Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6]P(=O)(OCC)OCC)=[CH:4][C:3]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl:24][C:25]1[CH:38]=[CH:37][C:28]([C:29]([CH:34]2[CH2:36][CH2:35]2)=[C:30]([F:33])[CH:31]=O)=[CH:27][CH:26]=1.C[O-].[Na+]>O1CCCC1>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([CH:34]2[CH2:36][CH2:35]2)=[C:30]([F:33])[CH:31]=[CH:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[C:3]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:4]=2)=[CH:37][CH:38]=1
Reactant: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Reactant: CCOP(=O)(Cc1ccc(F)c(Oc2ccccc2)c1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A stirred solution of diethyl (4-fluoro-3-phenoxybenzyl)phosphonate (2.64 g, 7.8 mmol) and p-chloro-β-cyclopropyl-α-fluorocinnamaldehyde (1.35 g, 6 mmol) in tetrahydrofuran (20 ml) is treated with sodium methoxide (562 mg, 9.36 mmol) at 0° C., stirred at room temperature overnight, quenched with 2 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic extract is washed sequentially with water, 2 N aqueous hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel eluting with 1:9 ethyl acetate/hexanes gives the title product as a syrup (2.15 g, 87.7% yield) which is identified by 1H and 19F NMR spectral analyses.
Reaction SMILES: O1CCN([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)CC1.[CH2:49]([OH:51])[CH3:50]>>[CH2:49]([O:51][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=2)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]2[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=3)[CH:32]=[CH:31][N:30]=2)[CH:8]=1)[CH3:50]
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CCO
Product: CCOc1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)thio)propanoic acid 14, using ethanol in place of morpholine. 1H-NMR (300 MHz, DMSO, ppm): δ 12.49 (s, 1H), 9.57 (m, 1H), 8.98-8.96 (m, 1H), 8.41-8.38 (m, 2H), 7.88-7.54 (m, 10H), 7.16-7.10 (m, 2H), 4.63 (m, 2H), 4.14-4.12 (m, 2H), 3.88 (s, 2H), 2.60-2.58 (m, 2H), 1.37-1.35 (t, J=3 Hz, 3H). MS (ES, m/z): 638 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][CH3:24])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH2:21][CH3:22])[CH:14]=2)=[N:10][CH:11]=1)=[O:4].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:23]([C@H:2]1[NH:1][C:26](=[O:28])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([O:20][CH2:21][CH3:22])[CH:14]=3)=[N:10][CH:11]=2)[C:3]1=[O:4])[CH3:24]
Reactant: CCOc1cc(Oc2ncc(NC(=O)[C@H](N)CC)cn2)ccc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOc1cc(Oc2ncc(N3C(=O)N[C@H](CC)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 132 %

Procedure:
To a solution of ((2R)-2-amino-N-(2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-pyrimidinyl)butanamide (Intermediate 94, 62 mg) in dry dichloromethane (4 mL), TEA (158 μl, 1.13 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (25.2 mg, 0.085 mmol) in dry dichloromethane (2 mL) was then added dropwise and the reaction mixture was stirred at 0° C. for 20 minutes. The reaction mixture was evaporated under vacuum. The residue obtained was purified by silica gel chromatography chromatography (Companion system, 12 g silica cartridge) with Cyclohexane/EtOAc as eluents from 100/0 to 50/50 in 20 minutes and then 50/50 during 15 minutes to afford the title compound as a white solid (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:21][CH3:22])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1OC
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1OC)C1CCOCC1
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To a solution of methyl 5-chloro-2-methoxy-3-[(oxan-4-yl)amino]benzoate (220 mg, 0.73 mmol) in 1,2-dichloroethane (2 ml) at room temperature under nitrogen was added acetaldehyde (82 μl, 1.47 mmol) followed by acetic acid (0.25 ml, 4.4 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (0.47 g, 2.2 mmol) at room temperature. After stirring for 16 hours acetaldehyde (82 μl, 1.47 mmol) was added to the reaction mixture and stirred for 5 minutes before the addition of sodium triacetoxyborohydride (0.47 g, 2.2 mmol). After stirring for 24 hours, a further acetaldehyde (82 μl, 1.47 mmol) was added to the reaction mixture and stirred for 5 minutes before the addition of sodium triacetoxyborohydride (0.47 g, 2.2 mmol). The reaction was stirred for 24 h after which deionized water (10 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 127 mg (53%) of the title compound as a yellow oil. LC-MS 93%, m/z=328.4/330.