Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[S:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1.[OH:15][N:16]([C@@H:20]([C:22]#[CH:23])[CH3:21])[C:17]([NH2:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C=O)C.CC#N.CC#N.Cl[Pd]Cl.[Cu]I>[F:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:4]2[S:3][C:2]([C:23]#[C:22][C@H:20]([N:16]([OH:15])[C:17]([NH2:19])=[O:18])[CH3:21])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(Cc2ccc(I)s2)cc1
Reactant: C#C[C@@H](C)N(O)C(N)=O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCNCC
Product: C[C@H](C#Cc1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 17.8 %

Procedure:
To a solution of 2-iodo-5-(4-fluorophenylmethyl)thiophene (5.30 g, 16.6 mmol), prepared as in step 2, in anhydrous DMF (5.0 mL) was added (R)-N-hydroxy-N-(3-butyn-2-yl)urea (2.12 g, 16.6 mmol), triphenylphosphine (84 mg, 0.32 mmol), bis(acetonitrile)palladium(II) chloride (40 mg, 0.16 mmol), copper (I) iodide (16 rag, 0.08 mmol), and diethylamine (5.6 ml). The mixture was stirred under nitrogen at ambient temperature for 22 hours and concentrated in vacuo at 32° C. The residue was subjected to chromatography on silica eluting with 2-7% MeOH in CH2Cl2, crystallization from ethyl acetate-hexane and trituration in CH2Cl2 to afford (R)-N-{3-[5-(4-fluorophenylmethyl)thien-2-yl]-1-methyl-2-propynyl}-N-hydroxyurea as a cream-colored solid 0.94 g (18%). m.p. 135°-136° C.(dec). 1H NMR (DMSO-d6, 300 MHz) δ1.32 (d, J=6.0 Hz, 3H), 4.11 (s, 2H), 5.10 (q, J=6.0Hz, 1H), 6.54 (s, 2H), 6.81 (d, J=3.0Hz, 1H), 7.08 (d, J=3.0Hz, 1H), 7.10-7.18 (m, 2H), 7.25-7.32 (m, 2H), 9.33 (s, 1H). MS (DCI/NH3) m/e 319 (M+H)+. [a]D23° =+47.8° (C=1, MeOH). Anal calcd for C16H15FN2O2S: C, 60.36; H, 4.75; N, 8.80. Found: C, 60.31; H, 4.79; N, 8.50.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[N:24][CH:23]=[C:22]([CH3:26])[N:21]=1>>[Br:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[N:24][CH:23]=[C:22]([CH3:26])[N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cncc(Br)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Br
Product: Cc1cncc(-c2cc(C)c(Br)c(C)c2)n1

Procedure:
The title compound is prepared from 2-bromo-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-6-methyl-pyrazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.04 min; Mass spectrum (ESI+): m/z=277/279 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cccs1

Procedure:
70 mg (0.271 mmol) of 2-amino-6-sulfanyl-4-thiophen-2-ylpyridine-3,5-dicarbonitrile, together with 79 mg (0.325 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 91 mg (1.084 mmol) of sodium bicarbonate, were stirred in 2 ml DMF at room temperature overnight. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Chromasil, water/acetonitrile—without acid). This gave 94 mg (71% of theory) of the target compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:20]=[C:19](Cl)[N:18]=[CH:17][C:16]=3[N:22]=2)=[C:9]([F:23])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([C:36](B(O)O)=[CH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)Cl>O1CCOCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:20]=[C:19]([C:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH2:37])[N:18]=[CH:17][C:16]=3[N:22]=2)=[C:9]([F:23])[CH:8]=1
Reactant: C=C(B(O)O)c1ccccc1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2cnc(Cl)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=C(c1ccccc1)c1cc2sc(-c3ccc(C4OCCCO4)cc3F)nc2cn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-chlorothiazolo[4,5-c]pyridine (1.00 g, 2.85 mmol), (Amphos)2PdCl2 (0.0505 g, 0.0713 mmol), potassium carbonate (1.34 g, 9.69 mmol), 1-phenylvinylboronic acid (0.928 g, 6.27 mmol) in 12 mL dioxane and 3 mL water was heated to 60° C. overnight in a sealed tube. Additional (Amphos)2PdCl2 (0.0505 g, 0.0713 mmol) was added and the temperature raised to 90° C. After 3 h, the homogeneous reaction mixture was cooled and treated with water and DCM. The organic layer was extracted with DCM, and combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The solid was suspended in MTBE and filtered to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylvinyl)-thiazolo[4,5-c]pyridine as an off-white solid. MS (ESI) m/z: calculated: 418.1; Observed: 419.0 (M++1).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH3:17])=[C:6]([NH:18][C:19](=O)[CH2:20][C:21]2[S:25][CH:24]=[N:23][CH:22]=2)[CH:5]=1.CO.[OH-].[Na+]>C1COCC1>[CH3:17][C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:27])=[CH:5][C:6]=2[N:18]=[C:19]1[CH2:20][C:21]1[S:25][CH:24]=[N:23][CH:22]=1
Reactant: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c(NC(=O)Cc2cncs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CCCC[C@H]1n1c(Cc2cncs2)nc2cc(C(=O)O)ccc21
Yield: 99.7 %

