Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[N:8]([CH2:11][Si:12]([O:16][CH3:17])([O:14][CH3:15])[CH3:13])=[C:9]=[O:10]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:9](=[O:10])[NH:8][CH2:11][Si:12]([O:16][CH3:17])([O:14][CH3:15])[CH3:13])[N:3]=1
Reactant: CO[Si](C)(CN=C=O)OC
Reactant: Cc1cc(C)[nH]n1
Solvent: CCOC(C)=O
Product: CO[Si](C)(CNC(=O)n1nc(C)cc1C)OC
Reaction time: 1 h

Procedure:
A stirred solution conditioned at a temperature of 50° C. of 10.0 g of 3,5-dimethylpyrazole in 80 ml of ethyl acetate was admixed dropwise with 16.8 g of (isocyanatomethyl)dimethoxy(methyl)silane and the clear solution was stirred for 60 min. Distillative removal of the solvent under reduced pressure gave 3,5-dimethyl-1-{[dimethoxy(methyl)silyl]methylcarbamoyl}pyrazole in quantitative yield with a purity of >95% (analysis by 29Si and 1H NMR).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[CH:7][C:6]([CH3:13])=[CH:5]2.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[O:16]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[C:7]([CH:15]([OH:16])[C:14]([O:18][CH2:19][CH3:20])=[O:17])[C:6]([CH3:13])=[CH:5]2
Reactant: CCOC(=O)C=O
Reactant: Cc1cc(O)c2ccc(Br)cc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(O)c1c(C)cc2cc(Br)ccc2c1O
Reaction time: 0.75 h

Procedure:
To a mixture of 6-bromo-3-methylnaphthalen-1-ol (3.79 g, 15.98 mmol) in anhydrous dichloromethane (150 mL) at −40° C. was added a 1M titanium(IV) chloride solution in dichloromethane (20.78 mL, 13.78 mmol) and stirred for 45 min. Ethyl glyoxalate (2.45 g, 23.97 mmol) dissolved in dichloromethane (10 mL) was added over 15 minutes and stirred for 1 hour at −40° C. The reaction was quenched by the addition of Rochelle's salt solution and stirred at room temperature for 2.5 hours. The resulting mixture was washed with water and aqueous layer back-extracted with dichloromethane (2×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to give the desired compound. LCMS-ESI− (m/z): [M−H]− calcd for C15H15BrO4: 338.18. Found: 338.8.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].C(N(CC)CC)C.[OH:16][CH2:17][C:18]([CH3:35])([CH3:34])[C@@H:19]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:16][CH2:17][C:18]([CH3:35])([CH3:34])[C@@H:19]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:30])([CH3:29])[CH3:31])/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])(=[O:7])=[O:6]
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)CO
Reactant: O=S(=O)(Cl)CCCCl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 84.3 %