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.35 (d, J=2.6 Hz, 1H), 7.09 (d, J=2.6 Hz, 1H), 3.98 (dd, J=11.3, 4.2 Hz, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.48 (tt, J=11.6, 4.0 Hz, 1H), 3.36 (td, J=11.8, 1.9 Hz, 2H), 3.15 (q, J=7.0 Hz, 2H), 1.78 (qd, J=12.2, 4.6 Hz, 2H), 1.72-1.59 (m, 2H), 0.99 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[C:7]2[O:13][CH:14]=[CH:15][C:6]=2[C:5]=1[O:16][CH3:17])=[O:3].C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27]Br>>[C:2]([C:4]1[C:9]([O:10][CH2:27][CH2:26][CH2:25][Br:24])=[C:8]([O:11][CH3:12])[C:7]2[O:13][CH:14]=[CH:15][C:6]=2[C:5]=1[O:16][CH3:17])(=[O:3])[CH3:1]
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1c(C(C)=O)c(OCCCBr)c(OC)c2occc12
Yield: 88 %

Procedure:
Khellinone (400 mg, 1.7 mmol, 0.3 M), K2CO3 (3 eqs) and 1,3-dibromopropane (3 eqs) were reacted according to General Procedure A. The crude product was purified by flash chromatography, eluting with ethyl acetate:petroleum ether (15:85) to afford the title compound as a clear oil (530 mg, 88%). 1H NMR (300 MHz, CDCl3): δ 2.24 (quintet, J=6.2 Hz, 2H), 2.51 (s, 3H), 3.57 (t, J=6.6 Hz, 2H), 3.97 (s, 3H), 4.07 (s, 3H), 4.19 (t, J=6.4 Hz, 2H), 6.86 (d, J=2.2 Hz, 1H), 7.56 (d, J=2.2 Hz, 1H). MS (ES+) m/z 356.8/358.8 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:20])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=2)=[C:5]2[CH2:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24][C:4]=12)[CH3:2].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)(C)C.[OH-].[Na+].C(#N)C>[CH3:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:24][C:23]([CH3:25])([CH3:26])[CH2:22][CH2:21][C:5]=23)=[O:20])[CH:16]=[C:15]([CH3:17])[C:14]=1[O:18][CH2:27][CH:29]1[CH2:30][O:31]1
Reactant: ClCC1CO1
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)c2c1CC(C)(C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)O
Product: CCc1sc(C(=O)CCc2cc(C)c(OCC3CO3)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-(4-hydroxy-3,5-dimethyl-phenyl)-propan-1-one (75 mg, 0.20 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1.7 mL) is treated with epichlorohydrine (75 mg, 0.60 mmol) and the mixture is stirred at rt for 1 h. The mixture is diluted with acetonitrile (1 mL) and separated by prep. HPLC (Phenomenex Aqua, 75×30 mm ID, 10 μm, 10-95% acetonitrile in water containing 0.5% formic acid) to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (50 mg) as a colourless resin; LC-MS: tR=1.21 min, [M+1]=427.41.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([CH:14]([C:11]2[CH:10]=[CH:9][C:8]([CH3:7])=[CH:13][CH:12]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
33.5 g (0.3 mol of potassium tert-butoxide are initially introduced into 100 ml of anhydrous DMF at 0° C., and 51.6 g (0.25 mol) of the compound from Example XX in 250 ml of anhydrous DMF are added dropwise. The mixture is stirred at 0° C. for 30 min and 32.2 ml (0.3 mol) of cyclopentyl bromide in 150 ml of anhydrous DMF are added dropwise at 5°-15° C. and the mixture is stirred at 25° C. for 20 h. After concentrating, the residue is partitioned between water and diethyl ether, and the ether phase is dried over sodium sulphate and concentrated. The product crystallizes out.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([OH:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([O:15][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClCCN1CCCCC1
