Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14]1.[Cl:20][C:21]1[C:34]([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[C:33]([Cl:41])[CH:32]=[CH:31][C:22]=1[O:23][C@H:24]1[CH2:27][C@H:26]([CH2:28][NH:29][CH3:30])[CH2:25]1>C1COCC1>[ClH:20].[Cl:20][C:21]1[C:34]([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[C:33]([Cl:41])[CH:32]=[CH:31][C:22]=1[O:23][C@H:24]1[CH2:27][C@H:26]([CH2:28][N:29]([CH3:30])[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16]2)=[O:19])[CH2:25]1
Reactant: O=C(O)C1CCC1
Reactant: CNC[C@H]1C[C@H](Oc2ccc(Cl)c(CN3CCCC3)c2Cl)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C[C@H]1C[C@H](Oc2ccc(Cl)c(CN3CCCC3)c2Cl)C1)C(=O)C1CCC1
Product: Cl
Reaction time: 0.5 h

Procedure:
CDI (227 mg, 1.40 mmol) was added to a solution of cyclobutanecarboxylic acid (CAS 3721-95-7, 140 mg, 1.40 mmol) in THF (3 mL). The mixture was stirred for 30 min, and a solution of Example 377, ({trans-3-[2,4-Dichloro-3-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)methylamine (400 mg, 1.165 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 16 h at room temperature and evaporated. CHCl3 (5 mL), a saturated solution of K2CO3 (0.5 mL), and water (0.5 mL) were added to the residue under stirring. The layers were separated, and the aqueous one was subjected to extraction with chloroform. The combined extracts were dried and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 1 g, CHCl3/MeOH 100:0→80:10). Fractions containing the target product were evaporated. The residue was dissolved in ether (1 mL), and 4M HCl/dioxane (0.3 mL) was added under stirring. The obtained mixture was evaporated and dried in vacuo to afford the title compound (455 mg, 84%) as a light-yellow amorphous solid. LCMS data: 424.1, 425.1, 426.1, 427.1 (M+H) (calculated for C22H30Cl2N2O2 425.4). 1H NMR-data (DMSO-d6): 10.5 (brs, 1H, NH+), 7.54, 7.53 (2d, 1H, J=9 Hz, Ar—H); 7.12, 7.09 (2d, 1H, J=9 Hz, Ar—H); 4.89-5.06 (m, 1H); 4.59 (s, 2H, CH2); 3.48-3.59 (m, 2H), 3.19-3.48 (m, 5H); 2.77, 2.86 (2s, 3H, NCH3), 2.53-2.66 (m, 1H), 1.82-2.33 (m, 13H); 1.66-1.79 (m, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[C:23]=2[F:26])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4F)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (32 mg, 18%), MS (ISP) m/z=365.5 [(M+H)+], mp 205.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (157 mg, 0.5 mmol) and commercially available 2,3,4-trifluorophenylboronic acid (114 mg, 0.65 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)=O.[NH2:20][CH2:21][CH2:22][SH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:19][C:17]1[CH:16]=[C:4]([C:5]23[S:23][CH2:22][CH2:21][N:20]2[C:9](=[O:11])[C:8]2[C:7]3=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[C:2]([CH3:1])[CH:18]=1
Reactant: Cc1cc(C)cc(C(=O)c2ccccc2C(=O)O)c1
Reactant: NCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cc(C)cc(C23SCCN2C(=O)c2ccccc23)c1
Yield: 53 %

Procedure:
10 mmol 2-(3,5-dimethylbenzoyl)-benzoic acid were dissolved in 100 ml of xylene and, after addition of 20 mmol cysteamine, as well as a catalytic amount of p-toluenesulphonic acid, heated for 2 h under reflux on a water separator. The solvent was then removed in a vacuum and the residue recrystallised from ethanol. Yield 53%, m.p. 163° C.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([OH:26])[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3].[Cl:29][C:30]1[C:31](Cl)=[N:32][CH:33]=[C:34]([CH:40]=1)[C:35]([O:37][CH2:38]C)=[O:36].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:29][C:30]1[CH:40]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[CH:33]=[N:32][C:31]=1[O:26][C:24]1[CH:23]=[C:13]([C:14]([NH:16][C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[O:15])[CH:12]=[C:11]([O:10][C@@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:4])[CH3:1])([CH3:28])[CH3:27])[CH:25]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)Nc3ccn(C)n3)c2)c(Cl)c1
Yield: 77.4 %

