Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH:11]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][CH2:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=CCc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(CCNCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
2-(3-nitrophenyl)acetaldehyde (1.2 g, 7.33 mmol) was dissolved in methanol (50 mL) and 4-fluorobenzylamine (1.88 g, 14.67 mmol) was added at 15° C. followed by 1-2 drops of glacial acetic acid. The reaction was stirred at room temperature for 2 hours then sodium borohydride (0.14 g, 3.6 6 mmol) was added in lots at 0-10° C. and the solution allowed to warm to room temperature and stirred for a further 2 hours. The reaction mixture was poured into sodium bicarbonate solution (75 mL) and stirred for 15 minutes. The mixture was extracted with EtOAc (2×60 mL) then the combined organic extracts were washed with brine (50 mL) and dried (Na2SO4). The solvents were removed under reduced pressure to afford the crude compound which was purified by column chromatography on neutral silica gel using 1-2% methanol in DCM to afford the title compound (0.793 g, 40%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>CN(C)C=O.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Temperature: 0 °C
Yield: 77.6 %

Procedure:
To a solution (100 mL) of tert-butyl 3-(4-hydroxyphenyl)propanoate (5.5 g, 24.7 mmol) in N,N-dimethylformamide was added 60% sodium hydride (1.09 g, 27.2 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 15 min. Then, 3-bromobenzylbromide (6.55 g, 25.91 mmol) was added to this mixture with stirring at 0° C., and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (7.5 g, yield 78%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=[O:20])[C:12]([CH:15]1[O:19][CH2:18][CH2:17][O:16]1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[O:16]1[CH2:17][CH2:18][O:19][CH:15]1[C:12]([CH3:14])([CH3:13])[C:11](=[O:20])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C(=O)CCl)C1OCCO1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C(=O)COc1ccc(F)cc1)C1OCCO1
Yield: 72.1 %

Procedure:
A mixture of 16.7 g (0.15 mol) of 4-fluorophenol, 29 g (0.15 mol) of 1-chloro-3-(1,3-dioxolan-2-yl)-3-methylbutan-2-one and 23.4 g (0.17 mol) of powdered potassium carbonate in 300 ml of methyl ethyl ketone is heated under reflux for 16 hours. The mixture is allowed to cool and filtered. The filtrate is evaporated down, the residue is taken up with dichloromethane, the solution is washed once with 5% strength sodium hydroxide solution and once with water, dried over sodium sulphate and evaporated down, and the residue is distilled. 29 g (72% of theory) of 3-(1,3-dioxolan-2-yl)-1-(4-fluorophenoxy)-3-methylbutan-2-one of boiling point 143° C. to 145° C./0.1 mbar are obtained. ##STR93##
Reaction SMILES: [H-].[Na+].C([O:6][CH2:7][CH:8]([F:10])[F:9])(=O)C.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[F:9][CH:8]([F:10])[C:7](=[O:6])[CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(=O)OCC(F)F
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under nitrogen, 46.7 g (1.168 mol) of sodium hydride (60% dispersion in paraffin) were added to 600 ml of tetrahydrofuran. At 35° C. a mixture of 125 g (1.008 mol) of difluoroethyl acetate and 88.7 g (1.010 mol) of ethyl acetate was added dropwise while the temperature was maintained at below 40° C. This was followed by further stirring at room temperature overnight. The reaction mixture was carefully poured into 1.7 L of ice-water and adjusted to pH 3 with sulphuric acid. The reaction mixture was extracted twice with 500 ml of methyl tert-butyl ether each time, the combined organic phases were washed twice with saturated sodium chloride solution, dried over sodium sulphate and concentrated at 40° C. and 150 mbar before distillation at 60 mbar (Vigreux column). The product was obtained at 85-87° C. as a colourless liquid (104 g, 62% of theory having a purity of >99% (GC)).
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[NH:3]1.[H-].[Na+].CCOP(Cl)(OCC)=O.[CH2:24]([C:26]1[O:30][N:29](C)[CH:28]([N+]#[C-])[N:27]=1)[CH3:25].[CH3:34][N:35](C=O)[CH3:36]>C(O)(=O)C>[CH2:24]([C:26]1[O:30][N:29]=[C:28]([C:34]2[N:35]=[CH:36][N:3]3[C:4]4[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=4[CH2:6][CH2:7][CH2:8][C:2]=23)[N:27]=1)[CH3:25]
Reactant: O=C1CCCc2ccccc2N1
Reactant: [C-]#[N+]C1N=C(CC)ON1C
Reactant: CN(C)C=O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(-c2ncn3c2CCCc2ccccc2-3)no1
Temperature: -20 °C