Reactant: Cc1nc(O)nn1-c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nc(OCCN2CCCCC2)nn1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ol (0.41 mmol) was dissolved in methanol (150 mL) at room temperature. A solution of potassium carbonate in water (30 mL) was added dropwise until pH 9. After 15 min under stirring a solution of 1-(2 chloroethyl) piperidine hydrochloride (0.62 mmol) in water (100 mL) was added. The reaction was stirred at room temperature overnight. The methanol was evaporated and after extraction with CH2Cl2 the organic layer was dried over MgSO4 then evaporated and finally purified by chromatography in silica gel to give 1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yloxy]ethyl}piperidine (0.03 g, yield 20%) as a dark orange oil. H1NMR (300 MHz, CDCl3, 25° C.) δ: 7.53 (d, J=2.4 Hz, 1H); 7.48 (d, J=8.6 Hz, 1H); 7.23 (dd, J=2.4 Hz, 1H); 4.33 (t, J=5.9 Hz, 2H); 2.71 (t, J=5.9 Hz, 2H); 2.44 (t, J=4.9 Hz, 4H); 2.40 (s, 3H); 1.51 (q, J=5.5 Hz, 4H); 1.34 (m, 2H) ppm. EM (ES+) m/z=355 (100%) [M+H]+. C16H20Cl2N4O (355.26) calc. C, 54.09%; H, 5.67%; N, 15.77%. found C, 53.80%; H, 5.72%; N, 15.48%.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:20]1[NH:25][CH2:24][CH2:23][N:22]2[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][CH:21]12.C(O)(=O)C.C([BH3-])#N.C[NH+](C)C>CO>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:25]3[CH2:24][CH2:23][N:22]4[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][CH:21]4[CH2:20]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C1CCCC2CNCCN12
Agent: C[NH+](C)C
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCCC2CN(C3CN(C(c4ccccc4)c4ccccc4)C3)CCN12
Temperature: 120 °C
Yield: 27.6 %

Procedure:
To a solution of 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 1.32 g, 5.6 mmol) and octahydro-6H-pyrido[1,2-a]pyrazin-6-one hydrochloride (see Bioorg. Med. Chem.; 2004; 71-86; 1.30 g, 6.8 mmol), in methanol (10 mL) was added acetic acid (1 mL). The solution was mixed with (polystyrylmethyl) trimethylammonium cyanoborohydride (4.2 mmol/g, 1.67 g, 8.8 mmol) and the mixture was heated for 5 min at 120° C. using microwave single node heating. The resin was filtered off and then the solvent was removed by evaporation. The product was purified by means of silica gel chromatography using a mixture of ammonia saturated methanol (2%) and methylene chloride. There was obtained 0.58 g (28%) of 2-[1-(diphenylmethyl)azetidin-3-yl]octahydro-6H-pyrido[1,2-a]pyrazin-6-one as an oil. 1H NMR (500 MHz, CDCl3): 1.4 (q, 1H), 1.7 (t, 2H), 1.8-2.0 (m, 3H), 2.3-2.4 (m, 1H), 2.4-2.5 (d, 1H), 2.7-2.8 (t, 3H), 3.0 (m, 3H), 3.4-3.6 (m, 3H), 4.5 (s, 1H), 4.6 (d, 1H), 7.2 (m, 2H), 7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 376 (M+1)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.CCCCCC.[Cl:12][C:13](=[CH2:22])[CH2:14][CH:15]([CH2:20][CH3:21])[C:16]([O:18][CH3:19])=[O:17].C(I)C>C1COCC1>[Cl:12][C:13](=[CH2:22])[CH2:14][C:15]([CH2:1][CH3:2])([CH2:20][CH3:21])[C:16]([O:18][CH3:19])=[O:17]
Reactant: C=C(Cl)CC(CC)C(=O)OC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Solvent: CCCCCC
Product: C=C(Cl)CC(CC)(CC)C(=O)OC
Reaction time: 0.75 h

Procedure:
(0.80 mL, 5.7 mmol) in THF (5 mL) was added a 1.6M solution of butyllithium in hexane (3.4 mL, 5.4 mmol) over a 5 minute period and stirring was continued for an additional 45 min. Then a solution of methyl 4-chloro-2-ethyl-4-pentenoate (800 mg, 5 mmol) from Example 27, Step A, in THF (2 mL) was added and the reaction was stirred at 0° C. for another 30 minutes. Then ethyl iodide (440 μL, 5.5 mmol) was added and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with NH4OAc buffer (50 mL of 25% w/v) and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude product was purified by Kugelrohr distillation (b.p. 120° C. at 0.1 mm Hg) to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[C:57]=2[F:66])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:68]=[CH:67][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:63])[F:64])[C:57]=2[F:66])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.2 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 106 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(2-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 4 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 112 mg light yellow solid (73%). MS (ISP) 497.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Nitrophenol(41 mmoles, 5.1 g) was dissolved in DMF (500 ml) and treated with sodium hydride (41 mmoles previously washed with hexane). After stirring at room temperature for 1 hr, 2-chloroquinoline (40 mmoles, 6.5 g) was added dropwise and stirred for 16 hr at room temperature followed by refluxing for 6 hr. Water was added to the cooled solution and the product was extracted with ethyl acetate. The ethyl acetate solution was washed with water, and 5N NaOH, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with ethyl acetate/hexane to yield 2-(4-nitrophenoxy)quinoline. 3.1 mmoles, 8%. Mass Spec (FD) 266. Calcd for C15H10N2O3 : C 67.45; H, 3.84; N, 10.40. Found: C, 65.84; H, 3.88; N, 8.47.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C@@H:17]([OH:27])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].N1C=CN=C1.[Si:36](Cl)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:29])([CH3:28])[C@@H:17]([O:27][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 70 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