Procedure:
Following the general procedure for the preparation of neopentyl sulfonylester intermediates of Description 10, 25.7 mL (37.4 g, 211.4 mmol) of 3-chloropropylsulfonyl chloride in 500 mL of anhydrous dichloromethane (DCM) in the presence of 25.8 g (211.4 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP) and 29.5 mL (21.4 g, 211.4 mmol) of triethylamine (Et3N, TEA) was reacted at ca. 0° C. with 40.5 g (133.9 mmol) of methyl (2E)(4S)-6-hydroxy-5,5-dimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)hex-2-enoate (4). After work-up and isolation, the crude material was purified by silica gel column chromatography using methyl tert-butyl ether (MTBE) and hexane (Hxn) mixtures (MTBE/Hxn=1:6→MTBE/Hxn=1:5→MTBE/Hxn=1:4) to provide 50.0 g (84% yield) of the title compound (15a) as a pale-yellow oil. Rf=0.46 (MTBE/Hxn=1:4). 1H NMR (400 MHz, CDCl3): δ=0.01 (s, 3H), 0.09 (s, 3H), 0.93 (s, 9H), 0.97 (s, 3H), 0.98 (s, 3H), 2.30-2.38 (m, 2H), 3.27-3.33 (m, 2H), 3.68-3.73 (m, 2H), 3.77 (s, 3H), 3.98 (d, J=9.6 Hz, 1H), 4.10 (d, J=9.2 Hz, 1H), 4.11 (dd, superimposed, J=6.4, 1.6 Hz, 1H), 5.97 (dd, J=15.6, 1.2 Hz, 1H), 6.90 (dd, J=15.6, 6.8 Hz, 1H) ppm. MS (ESI) m/z 442.9 (M+H)+, 464.9 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].[F:11][C:12]([F:27])([S:23](F)(=[O:25])=[O:24])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]>CCOCC>[F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][O:4][S:23]([C:12]([F:11])([F:27])[C:13]([F:21])([F:22])[C:14]([F:19])([F:20])[C:15]([F:18])([F:17])[F:16])(=[O:25])=[O:24]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OCC(F)(F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,2,3,3-Tetrafluoropropanol (2.64 g) was added to a suspension of sodium hydride (1.08 g) in dry ether (50 ml) at 0° C. under an argon atmosphere. Stirred at 0° C. for 15 minutes. Perfluoro-1-butanesulphonyl fluoride (12.08 g) was slowly added. Stirred at reflux for 3 hours, cooled and carefully quenched with H2O. Extracted with ether, twice. The combined extracts were washed with saturated brine, dried over MgSO4, filtered and evaporated to give 2,2,3,3-tetrafluoropropyl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate as an oil. Yield 5.47 g. NMR Spectrum: (CDCl3) δ 5.9 (tt, 1H), 4.75 (t, 2H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:13]1([O-:22])[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>CN(C)C=O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:19]([C:16]2[CH:15]=[CH:14][N+:13]([O-:22])=[CH:18][CH:17]=2)=[O:21])=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1cc[n+]([O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cc[n+]([O-])cc1
Reaction time: 0.75 h

Procedure:
1,1'-Carbonyldiimidazole (3.829 g, 23.6 mmol) was added to a suspension of 4-pyridinecarboxylic acid-1-oxide (2.986 g, 21.5 mmol) in dry dimethylformamide (50 ml) and the resulting solution was stirred for 45 minutes and treated with a solution of 4-chlorobenzenamine (3.012 g, 23.6 mmol) in dry dimethylformamide (20 ml). After 18 hours, the solution was evaporated in vacuo to give an oil which slowly solidified. The solid was recrystallised from ethyl acetate-cyclohexane and suspended in saturated aqueous sodium bicarbonate solution. The mixture was stirred vigorously for 20 minutes, filtered, and the crystals washed with water (3×10 ml) and ethanol (3×10 ml) and dried in vacuo to give the title compound as a quarter hydrate (1.614 g), m.p. 247°-249°.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:17]([CH3:20])[CH2:18][OH:19].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH2:52]([O:54][C:55](=[O:67])[CH2:56][C:57]1[C:58]2[CH:65]=[CH:64][C:63](O)=[CH:62][C:59]=2[S:60][CH:61]=1)[CH3:53]>C1(C)C=CC=CC=1>[CH2:52]([O:54][C:55](=[O:67])[CH2:56][C:57]1[C:58]2[CH:65]=[CH:64][C:63]([O:19][CH2:18][CH:17]([C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=4)[S:6][C:2]=3[CH3:1])[CH3:20])=[CH:62][C:59]=2[S:60][CH:61]=1)[CH3:53]
Reactant: CCOC(=O)Cc1csc2cc(O)ccc12
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1csc2cc(OCC(C)c3nc(-c4ccc(C(F)(F)F)cc4)sc3C)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A solution of 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol (226 mg, 0.75 mmol) in toluene (4.0 mL) is degassed and filled with nitrogen for 3 times. O this solution is added 1,1′-(azodicarbonyl)-dipiperidine (190 mg, 0.75 and mmol) and tributylphosphine (0.186 mL, 0.75 mmol) under nitrogen at 0° C., followed by addition of (6-hydroxy-benzo[b]thiophen-3-yl)-acetic acid ethyl ester (120 mg, 0.5 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight, the mixture is loaded on silica gel column. Chromatography yields the title compound (250 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:28][NH2:29]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([CH2:2][NH:29][CH3:28])[CH:27]=[CH:26][CH:25]=2)[S:8]1(=[O:24])=[O:23]
Reactant: CN
Reactant: O=S1(=O)N(Cc2cccc(CBr)c2)c2ccccc2N1c1ccccc1F
Product: CNCc1cccc(CN2c3ccccc3N(c3ccccc3F)S2(=O)=O)c1
Yield: 71 %