Procedure:
2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine (10 mmol) was dissolved in dry DMF (15 ml) and charged with sodium hydride (13 mmol. The resulting solution was cooled under N2 to -20° C., whereafter chlordiethylphosphate (13 mmol) was added. The reaction mixture was kept under N2 with stirring at -20° C. and was charged with a -30° C. cold solution of 5-ethyl-3-isocyano-methyl-1,2,4-oxadiazol (13 mmol) and K-t-butylate (13 mmol) in dry DMF (10 ml). The resulting reaction mixture was allowed to heat to room temperature, whereafter 5 ml of glacial acetic acid was added. The resulting mixture was filtered which gave 0.36 g of the title compound. M.p. 150.7°-150.8° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c6) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7](Br)[CH:6]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:56][O:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62][SH:63])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:6]=[C:7]([S:63][CH2:62][C:61]2[CH:64]=[CH:65][C:58]([O:57][CH3:56])=[CH:59][CH:60]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)[CH3:2]
Reactant: COc1ccc(CS)cc1
Reactant: CCOC(=O)c1cc(F)cc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(F)cc(SCc2ccc(OC)cc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a room temperature, degassed solution of 3-Bromo-5-fluoro-benzoic acid ethyl ester (4.0 g, 16.2 mmol) in dioxane (100 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.48 g, 0.82 mmol), 4-methoxy-benzylmercaptan (2.26 mL, 16.2 mmol), DIEA (5.6 mL, 32.4 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.37 g, 0.41 mmol). The resulting mixture was warmed to 90° C. and stirred for 2 hrs, then cooled to room temperature. The mixture was subjected to standard aqueous workup, and the crude residue was filtered through a pad of silica gel to afford the title compound.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH:14](Cl)[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7].[CH3:21][SH:22]>C(Cl)CCl>[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH:14]([S:22][CH3:21])[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CS
Reactant: CC(C)NCC(Cl)c1ccc(O)c(NS(C)(=O)=O)c1
Agent: Cl
Solvent: ClCCCl
Product: CSC(CNC(C)C)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 1-g sample of 2'-hydroxy-5'-[1-chloro-2-(isopropylamino)ethyl]methanesulfonanilide hydrochloride is slowly added to 5 mL of methylmercaptan in 25 mL of ethylene dichloride at 0° to -10° C. under N2 atmosphere. This mixture is first stirred several hours at ice-bath temperature and then stirred at ambient temperature for 24 hours. The mixture is filtered. The filter cake is washed with ethylene dichloride, added to water, and basified with 10% NaOH solution to pH 10 in an ice bath. The aqueous mixture is extracted several times with methylene chloride. The combined extracts are dried over MgSO4 and evaporated to dryness thus yielding the crude product compound.
Reaction SMILES: [CH:1]([Si:4]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[N:16]3[CH:17]=[C:18]([O:21][C@H:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C@@H:25]([NH2:32])[CH2:24][CH2:23]4)[CH:19]=[CH:20][C:15]3=[N:14][N:13]=2)[CH2:7]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:32][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([N:8]5[CH2:9][CH2:10][CH2:11][C@H:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:33]([CH3:35])[CH3:34])[CH:36]([CH3:38])[CH3:37])[CH2:7]5)=[N:13][N:14]=4)[CH:17]=3)[CH2:23][CH2:24]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Yield: 60 %

Procedure:
A solution of Intermediate 63c (140 mg, 0.261 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 106 mg, 0.261 mmol) in 1,4-dioxane (3 mL) and DIPEA (70 μL, 0.4 mmol) was stirred at 90° C. for 3 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a pale brown gum (124 mg, 60%). LCMS (Method 3): Rt 5.43 min, m/z 791 [MH+].
Reaction SMILES: [F-:1].[Cs+].[CH2:3]([Sn:7](C1SC=CC=1)([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].ClCCl>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Sn:7]([F:1])([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [F-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC[Sn](F)(CCCC)CCCC
Temperature: 120 °C
Reaction time: 12 h