Procedure:
0.35 g 4-((1R,2R)-2-Methyl-cyclohexylamino)-3-(2-thiazol-5-yl-acetylamino)-benzoic acid methyl ester was dissolved in 6 ml of THF and 3 ml of methanol and 7 ml of 2 M aqueous sodium hydroxide solution were added at rt for 4 h. The reaction was concentrated and the pH was adjusted to 5 by addition of 2 M aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate and concentrated to afford 0.32 g (95%) of 1-((1R,2R)-2-Methyl-cyclohexyl)-2-thiazol-5-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][S:4][C:3]1=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[Mg]>CO.O1CCCC1.O.C(O)(=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C(=O)O)c1ccc(C=C2SCCC2=O)cc1
Agent: [Mg]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C(=O)O)c1ccc(CC2SCCC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
2-[4-(3-Oxothiolan-2-ylidenemethyl)phenyl]propionic acid (500 mg) obtained in Example 14 was dissolved in a mixture of methanol (20 ml)/tetrahydrofuran (10.0 ml)/water (5.0 ml)/acetic acid (1.1 ml), and to the solution was added magnesium (150 mg). The mixture was stirred at room temperature for 2 hours, and then further magnesium (80 mg) was added, and further the solution was stirred for 2 hours. To the reaction mixture was added water and acetic acid, the solution was concentrated under reduced pressure. Saturated brine was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (132 mg, 26%).
Reaction SMILES: [OH:1][C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>O>[C:19]1([C:2]2([O:1][C:25](=[O:28])[CH2:26][CH3:27])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC1(c2ccccc2)CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(=O)OC1(c2ccccc2)CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
A mixture of 4 g. (0.0125 mole) of 3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole, 1.19 g. (0.0125 mole) of propionyl chloride and 7 g. of potassium carbonate in 50 ml. of chloroform was allowed to stir for 2 hours. Then 0.4 g. of additional propionyl chloride was added and allowed to stir another 30 minutes. The mixture was treated with 50 ml. of water and allowed to stir 30 minutes. The chloroform layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to an oil. The oil was crystallized from benzene-isooctane and yielded 3.0 g. (64%) of product which melted at 140°-142° C. After an additional recrystallization the analytical sample melted at 142°-144° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([CH3:22])=[CH:18][C:19](Cl)=[O:20]>CC(C)=O.O>[CH3:16][C:17]([CH3:22])=[CH:18][C:19]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(NC(=O)C=C(C)C)cc1
Temperature: 0 °C
Yield: 74.6 %

Procedure:
A mixture of p-anisidine (10 g, 81 mmol, Aldrich) and potassium carbonate (13.5 g, 97.5 mmol, Aldrich) in acetone (125 mL) was cooled to 0° C. and treated with dimethyl acryloyl chloride (10.2 mL, 89.3 mmol). The mixture was allowed to warm to room temperature overnight. The reaction was diluted with water and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, and purified by chromatography on SiO2 (0 to 100% ethyl acetate/dichloromethane) to give 3-methyl-N[4-(methyloxy)phenyl]-2-butenamide (12.4 g, 67%) as a light violet solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (s, 3 H), 2.13 (s, 3 H), 3.71 (s, 3 H), 5.82 (s, 1 H), 6.85 (d, J=9.0 Hz, 2 H), 7.52 (d, J=9.0 Hz, 2 H), 9.67 (s, 1 H); ESIMS (M+H)+=206.
Reaction SMILES: O[CH2:2][C:3]#[C:4][CH2:5][C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].N1C=CC=CC=1.P(Br)(Br)[Br:23]>C(OCC)C>[Br:23][CH2:2][C:3]#[C:4][CH2:5][C:6]#[C:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC#CCC#CCC#CCO
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC#CCC#CCC#CCBr