Procedure:
A solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (1.0 g, 2.47 mmol), ethyl 5,6-dichloronicotinate (0.57 g, 2.59 mmol), and potassium carbonate (0.855 g, 6.14 mmol) in acetonitrile (15 mL) was heated at 160° C. for 4 hours using microwave heating. The acetonitrile was removed in vaccuo and the residual oil partitioned between water (50 mL) and ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine, dried (MgSO4), and evaporated to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in hexane to give the desired compound (1.1 g). The analytical data indicated that transesterification had occurred at some stage in the procedure to furnish the methyl ester.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH2:21].C(Cl)Cl.CO.[NH4+].[OH-]>>[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and Nε-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=119-121° C.). The reaction was monitored by tlc (Rf=0.46 in 90:10:1 CH2Cl2/MeOH/NH4OH).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:23][CH3:24])(=[O:22])[CH2:13][C@H:14]([CH2:16][CH2:17][CH:18]=C(C)C)[CH3:15].S([O-])([O-])(=O)=S.[Na+].[Na+].O.O.I(O)(=O)(=O)=O>ClCCl.C1COCC1.O>[CH3:15][C@@H:14]([CH2:16][CH2:17][CH:18]=[O:9])[CH2:13][C:12]([O:23][CH3:24])=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C[C@@H](C)CCC=C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])O
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](C)CCC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a solution of 7.76 g (36 mmol) of 80% m-chloroperbenzoic acid in 200 ml of dry dichloromethane is added a solution of 6.00 g (32.6 mmol) of (S)-methyl citronellate 30 (prepared in 31-(1)) in 50 ml of dry dichloromethane, and the mixture is stirred at room temperature for one hour. The reaction mixture are added 5% aqueous solution of sodium thiosulfate and a dilute aqueous solution of sodium hydrogencarbonate, and the mixture is extracted with dichloromethane twice. The extract is washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. To a solution of the residue in 80 ml of THF is added a solution of 8.90 g (39 mmol) of periodic acid dihydrate in 80 ml of THF at 0° C. After additional stirring at room temperature for 20 minutes, the reaction mixture is diluted with water, and extracted with ether twice. The extract is washed with water, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 5.2 g of the crude desired aldehyde 31 as an oil, which is employed in the next step without further purification.
Reaction SMILES: [C:1]([O:9][C:10]1[C:27]([O:28][CH3:29])=[CH:26][C:13]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[C:22](OC)=[O:23])=[O:15])=[C:12]([N+:30]([O-:32])=[O:31])[CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10]1[C:27]([O:28][CH3:29])=[CH:26][C:13]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[CH:22]=[O:23])=[O:15])=[C:12]([N+:30]([O-:32])=[O:31])[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CCCCN1C(=O)c1cc(OC)c(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N2CCCC[C@@H]2C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 109 %

Procedure:
(R)-Methyl 1-(4-(benzoyloxy)-5-methoxy-2-nitrobenzoyl)piperidine-2-carboxylate (1.50 g, 3.50 mmol) in 30 ml of 1:1 DCM/benzene at −78° C. was added 7.5 ml of 1.0 M DIBAL in toluene under Ar in 10 min. The mixture was stirred at −78° C. for 1 hr and the reaction was quenched with 0.5 ml of methanol. The mixture was diluted with 150 ml of EtAc and 100 ml of 0.2 M HCl. The organic solvent layer was separated and was separated and the aqueous layer was extracted with EtOAc (3×80 ml). The organics were combined, dried over MgSO4, filtered, concentrated and purified on SiO2 chromatography eluted with EtAc/hexane (3:2) to afford 1.52 g (90%) of the title product. 1H NMR (CDCl3), 9.60 (s, 1H), 7.70 (s, 1H), 7.65-7.28 (m, 5H), 6.78 (m, 1H), 5.16 (s, 2H), 3.92 (s, 3H), 3.22, (m, 1H), 3.01 (m, 1H), 2.20 (m, 1H), 1.84 (m, 1H), 1.65-1.40 (m, 4H); 13C NMR 200.24, 171.31, 155.13, 154.78, 148.41, 146.20, 137.57, 135.47, 129.03, 128.73, 127.31, 109.83, 109.41, 71.61, 64.50, 56.96, 45.98, 25.25, 23.42, 18.70; MS m/z+421.1 (M+Na).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C>[CH:2]([C:3]1[S:5][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1)([CH3:6])[CH3:1]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(C(C)C)n1
Temperature: 70 °C
Yield: 108.2 %

Procedure:
A solution containing the product from Example 56A (8.6 g, 83.5 mmol) in ethanol (250 mL) was treated with ethyl bromopyruvate (12.6 mL, 100 mmol), and the mixture was heated at 70° C. for 3 hours, cooled to 25° C., concentrated, and partitioned between dichloromethane and saturated NaHCO3. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (18 g, 57% yield), which was used without further purification.
Reaction SMILES: ClC([O:4][CH2:5][CH:6]([CH3:8])C)=O.CN1CC[O:13]CC1.[Br:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([NH2:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:20]=[CH:21][CH:22]=1.C(OCC)(=O)C>O1CCCC1.O>[Br:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([NH:34][C:8]([CH:6]4[CH2:5][O:4]4)=[O:13])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CN1CCOCC1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1)C1CO1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 18 %