Procedure:
In an analogous manner to general procedure V, 1-[3(bromomethyl)benzyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.08 g, 0.18 mmol) was treated with methylamine (10 mL) to provide 0.05 g (71%) of 1-(3-{[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methyl}phenyl)-N-methylmethanamine. HRMS: calcd for C21H20FN3O2S+H+, 398.13330; found (ESI, [M+H]+), 398.1337; HPLC purity 95.4% at 210-370 nm, 7.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=2)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(O)cc2)c1)c1ccccc1
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a degassed solution of 1.3 mL DMF at room temperature containing (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (63 mg, 0.22 mmol), 4-iodophenol (121 mg, 0.55 mmol), and triethylamine (0.09 mL, 0.66 mmol) was added dichlorobis(triphenylphosphine)palladium(II) (15 mg, 0.022 mmol) and copper(I) iodide (4 mg, 0.022 mmol). After proceeding for 1 hour the reaction was partitioned between EtOAc and H2O. The mixture was filtered to remove an insoluble brown precipitate and the EtOAc layer was washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The brown film was chromatographed eluting with CHCl3/EtOAc to give a yellow solid which was recrystallized from CHCl3/hexane to give the title compound as an off-white solid (38 mg, 45%).
Reaction SMILES: [OH:1][C@@H:2](C(O)=O)[C@@H:3](O)C(O)=O.[NH2:11][C@H:12]([CH2:23][O:24][CH3:25])[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].[NH4+].[OH-]>O>[C:2]([NH:11][C@H:12]([CH2:23][O:24][CH3:25])[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:1])[CH3:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 2.5 °C

