Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[SH:6].[H-].[Na+].[C:9]1([CH:15]([O:22][C:23]([C:25]2[N:26]3[CH:29]([CH2:30][CH2:31][C:32]=2Cl)[C@@H:28]([NH:34][C:35](=[O:65])/[C:36](/[C:58]2[N:59]=[C:60]([NH2:64])[S:61][C:62]=2[Cl:63])=[N:37]\[O:38][C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:27]3=[O:66])=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[C:9]1([CH:15]([O:22][C:23]([C:25]2[N:26]3[CH:29]([CH2:30][CH2:31][C:32]=2[S:6][C:2]2[S:1][CH:5]=[N:4][N:3]=2)[C@@H:28]([NH:34][C:35](=[O:65])/[C:36](/[C:58]2[N:59]=[C:60]([NH2:64])[S:61][C:62]=2[Cl:63])=[N:37]\[O:38][C:39]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:27]3=[O:66])=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Cl)CCC23)c(Cl)s1
Reactant: Sc1nncs1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Sc4nncs4)CCC23)c(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,3,4-thiadiazole-2-thiol (0.5 g, 0.004 mol) in acetonitile (40 mL) was added sodium hydride (0.2 g, 0.0043 mol) and the mixture was stirred for 1 hour at room temperature. To the resulting suspension was added (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]-acetamido]-3-chloro-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (2.6 g, 0.003 mol), and the mixture was stirred for 48 hours. The solvent was evaporated and the residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and evaporated. The resulting solid was treated with diethyl ether (50 mL), and the solid that formed was filtered and dried to give 2.1 g of crude product. The crude product was purified by chromatography on silica gel, eluting with a gradient from ethyl acetate:hexane 1:2 to neat ethyl acetate. The title product was obtained (1.1 g.)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>O1CCCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:12][CH:11]=[CH2:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(C)nc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 6-methylpyridine-3-carbaldehyde (20 g, 0.16 mol) in tetrahydrofuran (400 mL) was added allylmagnesium bromide (246 mL, 0.246 mol) drop-wise at −40° C. The mixture was stirred at −20° C. for 10 minutes and a second aliquot of allylmagnesium bromide (82 mL, 82 mmol) was added drop-wise at −20° C. When thin layer chromatography (Eluent: 3:1 petroleum ether/ethyl acetate) indicated the reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) at 0° C. The resulting mixture was partitioned between ethyl acetate (200 mL) and water (100 mL), and the aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried, filtered, and concentrated in vacuo to afford the product as a yellow oil. Yield 25 g, 0.15 mol, 94%. 1H NMR (400 MHz, CDCl3) δ 8.42-8.48 (m, 1H), 7.61 (dd, J=8.0, 2.3 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 5.74-5.86 (m, 1H), 5.12-5.22 (m, 2H), 4.77 (dd, J=7.5, 5.5 Hz, 1H), 2.55 (s, 3H), 2.46-2.58 (m, 2H).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:16])C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([CH3:44])[CH3:43])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH3:55])=[CH:24][CH:23]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([CH3:44])[CH3:43])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:55]=[O:16])=[CH:26][CH:27]=1
Reactant: Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1)c1ccccc1
Temperature: 76 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
AIBN (1.0 mg, 6.1 μmol) was added to a stirring solution of NBS (4.6 mg, 0.026 mmol) and 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (11 mg, 0.024 mmol) in CCl4 (1 mL). The mixture was heated to 76° C. and allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (3.4 mg, 0.028 mmol) and subjected to microwave irradiation (150° C.) for 5 min. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give to give the expected product 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (7.5 mg, 0.016 mmol, 66% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.31 (1H, s), 8.84 (1H, s), 8.79 (1H, s), 8.65 (1H, s), 8.19-8.26 (3H, m), 7.89-7.97 (2H, m), 7.59-7.67 (1H, m), 7.54 (2 H, t, J=8.55 Hz), 7.42 (2H, d, J=7.93 Hz), 7.30 (2H, t, J=7.63 Hz), 7.13-7.23 (1H, m), 1.71 (6H, s). LC-MS retention time: 1.75 min; m/z (MH+): 479. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][CH3:10].Cl[S:12]([OH:15])(=[O:14])=[O:13]>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[CH:4][C:5]([OH:8])=[C:6]([S:12]([OH:15])(=[O:14])=[O:13])[CH:7]=1
Reactant: CCc1cc(O)ccc1Cl
Reactant: O=S(=O)(O)Cl
Solvent: Clc1ccccc1
Product: CCc1cc(O)c(S(=O)(=O)O)cc1Cl