Procedure:
A solution of 280 mg of 2,3-epoxy propoinic acid in 2.0 mL of tetrahydrofuran was cooled in an ice bath. A 0.42 mL portion of isobutyl chloroformate followed by a 0.48 mL portion of N-methylmorpholine were added. After 5 minutes, a suspension of 500 mg of N-(3-bromophenyl)-4,6-quinazolindiamine in 4 mL of tetrahydrofuran was added. The resulting reaction mixture was stirred at 0° C. for 3 hr., and then was diluted with 30 mL of water. The aqueous solution was extrated with 50 mL of ethyl acetate. The organic phase was separated, dried over Na2SO4 and filtered. The solvent was removed at reduced pressure to give a solid residue. Purification of the crude produt on preparative TLC afforded 109.9 mg of the product as yellow solid in 18 % yield; mp 228-300° C.; mass(m/e) 385.0264.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[CH:4]=[O:5].[CH3:11][S-:12].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:12][CH3:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cccc(Cl)c1C=O
Temperature: 25 °C

Procedure:
To a solution of 2,6-dichlorobenzaldehyde (20 g, 114.28 mmol) in N,N-dimethylformamide (200 ml), sodium thiomethoxide (8.81 g, 125.7 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature overnight, then poured into water. A yellow precipitate was collected by vacuum filtration and dried to afford 2-chloro-6-(methylthio)benzaldehyde (11. g), as a light yellow solid. (This method is general for other 2-haloaldehydes). 1H NMR (300 MHz, CDCl3): 10.6 (s, 1H), 7.4 (t, 1H), 7.2 (dd, 2H), 2.4 ppm (s, 3H). MW=187 confirmed by LC-MS, tr=13.18 min (Method Y) MH+=188.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:21][CH2:20][C@@H:19]([CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:21][CH2:20][C@@H:19]([CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18]2)=[N:5][CH:4]=1
Reactant: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.500 g, 2.29 mmol) 1:4 (MeOH/CH2Cl2) (40 mL) were added phenylmethyl [(3R)-3-pyrrolidinyl-methyl]carbamate (for a synthesis see WO2006002047 Preparation 23(b)) (0.536 g, 2.29 mmol) and triethylamine (0.351 mL, 2.52 mmol) and the resulting solution stirred at ambient temperature for 1 h. Na(OAc)3BH (1.46 g, 6.87 mmol) was added and the solution stirred an additional 18 hours. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil, (0.333 g, 33%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:4][C:3]=1[F:20].C(N(CC)CC)C.[CH2:28]([OH:30])[CH3:29].CN([CH:34]=[O:35])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O>[C:15]([O:14][C:13]([NH:12][C@@H:10]([CH3:11])[CH2:9][O:8][C:5]1[CH:4]=[C:3]([F:20])[C:2]([C:34]([O:30][CH2:28][CH3:29])=[O:35])=[N:7][CH:6]=1)=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CN(C)C=O
Reactant: C[C@@H](COc1cnc(Cl)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc(OC[C@H](C)NC(=O)OC(C)(C)C)cc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under a carbon monoxide atmosphere, a mixture of tert-butyl {(1S)-2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-1-methylethyl}carbamate (500 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (135 mg), triethylamine (0.229 mL), ethanol (5 mL) and DMF (5 mL) was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (402 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[CH:31][C:32]([N:38]1[CH2:43][C@H:42]([CH3:44])[NH:41][C@H:40]([CH3:45])[CH2:39]1)=[N:33]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[C@H:42]([CH3:44])[CH2:43][N:38]([C:32]3[CH:31]=[CH:30][C:29]4[C:34](=[CH:35][CH:36]=[CH:37][C:28]=4[Cl:27])[N:33]=3)[CH2:39][C@@H:40]2[CH3:45])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2ccc3c(Cl)cccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCC(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 5-chloro-2-(cis-3,5-dimethyl-piperazin-1-yl)-quinoline.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH3:20])=[CH:15][CH:14]=1.S([O-])([O-])(=O)=O.[Mg+2].C(O)(=O)C>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[N:1]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][O:5][C:6]3=[O:11])/[CH3:20])=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C/C(=N\c1cccc2c1COC2=O)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 36 h
Yield: 87.6 %