Procedure:
A suspension of (R)-2-amino-N-benzyl-3-methoxypropanamide (2R,3R)-dihydroxysuccinate (358.34 g, 1.0 moL, 1.0 eq) in water (720 mL) was cooled to 0-5° C., and the pH adjusted to 10 to 10.5 by the addition of aqueous 28% NH4OH at below 10° C. The reaction mixture was extracted with dichloromethane (2×720 mL and 1×360 mL). The organic phase was charged with 4-(dimethylamino)pyridine (3.66 g, 0.03 moL), followed by acetic anhydride (112.3 g, 1.1 moL) slowly under constant stirring at 10-15° C. The reaction mixture was stirred at 10-15° C. for 30 to 60 min. The reaction mixture was heated to 20-25° C. and stirred for 1 hour. The reaction mixture was charged with water (1254 mL) and sodium bicarbonate (109.21 g, 1.3 moL) and stirred for 1 hour. The phases were allowed to separate and the aqueous phase was extracted with dichloromethane (2×360 mL) and concentrated to a volume of about 720 mL, charged with ethyl acetate (2.9 L) and concentrated to a volume of about 720 mL. This operation is repeated until the KF is less than 0.5%. The reaction mixture was charged with ethyl acetate (2.9 L) and heated to 60-65° C. Charcoal (3% by weight) was charged and the reaction mixture was heated to reflux and stirred for one hour. The reaction mixture was cooled to 60° C., filtered and the solid was washed with hot (60° C.) ethyl acetate (360 mL). The filtrate was cooled to 45-50° C. and stirred there for at least 4 hours and then cooled at 0-5° C. at a rate of 10° C./hour. The suspension was stirred for at least 3 hours to 0-5° C. and filtered. The resulting solid was washed with ethyl acetate (2×180 mL) and dried under vacuum at below 50° C. until a LOD of NMT 0.5% was obtained, to provide (R)-2-acetamido-N-benzyl-3-methoxypropanamide as a white solid (186.3 g, 75%, HPLC purity=99.8%, HPLC enantiomeric purity=100%).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:15]=2)[O:10][C:9]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].[Na]>ClCCl>[C:1]([O:5]/[N:6]=[C:7]1\[CH:8]=[C:9]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:10][C:11]2[C:16]\1=[CH:15][CH:14]=[C:13]([C:17]#[C:18][CH2:19][CH2:20][O:21][S:40]([CH3:39])(=[O:42])=[O:41])[CH:12]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#CCCO)ccc12
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)O/N=c1\cc(-c2cc3ccccc3cn2)oc2cc(C#CCCOS(C)(=O)=O)ccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cold solution of 7-(4-Hydroxy-but-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (tert-butyl protected oxime of example 52) (200 mg, 0.485 mmol) and triethylamine (0.15 ml, 1.067 mmol) in dichloromethane (3 ml) was added dropwise methanesulfonyl chloride (75 μl, 0.970 mmol). The reaction mixture was stirred for 1.5 hours at 0° C. and poured onto a saturated solution of sodium hydrogenocarbonate. The product was extracted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated to dryness to yield methanesulfonic acid 4-{4-[(E)-tert-butoxyimino]-2-isoquinolin-3-yl-4H-chromen-7-yl}-but-3-ynyl ester. The methansulfonic ester was dissolved in dimethylformamide (4 ml) and treated with potassium carbonate (201 mg, 1.46 mmol) and methyl piperazine (73 mg, 0.728 mmol) and the mixture was stirred at 40° C. for 20 hours. The mixture was poured onto a saturated solution of sodium hydrogenocarbonate. The reaction mixture was extracted with dichloromethane, washed with water, brine, dried over sodium sulfate and absorbed over silica gel for purification by flash chromatography (gradient cyclohexane/dichloromethane: 0-45%) to yield 7-(but-3-en-1-ynyl)-2-Isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (156 mg, 82%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=C([CH:8]=[CH:9][CH:10]=1)N)([O-:3])=[O:2].[H-].[Na+].IC.[CH3:15][N:16]([CH3:19])[CH:17]=O>>[CH3:15][N:16]([CH3:19])[C:17]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
3-nitroaniline (1.0 g, 7.25 mmol) was dissolved in N,N-dimethylformamide (50 ml), added with sodium hydride (1.7 g, 21.7 mmol) and iodomethane (2.7 ml, 21.7 mmol) at 0° C. The resulting mixture was stirred for 4 hours at room temperature and poured into ice water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was then purified by flash column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (2.0 g, yield: 86%, yellow solid).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:65][N:66]([CH3:70])[CH2:67][CH2:68][NH2:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18](=[O:19])[NH:69][CH2:68][CH2:67][N:66]([CH3:70])[CH3:65])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
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: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCN(C)C)cc3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 31)(4.88 g, 11.50 mmol) and HATU (5.25 g, 13.80 mmol) was added DMF (2 mL). The resulting mixture was treated with DIPEA (6.02 mL, 34.5 mmol) then after 5 min with N1,N1-dimethylethane-1,2-diamine (1.317 g, 14.95 mmol). After 0.5 h most of the DMF was removed in vacuo. The residue was treated with EtOAc and saturated NaHCO3. Insoluble solid appeared which was isolated by filtration and dried under vacuum at 60° C. for 3 h to give tert-butyl ((2S,4R)-1-acetyl-6-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate as white solid (8.5 g), which was used without further purification in the subsequent reaction. The phases of the filtrate were separated, and the aqueous extracted with EtOAc (×2). The combined organic phases were washed with saturated NaHCO3(×3), dried over MgSO4 and concentrated in vacuo to give a liquid (2.1 g). This liquid was loaded onto a SCX cartridge (50 g, pre-conditioned with MeOH) the cartridge washed with MeOH (200 ml) and eluted with ammonia in MeOH (2M, 200 ml). The methanolic ammonia fractions were combined and concentrated in vacuo to give a further portion of tert-butyl ((2S,4R)-1-acetyl-6-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (0.3 g, 0.6 mmol, 5% yield) as an orange solid. LCMS (Formate, 2 min), Rt=0.94 min, MH+=495.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]([NH2:24])[C:17]2[C:22]([Cl:23])=[N:21][CH:20]=[CH:19][N:18]=2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2[NH:24][C:30](=[O:31])[N:18]3[CH:19]=[CH:20][N:21]=[C:22]([Cl:23])[C:17]=23)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Temperature: 80 °C