Procedure:
6 g of 1-hydroxy-2,5,8-tetradecatriyne prepared above, dissolved in 30 cm3 of ethyl ether, are introduced into a round-bottomed flask equipped with an argon inlet. 0.05 cm3 of pyridine is added and 1 cm3 of phosphorus tribromide is added dropwise, and the mixture is then brought to reflux for 3 hours.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:36]=[C:35]([Cl:37])[C:9]([C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[C:14]([OH:16])=[O:15])=[O:11])=[C:8]([Cl:38])[CH:7]=1.O=C1CCC(=O)N1[O:46][C:47](=O)[CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][NH:62][C:63](=[O:73])[CH2:64][CH2:65][N:66]1[C:70](=[O:71])[CH:69]=[CH:68][C:67]1=[O:72].CCN(C(C)C)C(C)C>>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@H:13]([NH:12][C:10](=[O:11])[C:9]2[C:8]([Cl:38])=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:47](=[O:46])[CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][NH:62][C:63](=[O:73])[CH2:64][CH2:65][N:66]3[C:70](=[O:71])[CH:69]=[CH:68][C:67]3=[O:72])=[CH:36][C:35]=2[Cl:37])[C:14]([OH:16])=[O:15])=[CH:23][CH:22]=1)=[O:34]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (214 mg, 0.3 mmol), 3-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (154 mg, 0.3 mmol), and DIPEA (388 mg, 522 uL, 3.0 mmol), and after HPLC purification, resulted in a white solid (52 mg, 17%). ES(+)-HRMS m/e calcd. for C44H49Cl4N5O13 (M+Na)+ 1018.1973, obsd. 1018.1965.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](F)[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:17][N:18]([CH3:28])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:11]=[C:10]([O:27][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][N:18]([CH3:17])[CH3:28])=[CH:26][CH:25]=2)[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CN(C)CCc1ccc(O)cc1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(Oc2ccc(CCN(C)C)cc2)cc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 29.1 %

Procedure:
534 mg of methyl 2-chloro-4-fluoro-5-methylsulfonylbenzoate, 331 mg of 4-(2-dimethylaminoethyl)phenol and 2.0 g of Cs2CO3 were dissolved in 10 ml of NMP and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was poured onto 150 ml of a saturated aqueous NaHCO3 solution and extracted 3 times using 100 ml of EA each time. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo. Chromatography on silica gel using EA/MeOH 3:1 yields 240 mg of a viscous oil.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C([C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)C)CC2)CC1)CC.[Li+].CC([N-]C(C)C)C.CCOCC.CC(C([Si](C)(C)C)=C)=O.[OH-].[K+]>C(O)C.[Pd].C([O-])([O-])=O.[Ca+2].CCOCC.C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH:16]3[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C3=CC(=O)CCC3)CC2)CC1
Agent: [Pd]
Agent: C=C(C(C)=O)[Si](C)(C)C
Agent: CC(C)[N-]C(C)C
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C3CCCC(=O)C3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6.5 g of 3-[trans-4-(trans-4-n-propyl-cyclohexyl)-cyclohexyl]-cyclohex-2-enone [m.p. 96.5°; obtainable by reacting trans-4-(trans-4-n-propycyclohexyl)-acetylcyclohexane with LDA/ether at -85°, adding 1-(trimethylsilyl)-vinyl methyl ketone at -95°, allowing the mixture to warm up to room temperature, adding methanolic KOH and working up in the customary manner (silica gel; 5:3.5:1.5 petroleum ether:methylene chloride:ether)] in 210 ml of ethanol is added to a suspension of 1.7 g of 5% Pd/CaCO3 in 75 ml of ethanol, and the mixture is stirred under hydrogen for 2 hours. Removing the catalyst and working up in the customary manner gives 3-[trans-4-(trans-4-n-propylcyclohexyl)-cyclohexyl]-cyclohexanone, m.p. 1.5°, c.p. 158.2°
Reaction SMILES: Cl.[C:2]([NH:5][C@:6]1([C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:10]([CH2:11][CH2:12][CH2:13][B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)[CH2:9][NH:8][CH2:7]1)(=[O:4])[CH3:3].CCN(CC)CC.[Cl:37][C:38]1[CH:47]=[C:46]2[C:41]([CH2:42][CH:43]([CH:55]=O)[N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:45]2)=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:2]([NH:5][C@:6]1([C:23](=[O:24])[NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:10]([CH2:11][CH2:12][CH2:13][B:14]2[O:18][C:17]([CH3:19])([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15]2)[CH2:9][N:8]([CH2:55][CH:43]2[CH2:42][C:41]3[C:46](=[CH:47][C:38]([Cl:37])=[CH:39][CH:40]=3)[CH2:45][N:44]2[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(CC2Cc3ccc(Cl)cc3CN2C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
A stirred mixture of (3R,4S)-3-acetamido-N-tert-butyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxamide hydrochloride (226 mg, 0.524 mmol) and Et3N (0.110 mL, 0.786 mmol) in methylene chloride (2.5 mL) was treated with a solution of tert-butyl 7-chloro-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (155 mg, 0.524 mmol) in methylene chloride (2.5 mL). After stirring for 20 min, sodium triacetoxyborohydride (233 mg, 1.10 mmol) was added and stirring was continued for 1 h. The resulting mixture was carefully quenched with saturated aqueous NaHCO3 (5 mL), diluted with saturated aqueous sodium chloride (15 mL) and extracted with methylene chloride (4×15 mL). The combined organic phase was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (40 g column, 2-4% MeOH in ethyl acetate) gave tert-butyl 3-({(3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidin-1-yl}methyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (296 mg, 84%, mixture of diastereomers) as a clear gum. LC-MS gives ESI+MS found for C35H56BClN4O6 m/z 675.4 (M+H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[CH3:12][O:13]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:34][C:35]1[C:40]([O:41][CH3:42])=[C:39]([OH:43])[C:38]([Br:44])=[CH:37][C:36]=1[CH2:45][C:46]([CH3:50])([CH3:49])[CH:47]=O>C1COCC1.Cl>[Br:34][C:35]1[C:40]([O:41][CH3:42])=[C:39]([OH:43])[C:38]([Br:44])=[CH:37][C:36]=1[CH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][CH:12]=[O:13]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(O)c(Br)cc(CC(C)(C)C=O)c1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1c(O)c(Br)cc(CC(C)(C)CC=O)c1Br
Reaction time: 0.25 h