Procedure:
Step a) Under inert atmosphere, to a mixture of chromophore 1, 1 mol % catalysator Pd(PPh3)4, 1 equivalent of CsF in toluene, 1.2 equivalent of tributylstannyl-thiophene were added. The reaction mixture was stirred at 120° C. for 12 h. After cooling to room temperature, dichloromethane was added. The white salt (Bu3SnF) formed during the reaction was filtered off and the solvent removed under reduced pressure. Purification of the crude product was performed by column chromatography on silica gel with (4/6) dichloromethane/ethylacetate to give the pure thiophene derived squarylium dye 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)=[O:6].C([C:29]1[C:30]([N:36]=[CH:37][N:38]([CH3:40])C)=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([S:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:2]([NH:1][C:40]3[C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[N:31][C:30]=4[N:36]=[CH:37][N:38]=3)[CH:3]=2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(C(=O)NCc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)NCc4ccc(Br)cc4)ccc3Sc3ccc(O)cc3)ncnc2n1
Yield: 40 %

Procedure:
The product of Example 33A was reacted with the product of Example 9B using the procedure of Example 22C substituting the product of Example 33A for the product of Example 22B and substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (40 mg, 40%). 1H NMR (500 MHz, DMSO-D6) δ ppm: 2.67 (s, 3 H) 4.41 (d, J=6.22 Hz, 2 H) 6.83 (d, J=8.82 Hz, 2 H) 6.86-6.95 (m, 1 H) 7.25 (d, J=8.30 Hz, 2 H) 7.28 (d, J=8.82 Hz, 2 H) 7.50 (d, J=8.30 Hz, 2 H) 7.52-7.59 (m, 1 H) 7.65-7.80 (m, 1 H) 7.81-7.98 (m, 1 H) 8.49-8.63 (m, 1 H) 8.69-8.84 (m, 1 H) 8.93-9.01 (m, 1 H) 9.83-9.97 (m, 1 H) 10.11 (s, 1 H); MS (ESI+) m/z 572/574 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].Br[CH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.[CH3:33][N:34]([CH3:43])[CH2:35][CH2:36][N:37]1[C:41]([SH:42])=[N:40][N:39]=[N:38]1.[OH-].[Na+].O>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:16][C:17]1[CH:32]=[CH:31][C:20]([C:21](=[O:22])[C:23]2[CH:28]=[CH:27][C:26]([CH2:29][S:42][C:41]3[N:37]([CH2:36][CH2:35][N:34]([CH3:43])[CH3:33])[N:38]=[N:39][N:40]=3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1
Reactant: CN(C)CCn1nnnc1S
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(CBr)cc1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(CSc5nnnn5CCN(C)C)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.1 %

Procedure:
In DMF (20 ml) were dissolved 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (1.03 g), 4,4'-bis(bromomethyl) benzophenone (1.75 g), 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole (865 mg), and 1N-sodium hydroxide/water (11 ml) and the solution was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia=50:1:0.1) and crystallized from methanol to provide the title compound as colorless solid (337 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][O:39][NH2:40])=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([CH2:38][O:39][NH:40][C:18]([C:17]2[CH:21]=[CH:22][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:15][CH:16]=2)=[O:20])=[CH:36][CH:35]=1
Reactant: NOCc1ccc(Cl)cc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NOCc4ccc(Cl)cc4)cc3)c(C#N)cc21
Reaction time: 0.33 h
Yield: 21.1 %