Procedure:
A solution C-(3-benzyloxy-phenyl)-C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride (5 g, 13.8 mmol) and CDI (2.46 g, 15.19 mmol) in anhydrous THF (70 mL) was charged with DIEA (2.40 mL, 13.8 mmol) and heated to 80° C. for 1 h and then concentrated in vacuo. The crude material was partitioned between EtOAc and H2O and separated. The aqueous layer was washed with EtOAc (3×) and the combined organic layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by chromatography on silica gel [eluting with 5% MeOH in DCM], to yield the desired product as a yellow solid; 1H NMR (DMSO-d6, 400 MHz) δ 5.17 (s, 2H), 6.86 (d, J=5.2 Hz, 1H), 7.10-7.16 (m, 2H), 7.22-7.23 (m, 1H), 7.34-7.48 (m, 6H), 7.50 (d, J=7.9 Hz, 1H); MS (ES+): m/z=352.15 (100) [MH+], HPLC: tR=3.19 min (MicromassZQ, polar—5 min)
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19]S(C)(=O)=C>CS(C)=O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[CH2:19][CH:14]3[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)/C=C/c1ccc(C2CCCCC2)cc1
Reactant: C=S(C)(C)=O
Solvent: CS(C)=O
Product: COC(=O)C1CC1c1ccc(C2CCCCC2)cc1
Reaction time: 3 h
Yield: 70.8 %

Procedure:
To a solution of (E)-methyl 3-(4-cyclohexylphenyl)acrylate (200 mg, 0.82 mmol) in DMSO (20 mL) was added freshly prepared Corey's reagent (92 mg, 0.98 mmol) at RT and stirred for 3 h. The reaction was quenched with cold water and then extracted with EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and then concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc/95% hexanes to afford methyl 2-(4-cyclohexylphenyl)cyclopropanecarboxylate (150 mg, 47%) as a solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[CH:17].C(N(C(C)C)CC)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(#N)C>[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[C:17][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4]
Reactant: C#CCN(C)C
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC#Cc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A resealable tube was charged with 2-bromo-5-(trifluoromethyl)aniline (1.00 g, 4.16 mmol), 1-dimethylamino-2-propyne (0.520 g, 6.20 mmol), PdCl2(PPh3)2 (0.15 g, 0.21 mmol), copper iodide (0.80 mg, 0.42 mmol), diisopropylethylamine (1.0 mL) and acetonitrile (3.0 mL). The system was purged with argon, the tube sealed and the mixture stirred at room temperature for 20 h. The reaction mixture was filtered through celite and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0-10% methanol-dichloromethane) to afford 2-(3-dimethylamino-1-propynyl)-5-(trifluoromethyl)aniline as a brown oil. MS m/z=243 [M+H]+. Calc'd for C12H13F3N2: 242.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:25])[C:14](=[O:24])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:25])[C:14](=[O:24])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28]([O:27][CH3:26])=[O:37])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(C)C(=O)CCc2ccc(O)cc2)cc1OC
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCC(=O)N(C)CCc2ccc(OC)c(OC)c2)cc1
Yield: 60.6 %

Procedure:
N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(4-hydroxyphenyl)-N-methylpropanamide (198 mg, 0.577 mmol), 2-bromomethyl-benzoic acid methyl ester (139 mg, 0.605 mmol) and potassium carbonate, anhydrous (120 mg, 0.864 mmol) were mixed in acetonitrile (15 ml). The mixture was heated to reflux overnight and then evaporated to dry. Water and ethyl acetate were added and the two phases were separated. The organic phase was dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using heptane/DCM (50:50), then DCM and then MeOH/DCM (0.5:99.5) as eluant gave 172 mg the desired product, yield 61%.