Procedure:
In a 1-liter four-necked glass flask is prepared a solution mixture of 100 g of 4-chloro-3-ethylphenol and 200 g of monochlorobenzene. While the mixture is maintained at a temperature of 25°-30° C., 80 g of chlorosulfonic acid is added dropwise. After the mixture is maintained at the same temperature for 3 hours, the reaction mass of 5-chloro-4-ethyl-2-hydroxybenzenesulfonic acid is obtained and 75.1 g of acetic acid is added to the reaction mass. After 1.33 g of aluminium chloride and 0.67 g of sulfur chloride are added, 110 g of sulfuryl chloride is added dropwise. After the addition is completed, the temperature of the mixture is raised to 35° C. and the mixture is maintained at the temperature for 5 hours. In a 2-liter flask is charged 960 g of water, and the reaction mass is poured into the flask under stirring. The reaction mixture is separated into an aqueous layer and an oil layer, and the lower oil layer is removed to obtain aqueous solution of 3,5-dichloro-4-ethyl-2-hydroxybenzenesulfonic acid. After cooling to 20° C., 184 g of a 70% nitric acid solution is added dropwise, maintaining the temperature at 20°-25° C. After the addition is completed, the reaction mixture is heated to 45° C. and maintained at the temperature for 4 hours. The reaction mixture is cooled to 20° C. and filtered. The product is washed with water and dried to give 2,4-dichloro-3-ethyl-6-nitrophenol.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:12]1[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]2[C:11]=1[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]2
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccccc1Cl)CCNCC2
Yield: 49.9 %

Procedure:
The title compound (90 mg) was prepared according to Example 189 using 266 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 292 mg of 2-chlorophenylboronic acid. MS (ESI): exact mass calculated for C16H20ClN3, 289.13; found, m/z 290.4 [M+H]+, 292.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.65-7.63 (m, 1H), 7.58-7.49 (m, 2H), 7.41-7.39 (m, 1H), 4.66 (br s, 2H), 4.16 (m, 1H), 4.00-3.44 (m, 2H), 3.0-2.6 (m, 2H), 1.47-1.38 (m, 6H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12](O)[C@H:11]([CH3:16])[O:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.P([N:64]=[N+:65]=[N-:66])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>C1COCC1>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:64]=[N+:65]=[N-:66])[C@H:11]([CH3:16])[O:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: C[C@@H]1O[C@H](O[Si](C)(C)C(C)(C)C)CC[C@H]1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1O[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N=[N+]=[N-]
Reaction time: 18 h
Yield: 56 %

Procedure:
To a solution of the alcohol from step 3 herein (62 mg, 0.25 mmol) in dry THF (2.5 ml), at room temperature, under argon, were added successively Ph3P (66 mg, 1 eq.), DEAD (40 μl, 1 eq.) and (PhO)2 PON3 (54 μl, 1 eq.) and the solution was stirred for 18 hours. The THF was evaporated and the crude oil was purified by flash chromatography (silica gel, 95:5 hexanes/EtOAc) to give 38 mg (56%) of the titled azide as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:25]([C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([C:19]3[N:18]=[C:17]([C:16]([F:31])([F:15])[F:32])[O:21][N:20]=3)[CH:23]=2)=[O:26])[CH2:11][CH2:10]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)CC1
Yield: 28 %

Procedure:
This compound was synthesized from 1-(2-methoxy-phenyl)-piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (63 mg, yield 28%). 1H NMR (400 MHz, CDCl3) δ 8.22-8.19 (m, 2H), 7.69-7.60 (m, 2H), 7.08-7.04 (m, 1H), 6.96-6.89 (m, 3H), 4.02 (m, 2H), 3.89 (s, 3H), 3.64 (m, 2H), 3.18 (m, 2H), 3.04 (m, 2H). MS (ESI) m/z: Calculated for C21H19F3N4O3: 432.14. found: 433.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([OH:12])[CH:10]=[CH2:11].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:9]([O:12][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1)[CH:10]=[CH2:11]
Reactant: C=CCO
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CCOc1cc(Cl)ncn1
Temperature: 85 °C
Reaction time: 14 h
Yield: 51.5 %