Procedure:
Lithium bis(trimethylsilyl)amide solution (20 ml, 20 mmol, 1M in THF) was added to a mixture methoxy methyl triphenyl phosphonium chloride (6.9 g, 20 mmol) in 25 ml THF dropwise at 0° C. and stirred for 15 min and it was added to a mixture of the product of STEP 3 (2.6 g, 7.1 mmol ) in 15 ml THF dropwise at 0° C. After 5 min, the reaction was quenched with H2O. The product was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with H2O, brine, dried with Na0.2SO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/3) to give a brown oil in 1.14 g. It was dissolved in 20 ml THF and 20 ml 2N HCl. The reaction was stirred at room temperature for 30 min. THF was evaporated. The product was extracted with ethyl acetate and washed H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with Na2SO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/3) to yield a viscous oil in 0.783 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@@H:14]1[O:31][C:18]2=[C:19]3[C:23](=[CH:24][CH:25]=[C:17]2[O:16][CH2:15]1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]3>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][C@H:14]2[O:31][C:18]3=[C:19]4[C:23](=[CH:24][CH:25]=[C:17]3[O:16][CH2:15]2)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]4)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1cc2c3c(ccc2[nH]1)OC[C@H](CO)O3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2c3c(ccc2[nH]1)OC[C@@H](COS(=O)(=O)c1ccc(C)cc1)O3
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
4-Toluenesulphonyl chloride (2.23 g) was added in one portion to a stirred solution of ethyl (S)-2,3-dihydro-2-(hydroxymethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxylate (2.65 g) in dry dichloromethane (120 ml) at 0° C. 4-Dimethylaminopyridine (1.52 g) was then added and the cooling bath removed. The resulting solution was stirred at ambient temperature for 72 hours, then diluted with dichloromethane (150 ml) and washed successively with water (80 ml), saturated aqueous copper sulphate solution (2×100 ml), and then dried over sodium sulphate. Evaporation of the solvent under reduced pressure gave a purple foam which was purified by flash column chromatography on silica eluting with a 1:1 mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate, to give ethyl (S)-2,3-dihydro-2-[(4-toluenesulphonyloxy)methyl]-7H-1,4-dioxino[2,3-e]indole-8-carboxylate (3.71 g) as a colourless oil which solidified on standing.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:28](/B(O)O)=[CH:29]\[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][CH:3]=[C:2]3/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[OH:13])=[CH:22][CH:23]=1
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc2nccc(Br)c2c1
Reactant: OB(O)/C=C/c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc2nccc(/C=C/c3ccccc3)c2c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of (4-bromoquinolin-6-yl)bis(4-chlorophenyl)methanol (50 mg, 0.109 mmol), (E)-styrylboronic acid (25.8 mg, 0.17 mmol), Pd(OAc)2 (2.44 mg, 0.0109 mmol), SPhos (8.9 mg, 0.022 mmol) and K3PO4 (46 mg, 0.218 mmol) was warmed to 30° C. for 7 hr under argon and then stirred at room temperature overnight. The reaction was quenched with water. The solids were filtered. The aqueous layer was extracted with EtOAc twice. The organic layers and solids (which were dissolved in EtOAc) together were concentrated and the crude material was purified by silica column chromatography (35% EtOAc/hexanes) to yield (E)-bis(4-chlorophenyl)(4-styrylquinolin-6-yl)methanol. (M+H)+: 482, 484.