3β-Hydroxy-4,4-dimethylchol-5-en-24-oic acid methyl ester (19.1 g) is suspended in 390 ml of N,N-dimethylformamide (hereinafter designated DMF) and 39 g of imidazol and 34.6 g of tert-butyldimethylsilyl chloride is added. The reaction mixture is stirred at 70° C. for 20 hours. After aqueous work-up, a crude product 23.9 g is isolated. Crystallization from tetrahydrofurane/methanol (hereinafter tetrahydrofurane and methanol are designated THF and MeOH, respectively) yields 3β-tert-butyldimethylsilyloxy-4,4-dimethyl-chol-5-en-24-oic acid methyl ester (19.55 g). Melting point: 144-146° C. 1H-NMR (CDCl3, 300 MHz): δ=5.52 (1H, m); 3.66 (3H, s); 3.18 (1H, m); 0.89 (9H, s); 0.02 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([NH:32]C(=O)OC(C)(C)C)=[CH:27][C:26]=3[F:40])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:41][CH3:42].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:40])=[CH:27][C:28]([NH2:32])=[CH:29][C:30]=3[F:31])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:41][CH3:42]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(NC(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(N)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylcarbamate (75 g, 0.12 mmol) in DCM (300 mL) was added TFA (300 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 2 h and evaporated to give 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzenamine as a light-pink foam (62 g, quant). 1H NMR (400 MHz, CDCl3): δ 7.65 (s, 1H), 7.20-7.23 (d, 1H), 6.92-6.96 (t, 2H), 6.41-6.50 (m, 6H), 3.91 (s, 2H), 3.79 (s, 3H), 1.58 (s, 6H).
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[SH:10][C:11]1N[N:14]=[N:13][CH:12]=1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.N.OS(O)(=O)=O>ClCCl.C(OCC)(=O)C>[CH3:7][Si:4]([CH3:5])([CH3:6])[N:3]1[C:11]([S:10][Si:4]([CH3:7])([CH3:6])[CH3:5])=[CH:12][N:13]=[N:14]1
Reactant: Sc1cnn[nH]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)Sc1cnnn1[Si](C)(C)C
Yield: 96 %

Procedure:
1.52 ml of hexamethyldisilazane (7.3 mmoles) were added to a refluxing mixture of 0.49 (4.86 mmoles) of 5-mercapto-1,2,3-(1H)-triazole, 5 mg (0.207 mmole) of saccharin, 10 ml of ethyl acetate and 15 ml of dichloromethane and the ammonia evolved was titrated with 1 N H2SO4 by the method described in Example 1A. It was found that 2 equivalents (4.9 mmoles) were evolved after refluxing for 30 minutes. Volatile materials were evaporated in vacuo to obtain 1.19 g (96%) of 1-trimethylsilyl-5-trimethylsilylthio-1,2,3-triazole NMR Spectrum was taken in carbon tetrachloride solution: Δ0.31 (9H); 0.48 (9H); 7.46 (1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[CH2:6][C:5]2=O.C[Si]([N:28]=[C:29]=[N:30][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[CH2:6]/[C:5]/2=[N:30]\[C:29]#[N:28]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1CC(c2ccc(OC(F)(F)F)cc2)Oc2ccc(Br)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(c2ccc(OC(F)(F)F)cc2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of 6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-one (530 mg, 1.37 mmol) in anhydrous DCM (15 mL) was added TiCl4 (1 M solution in DCM, 2.74 mL, 2.74 mmol) dropwise within 15 min at room temperature. After the addition, the reaction mixture was stirred for 1 h. To this mixture was added Bis-trimethylsilylcarbodiimide (561.6 mg, 3 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (80 g) and extracted with DCM (3×50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give (E)-N-(6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-ylidene)cyanamide (540 mg, 90%), which was used in the next step without further purification.