Procedure:
To a solution of 7.5 g (50.3 mmol) of 4,6-dichloropyrimidine and 3.61 ml (3.07 g, 52.9 mmol) of allyl alcohol in 40 ml of dioxane were added 19.6 g (60.4 mmol) of cesium carbonate. The suspension was stirred for 14 h at 85° C. and then allowed to cool to room temperature. The solution was filtered, and the salts were washed with ethyl acetate. The filtrate was concentrated in vaccuo and purified by flash chromatography on silicagel using ethyl acetate as eluant to yield 4.42 g (25.9 mmol, 51%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:18].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[O:29]>O1CCCC1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[NH:27][C:28](=[O:29])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:18]
Reactant: CCOC(=O)c1cc(-c2ccc(N)c(C)c2)no1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)c(C)c2)no1
Yield: 75 %

Procedure:
Ethyl 3-(4-amino-3-methylphenyl)isoxazole-5-carboxylate (1.0 equiv.), 2,4-difluoro phenyl isocyanate (1.2 equiv.) and tetrahydrofuran in a round-bottom flask was stirred at room temperature for 48 hours. The solid precipitate was filtered and washed with a minimum quantity of THF and dried in vacuo to afford the title compound as a white solid (75%); 1H NMR (300 MHz, DMSO-d6) δ: 1.29-1.34 (t, J=7.0 Hz, 3H), 2.29 (s, 3H), 4.32-4.39 (q, 2H), 7.00-7.05 (m, 1H), 7.26-7.33 (m, 1H), 7.72-7.75 (d, J=8.4 Hz, 1H), 7.80 (s, 2H), 8.09-8.16 (m, 2H), 8.45 (s, 1H), 9.09 (s, 1H); IR (KBr) 3297, 3134, 2991, 1727, 1654, 1590, 1558, 1500, 1460, 1424, 1287, 1250, 1139, 1029, 841 cm1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH:9]1([CH2:15][C@H:16]([N:20]2[C:24](=[O:25])[C@H:23]([CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[NH:22][C:21]2=[O:33])[C:17](O)=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([CH2:15][C@H:16]([N:20]2[C:24](=[O:25])[C@H:23]([CH2:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[NH:22][C:21]2=[O:33])[C:17]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Product: Cc1ccc(NC(=O)[C@H](CC2CCCCC2)N2C(=O)N[C@@H](CC3CCCCC3)C2=O)nc1

Procedure:
By using the conditions described in Step (iv) of Example 17, 2-amino-5-methylpyridine was condensed with (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidinyl]propanoic acid [Example 17, Step (iii)] to give the title compound as a colorless foam: EI-HRMS m/e calcd. for C25H36N4O3 (M+) 441.2866, found 441.2869.
Reaction SMILES: Cl.C1(C)C=CC=CC=1.C=[N:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH2:10])=[CH:17][N:16]=1
Reactant: C=NCc1ccc(Cl)nc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NCc1ccc(Cl)nc1
Yield: 90 %

