 16 hours at room temperature. About 400 ml of dichloromethane is drawn off in a rotary evaporator. Then, the reaction mixture is mixed with 312 ml of saturated ammonium chloride solution with slight cooling, and it is stirred vigorously for 20 minutes. After being extracted two times with diethyl ether (800 ml each), the combined organic phases are washed with water and brine. The residue that remains after the solvent is spun off is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 15.59 g (75.3%) of the desired compound is isolated.
Reaction SMILES: C([O:3][C:4](=[O:41])[C@@H:5]([NH:10][C:11](=[O:40])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH2:25][C@H:26]([OH:39])[C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:28]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>>[OH:39][C@H:26]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:28]=1)[CH2:25][NH:24][CH:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([NH:10][C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:41])=[O:3])=[O:40])=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from 2-(4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoylamino)-4-methyl-pentanoic acid ethyl ester (which was obtained in Example 198) by sodium hydroxide hydrolysis as a white solid; mp >177° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.87 (d, J=6.3 Hz, 3H), 0.90 (d, J=6.3 Hz, 3H), 1.35-1.75 (m, 5H), 1.90-2.00 (m, 2H), 2.60-2.90 (m, 5H), 2.94 (s, 3H), 3.65-3.80 (m, 2H), 4.25-4.35 (m, 1H), 4.60-4.65 (m, 1H), 6.85 (d, J=8.3 Hz, 1H), 6.90 (d, J=8.9 Hz, 2H), 7.05 (dd, J=8.3,1.9 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 7.73 (d, J=8.9 Hz, 2H), 7.98 (d, J=7.7 Hz, 1H); MS (ES) m/z: 561.3 (M-H)−; HRMS Calcd. for C27H37N4O7S(M−H)−: 561.2377. Found: 561.2381.
Reaction SMILES: Cl.CO[C:4](=[NH:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[OH:10][CH2:11][C:12]([CH2:14]O)=O.[NH3:16]>>[C:5]([C:4]1[NH:9][CH:14]=[C:12]([CH2:11][OH:10])[N:16]=1)([CH3:6])([CH3:7])[CH3:8]
Reactant: N
Reactant: O=C(CO)CO
Reactant: COC(=N)C(C)(C)C
Agent: Cl
Product: CC(C)(C)c1nc(CO)c[nH]1

Procedure:
A mixture of 326 gm. of pivalimidic acid methyl ester hydrochloride and 193.5 gm. of 1,3-dihydroxyacetone in 2 liters of liquid ammonia are reacted as desribed in Example 3, giving the desired product, m.p. 212°-221° C.
Reaction SMILES: [N:1]12[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]2.[C:27](Cl)(=[O:30])[O:28][CH3:29]>>[C:27]([N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:28][CH3:29])=[O:30])[CH2:20][CH2:19][N:10]2[CH2:11][CH2:12][N:13]([C:27]([O:28][CH3:29])=[O:30])[CH2:14][CH2:15][N:16]([C:27]([O:28][CH3:29])=[O:30])[CH2:17][CH2:18][N:1]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:26][CH2:25]1)([O:28][CH3:29])=[O:30]
Reactant: C1CNCCN2CCNCCNCCN(CCN1)CCOCCOCC2
Reactant: COC(=O)Cl
Product: COC(=O)N1CCN2CCOCCOCCN(CCN(C(=O)OC)CC1)CCN(C(=O)OC)CCN(C(=O)OC)CC2