Procedure:
4-(6-cyano-4-(methoxycarbonyl)-3,4-dihydro-2H-chromen-7-yloxy)benzoic acid (from Example 7, Step B) (17 mg, 0.0481 mmol) was diluted with CH2Cl2 (1 mL) followed by the addition of oxalyl chloride in CH2Cl2 (2M in CH2Cl2) (0.0289 mL, 0.0577 mmol) and 1 drop of DMF. This was stirred for 20 minutes followed by the addition of O-(4-chlorobenzyl)hydroxylamine (15.2 mg, 0.0962 mmol) and N,N-diisopropylethylamine (0.0335 mL, 0.192 mmol). After stirring for 30 minutes the reaction was loaded directly onto a Biotage 12i eluting with hexane:ethyl acetate (1:1) to yield the title compound (5 mg, 21.1% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)#[N:15]>O1CCCC1.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
Under the argon atmosphere, 4-methylpiperazine (2.00 g, 20.0 mmole) and potassium carbonate (3.41 g, 24.7 mole) were added to a solution of 4-cyanobenzyl bromide (3.20 g, 16.3 mole) in tetrahydrofuran (30 ml). After stirring at room temperature for 18 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated aqueous saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-(4-methyl-1-piperazinylmethyl)benzonitrile as a colorless crystalline powder (1.49 g, 42.4%).
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.CCOC(C)=O>[CH:9]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]([CH2:4]3)[CH:2]1[NH:1][C:12](=[O:14])[CH3:13])[CH2:8]2
Reactant: CC(=O)OC(C)=O
Reactant: NC1C2CC3CC(C2)CC1C3
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
A solution of 2-aminoadamantane (20 g, 108 mmol) in dry pyridine (120 mL) was treated with acetic anhydride (12 mL, 128 mmol) and stirred overnight at rt. The mixture was dilute with EtOAc and washed with water, 1 N aq phosphoric acid and brine. The organic layer was dried, filtered and concentrated to give N-(2-adamantyl)acetamide (12.5 g, 60%). 1H NMR (400 MHz, CDCl3): δ=1.57 (m, 2H), 1.67 (m, 3H), 1.72 (m, 1H), 1.77 (m, 6H), 1.85 (m, 2H), 1.94 (s, 3H), 3.97 (t, 1H), 5.78 (br, 1H).
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(#N)C.CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][NH:15][CH:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:14][CH2:13]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(NCC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of trans-N-Boc-1,4-diaminocyclohexane (0.256 g, 1.19 mmol) and potassium carbonate (0.663 g, 4.80 mmol) in acetonitrile (15 mL) and DMF (5 mL) was added benzyl bromoacetate (0.21 mL, 1.33 mmol) under argon and the reaction was stirred at RT for 19 hr. The reaction was diluted with ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was carried forward without purification. ESI-MS m/z 363 (MH)+.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[N:32]1([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:41][C:40]=2[O:51][C:52]([F:55])([F:54])[F:53])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>ClCCl.O>[N:45]1([C:42]2[CH:43]=[CH:44][C:39]([CH2:38][N:32]3[CH2:37][CH2:36][N:35]([C:2]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:4])[CH2:34][CH2:33]3)=[C:40]([O:51][C:52]([F:54])([F:55])[F:53])[CH:41]=2)[CH2:46][CH2:47][O:48][CH2:49][CH2:50]1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: FC(F)(F)Oc1cc(N2CCOCC2)ccc1CN1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2ccc(N3CCOCC3)cc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A 50 mL round-bottom flask was charged with a solution of triphosgene (122 mg, 0.410 mmol, 0.71 equiv) in dichloromethane (20 mL). 1,1,1,3,3,3-Hexafluoropropan-2-ol (195 mg, 1.16 mmol, 2.00 equiv) and N,N-di-isopropylethylamine (598 mg, 4.63 mmol, 7.99 equiv) were added sequentially dropwise at 0° C. The resulting solution was stirred for 2 h at room temperature. 4-[4-(piperazin-1-ylmethyl)-3-(trifluoromethoxy)phenyl]morpholine (200 mg, 0.580 mmol, 1.00 equiv) was added. The resulting solution was stirred at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with H2O (15 mL). The resulting solution was extracted with dichloromethane (3×15 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (381 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 185 mg (59% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[4-(morpholin-4-yl)-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.34 (d, J=8.4 Hz, 1H), 6.74-6.83 (m, 2H), 5.72-5.80 (m, 1H), 3.86 (t, J=4.6 Hz, 4H), 3.52 (s, 6H), 3.16 (t, J=4.8 Hz, 4H), 2.46 (d, J=4.2 Hz, 4H). LCMS (ESI, m/z): 260 [M−C8H9F6N2O2]+.