Procedure:
On the other hand, 7 g of concentrated hydrochloric acid was added to the toluene layer, and the resulting water layer containing the hydrochloride salt of an N-methylidene-(2-chloro-pyridin-5-yl)methylamine oligomer (II-5) or a mixture of two or more such salts was separated. 3.2 g of methanol was added to the separated water layer, and the resulting mixture was treated for 3 hours at 60° C., yielding an aqueous solution of the hydrochloride salt of (2-chloropyridin-5-yl)methylamine. Analysis by HPLC revealed an amount of the (2-chloropyridin-5-yl)methylamine of 1.28 g (yield: 90%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:13](=O)[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH2:18][C:19]([CH3:21])=[CH2:20].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([N:27]=[C:13]2[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]([CH2:18][C:19]([CH3:21])=[CH2:20])=[C:8]2[CH3:7])=[CH:25][CH:24]=1
Reactant: C=C(C)CC1=C(C)C(=O)C(C)=C(C)C1=O
Reactant: Nc1ccc(Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: C=C(C)CC1=C(C)C(=Nc2ccc(Cl)cc2)C(C)=C(C)C1=O
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
Titanium tetrachloride (2.42 ml, 22.1 mmol) was added dropwise to a solution of pyridine (7.13 ml, 88.2 mmol) in 1,2-dichloroethane (40 ml) and, after completion of addition, the reaction mixture was heated under reflux for 20 minutes in an argon atmosphere. After cooling of the reaction mixture, to the mixture was added a solution of 3,5,6-trimethyl-2-(2-methyl-2-propenyl)-1,4-benzoquinone (3.00 g, 14.7 mmol) and p-chloroaniline (5.62 g, 44.1 mmol) in 1,2-dichloroethane (20 ml) and the mixture was stirred at 90° C. for 45 minutes in an argon atmosphere. The reaction mixture was cooled and filtered through Cerite and the filtrate was washed with a saturated saline solution, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 93:7) to obtain the desired compound as oil (4.43 g, yield: 96.0%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:14]COC)[CH2:13][CH2:12][CH2:11][CH2:10]1.[Li]CCCC.[B:23](OC(C)C)(OC(C)C)[O:24]C(C)C>C1COCC1>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[O:14][B:23]([OH:24])[C:2]=2[CH:7]=1
Reactant: COCOC1(c2ccc(C)cc2Br)CCCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)B(O)OC21CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a solution of 2-bromo-1-(1-(methoxymethoxy)cyclopentyl)-4-methylbenzene (2.2 g, 714 mmol) in THF (40 mL) at −78° C. was added n-BuLi (7.5 mL, 18.5 mmol) dropwise. The mixture was stirred at −78° C. for additional 1 h and then triisopropyl borate (2.8 g, 14.8 mmol) in 10 mL of THF was added below −70° C. The resulting mixture was kept stirring at −78° C. for 30 min and allowed to warm to rt and stirred overnight. Then it was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified on column chromatography to provide the product (1.2 g, yield 81%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([F:36])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:33])=[O:34])=[C:28]([F:36])[CH:27]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.09 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.43 g, 4.2 mmol/g loading, 10.2 mmol) followed by 4-bromo-2-fluorobenzenesulfonyl chloride (2.79 g, 10.2 mmol). The resulting solution was stirred at room temperature overnight, the resin was then filtered off, the solvent evaporated in vacuo and the residue was then passed through an SCX column eluting first with methanol and then by 2M ammonia in methanol. The basic fractions were combined and solvent evaporated in vacuo to afford a crude product which was dry loaded onto a column and purified further by chromatography using a Flashmaster and an elution gradient of 0 to 10% methanol in dichloromethane The relevant fractions were collected, combined and solvent evaporated to afford the title compound (E103). MS (ES+) m/e 472/474 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:25][N:26]([CH3:36])[C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])=[O:22])[CH2:16]2)([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:25][N:26]([CH3:36])[C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])=[O:28])=[O:22])[CH2:16]2)([OH:14])[CH2:9][CH2:10][CH2:11][CH:12]=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCO)c2cccc(Cl)c2)C1)C(=O)OCC[Si](C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(C[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCC=O)c2cccc(Cl)c2)C1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 100 mL, round-bottom flask was charged with (3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)piperidine-1-carboxamide (0.0544 g (0.0852 mmol), DMSO (2.5 mL) and Et3N (1 mL). The flask was cooled in an ice bath and a mixture of pyridine-sulphur trioxide complex (0.24 g, 1.51 mmol) and dry DMSO (2.5 mL) was added. After 10 min, the ice bath was removed. The reaction mixture was allowed to stir at rt for 3 h. The mixture was quenched with brine, extracted with EtOAc (3×) and dried over Na2SO4. Removal of the solvent left crude (3R)-3-((S)-1-(3-chlorophenyl)-4-formyl-1-hydroxybutyl)-N-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (0.1036 g), which was carried on to the next step without further purification. LC-MS (3 min) tR=2.43 min, m/z 658, 660 (MNa+), 636 (MH+), 618, 620.