Procedure:
In a manner similar to that described in Example 7, treat 4,7-dioxa-1,10,13,16,21,24-hexaazabicyclo[8,8,8]hexacosane (compound of Example 70C) with methyl chlorocarbonate to obtain 13,16,21,24-tetracarbomethoxy-4,7-dioxa-1,10,13,16,21,24-hexaazabicyclo[8,8,8]hexacosane as a viscous liquid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C@H:9]1[CH2:14][N:13]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[N:36]=[C:35]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=5)[CH:34]=[C:33]([C:47]([O:49][CH3:50])=[O:48])[C:20]=4[N:21](CC4C=CC(OC)=CC=4)[C:22]=3[CH:23]=2)[CH2:12][C@@H:11]([CH3:51])[O:10]1.C1(OC)C=CC=CC=1>>[CH3:51][C@H:11]1[CH2:12][N:13]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[N:36]=[C:35]([C:37]5[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=5)[CH:34]=[C:33]([C:47]([O:49][CH3:50])=[O:48])[C:20]=4[NH:21][C:22]=3[CH:23]=2)[CH2:14][C@@H:9]([CH3:8])[O:10]1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3n(Cc3ccc(OC)cc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N3C[C@@H](C)O[C@@H](C)C3)ccc12
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
TFA (3 mL) was added to a mixture of methyl 7-((2S,6R)-2,6-dimethylmorpholino)-5-(4-methoxybenzyl)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (27 mg, 0.045 mmol) and anisole (0.049 mL, 0.45 mmol) in a vial. The vial was sealed and heated at 60° C. for 3 hr and then 70° C. for an additional 4 hr. The solvent was removed and the residue was dissolved in EtOAc. This was washed with saturated aqueous NaHCO3 solution, brine, and then dried with sodium sulfate. Removal of the solvents followed by radial chromatography (step gradient elution with DCM containing 50 to 0% hexane followed by 10% EtOAc) to afforded methyl 7-((2S,6R)-2,6-dimethylmorpholino)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (16 mg, 0.034 mmol, 75% yield) as a yellow oil. MS (ESI) m/z 484.1 (M+H). 1H NMR (400 MHz, chloroform-d) d ppm 9.41 (1H, s), 8.42 (1H, s), 8.32 (1H, d, J=7.30 Hz), 8.27 (1H, d, J=8.56 Hz), 8.16 (1H, s), 7.55-7.66 (2H, m), 7.00 (1H, dd, J=8.81, 2.01 Hz), 6.92 (1H, d, J=2.01 Hz), 4.08 (3H, s), 3.85 (2H, ddd, J=10.45, 6.30, 2.39 Hz), 3.63 (2H, d, J=10.58 Hz), 2.51-2.61 (2H, m), 1.30 (6H, d, J=6.04 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](OC(OCC)OCC)C.[N-:23]=[N+:24]=[N-:25].[Na+]>C(O)(=O)C>[N:1]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH:13]=[N:25][N:24]=[N:23]1
Reactant: CCOC(OCC)OCC
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-n2cnnn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-aminobenzoate (1.65 g) in acetic acid (20 mL) is added triethylorthoformate (8 mL) and sodium azide (1.17 g) and the solution is heated at reflux for 4 h. After cooling and removing acetic acid in vacuo, water and dichloromethane are added and the organic layer is separated and dried (MgSO4) and concentrated. The crude ester is dissolved in methanol (30 mL) and 4 M aqueous NaOH solution (3 mL) is added and the solution is stirred at room temperature for 2 h. The mixture is neutralized with 6 M aqueous HCl, concentrated and then acidified with 6 M aqueous HCl. The precipitate is filtered off washing with water and dried by suction to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1)=O.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH2:24].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH:24][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1
Reactant: Cc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCC(C)(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404, Part D) (0.200 g, 0.777 mmol), 3,3-dimethylbutylamine (0.100 g, 0.777 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.8 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the pre-loaded column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with (2.0 M NH3 in methanol), ethyl acetate and hexanes. After concentrating, take the product up in CH2Cl2 (25 mL) and wash with 1.0 N NaOH solution (2×10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.110 g, 41.4%): MS ES+ 343.1 (M+H)+, base peak 242.0 (M-C6H14N)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=9.7 min, 94.3% purity.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]([F:28])([F:27])[O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C)C=O>[F:16][C:17]([F:27])([F:28])[O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:21][CH:20]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 60.2 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 4-trifluoromethoxy-benzyl bromide (77 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(4-trifluoromethoxy-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (110 mg, 60%) as a light yellow oil. APCI-MS (M+H) 381.
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[N:31]1([C:3]([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]3)=[CH:8][CH:9]=2)=[O:30])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1)N1CCOCC1
Yield: 40 %

Procedure:
As described for Example 10, 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (70 mg, 0.17 mmol) was converted, using morpholine instead of cyclopropanemethylamine, to the title compound (32 mg, 40%) which was obtained as a white foam. MS: m/e=469.1 [M+H]+.
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([C:10]2[CH:11]=[CH:12][C:13]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([F:7])[CH:9]=2)=[CH:22][CH:21]=1)[CH3:24]
Reactant: Brc1ccc[se]1
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1