Procedure:
To a solution of 4-aminoisobenzofuran-1(3H)-one (1 g, 6.7 mmol) and 1-(4-fluorophenyl)ethanone (1.4 g, 10.1 mmol) in toluene (35 mL) was added anhydrous magnesium sulfate (8.8 g, 73.7 mmol) and acetic acid (0.2 mL) at room temperature under N2. The reaction mixture was then stirred at 120° C. for 36 hr. The reaction mixture was cooled to 90° C. and filtered. After filter cake was washed with acetonitrile, the filtrates were combined and evaporated to dryness to obtain yellow solid, which was washed by petroleum ether to obtain the title compound as a white solid (1.58 g, yield 88%). LC-MS (ESI) m/z: 270 (M+1)+ 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.30 (s, 3H), 5.16 (s, 2H), 7.00-7.02 (d, J=7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.51-7.56 (t, J=7.6 Hz, 1H), 7.66-7.69 (d, J=7.6 Hz, 1H), 7.99-8.03 (m, 2H).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(Cl)(O[C:25](=[O:31])OC(Cl)(Cl)Cl)Cl.[CH3:33][NH:34][CH2:35][CH:36]([CH3:38])[CH3:37]>C1COCC1>[CH3:33][N:34]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:25]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)=[O:31]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CNCC(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CN(C)C(=O)N(C1CCCCC1)C1CCCCC1
Reaction time: 8 h

Procedure:
A solution of dicyclohexylamine (3.6 mL, 18 mmol) and triethylamine (5.6 mL, 40 mmol) in THF (64 mL) was added dropwise to a stirred solution of triphosgene (1.98 g, 6.7 mmol) in THF (35 mL) at room temperature. The reaction mixture was stirred overnight. Then, a solution of N-methylisobutylamine (2.2 mL, 18 mmol) and triethylamine (5.5 mL, 40 mmol) in THF (35 mL) was added. The reaction mixture was stirred overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, yielding N-methyl-N-isobutyl-N′,N′-dicyclohexylurea as a dark yellow oil. Yield: 4.8 g (90%). Oxalyl chloride (8 mL, 16 mmol, 2 M solution in dichloromethane) was added to a stirred solution of the urea (4.8 g, 16 mmol) in THF (65 mL). The reaction mixture was heated to reflux overnight and evaporated to dryness. Ammonia in methanol (7 mL, 49 mmol, 7 M solution in methanol) was added to a suspension of the formed solid in THF. The reaction mixture was heated to reflux overnight and evaporated to dryness. The product was neutralized and purified by treatment with aqueous sodium hydroxide solution. The organic layer was extracted with diethyl ether and dried over magnesium sulfate. Evaporation to dryness yielded the desired guanidine as a brown oil. Yield: 2.95 g (75%). 1H NMR (CDCl3, 300 MHz): δ 0.80 (d, 6 H), 1.20 (d, 12 H), 1.8 (sept, 1 H), 2.7 (s, 3 H), 2.83 (d, 2 H), 3.52 (sept, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ 19.1, 20.7, 25.6, 36.8, 46.4, 57.2, 164.7 ppm.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[C:11]([NH:13][C:14]([CH3:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=3)[C:11]([NH:13][C:14]([CH3:20])([CH3:19])[C:15]([F:16])([F:18])[F:17])=[O:12])[CH2:2][CH2:3]2)=[O:30])=[CH:27][CH:26]=1
Reactant: CC(C)(NC(=O)c1cccc(CN2CCNCC2)c1)C(F)(F)F
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3)CC2)c1)C(F)(F)F
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a stirred mixture of 3-(piperazin-1-ylmethyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (3.07 mmol, 1.01 g), 4-aminobenzoic acid (3.07 mmol, 0.421 g) and triethylamine (6.13 mmol, 0.855 mL, 0.621 g) in dichloromethane (30.7 mL) was added 1-propanephosphonic acid cyclic anhydride (6.13 mmol, 3.63 ml, 3.90 g, 50% solution in ethyl acetate). After 2 hours stirring, dichloromethane was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated to yield the title compound (640 mg).
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Mg].[P:11](Cl)(Cl)(Cl)=[O:12].Cl>C1(C)C(C)=CC=CC=1.O.C(OCC)C>[CH2:1]([P:11](=[O:12])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCl
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCP(=O)(CCCCCCCC)CCCCCCCC
Reaction time: 1 h

Procedure:
A solution of 44.5 g of octyl chloride in 300 cc of xylene was added dropwise to 12 g of degreased and dry magnesium immersed in a few cc of anhydrous diethyl ether, whilst heating until the reaction started. When the reaction had started, the octyl chloride was added in the cold. When all the octyl chloride solution had been added, stirring was continued for about 1 hour further. 13.8 g of phosphorus oxychloride were then added in the cold. The mixture was then heated to boiling under reflux for 2 hours 30 minutes. The solution was hydrolysed by the addition of 1 litre of water acidified with 100 cc of HCl. The organic phase was decanted, washed with distilled water and neutralised with sodium bicarbonate. After decanting, the organic phase was recovered and then steam-distilled or steam-stripped to remove the solvent without distilling the product. A white solid, trioctylphosphine oxide, was obtained.