Procedure:
A mixture of 34.2 g (0.16 mol) of 2-bromoselenophene, 40.0 g (0.16 mol) of 3-fluoro-4′-ethylbiphenyl-4-ylboronic acid, 10.0 g (8.65 mmol) of tetrakis-(triphenylphosphine)palladium(0) and 200 ml of 2 N sodium carbonate soln. in 500 ml of toluene/ethanol (2:3) is heated at 90° C. for 2 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with water, and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). 2-(4′-Ethyl-3-fluorobiphenyl-4-yl)-selenophene is obtained as a yellow solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:9].O[C:14]1[CH:15]=[C:16]([C:20]([CH3:23])([CH3:22])O)[CH:17]=[CH:18][CH:19]=1>C1(C)C=CC=CC=1>[OH:7][C:1]1[CH:6]=[C:5]([C:20]([C:16]2[CH:17]=[CH:18][C:19]([OH:9])=[CH:14][CH:15]=2)([CH3:23])[CH3:22])[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(O)c1cccc(O)c1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(O)cc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
A mixture of 1335 grams (14.2 moles) of phenol, 450 ml. of 75% aqueous sulfuric acid and 1800 ml. of toluene was stirred at room temperature while a solution of 450 grams (2.9 moles) of 3-hydroxyphenyldimethylcarbinol in 890 grams (9.5 moles) of phenol and 1800 ml. of toluene was added over three hours. The reaction mixture was stirred at room temperature for four hours and the aqueous layer was separated and discarded. The organic layer was washed twice with water, once with 10% sodium bicarbonate solution and again with water. Toluene and excess phenol were removed by vacuum distillation and the residue was recrystallized from toluene. There was obtained 371 grams (55% of theoretical) of the desired 2-(3-hydroxyphenyl)-2-(4-hydroxyphenyl)propane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.Cl[P:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[K+].C1OCCOCCOCCOCCOCC[O:43]C1>C1(C)C=CC=CC=1.O>[C:27]1([P:26]([CH2:14][C:13]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:43])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Temperature: 109 °C
Reaction time: 3.5 h
Yield: 581.7 %

Procedure:
2.02 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 13.1 g of toluene and, with ice-bath cooling, admixed with 1.67 g (7.51 mmol) of chlorodiphenylphosphine in 1.9 g of toluene. The mixture was heated at 109° C. for 3 h. After cooling to room temperature, 590 mg (8.94 mmol) of solid potassium hydroxide and 159 mg (0.582 mmol) of 18-crown-6 were added, and the mixture was stirred vigorously at 60° C. for 3.5 h. 30 ml of water was added to the warm reaction mixture. The mixture was briefly stirred at 60° C. and slowly cooled to 4° C., and the precipitated solid was filtered off. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under reduced pressure at 40° C. 1.82 g (59.5 percent; content: 95.9 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulphonamide was isolated in the form of a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:18]([O-])=O)[C:8]([O:16][CH3:17])=[C:9]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:18][C:7]1[C:8]([O:16][CH3:17])=[C:9]([C:11]([CH3:15])([CH3:14])[C:12]#[N:13])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1C(C)(C)C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1c(N)cc(C(C)(C)C)cc1C(C)(C)C#N
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a solution of 2-(5-tert-butyl-2-methoxy-3-nitrophenyl)-2-methylpropanenitrile (0.086 g, 0.311 mmol) in ethanol (3.1 mL), iron (0.087 g, 1.56 mmol), ammonium chloride (0.083 g, 1.56 mmol) and water (1.6 mL) were added, and the mixture was stirred for 3 hours under reflux. The reaction mixture was filtered and washed with ethanol. The obtained filtrate was evaporated under reduced pressure and the residue was dissolved in dichloromethane. After washing this solution with water and then saturated brine, the solution was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-30/70) to obtain 0.051 g of the captioned compound (67% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:12]=2[S:13][C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br>C(O)(=O)C.C(OCC)(=O)C.O>[Br:27][C:11]1[C:12]([S:13][C:14]([F:16])([F:17])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:10]=1[C:18]([F:21])([F:19])[F:20]
Reactant: FC(F)(F)Sc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)Sc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(p-chlorophenyl)-5-(trifluoromethyl)-3-[(trifluoromethyl)thio]pyrrole (1.03 g, 3.0 mmol) and sodium acetate (0.3 g, 3.6 mmol) in acetic acid is treated with bromine (0.58 g, 3.6 mmol), stirred for 30 minutes at room temperature and diluted with an ethyl acetate/water mixture. The organic phase is separated, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a semi-solid. Chromatography of the semi-solid using silica gel and hexanes gives the title product as a white solid (mp 87.0°-88.5° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.