Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2O.C(=O)=O.CC(C)=O.CCN(S(F)(F)[F:33])CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]2[F:33]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C(O)C1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2c(Br)cccc2C(F)C1
Temperature: 25 °C

Procedure:
To a flask containing tert-butyl 8-bromo-4-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-4) (622 mg, 1.895 mmol) was added anhydrous DCM (10 ml). The reaction mixture was then capped & cooled to −78 C (dry ice/acetone bath) while stirring under N2. Then added DAST (1.4 ml, 10.60 mmol) at −78 C. The reaction mixture was then stirred at −78 C. Followed by LC/MS. After 5 minutes at −78 C the reaction was quenched by dropwise addition of a saturated solution of NaHCO3 in water at −78 C (with a vent needle), then permitted to warm to room temperature, then the reaction mixture was suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated to yield. Purification by silica gel chromatography (0-15% EtOAc/Hex; 40 g ISCO); desired fractions concentrated to yield tert-butyl 8-bromo-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-5).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[Br:18]N1C(=O)CCC1=O.CCOC(C)=O>C(Cl)Cl.CC#N>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[C:15]([Br:18])[CH:16]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1(c2ccc(N)cc2)CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(N)c(Br)c2)CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 4-(4-amino-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 1.65 g, 7.01 mmol) in 100 mL of 1:1 DCM/CH3CN at 0° C. was slowly added N-bromosuccinimide (NBS) (1.25 g, 7.01 mmol) in 25 mL of 1:1 DCM/CH3CN under Ar. After stirring at 0° C. for 0.5 h, the mixture was treated with 50 mL of EtOAc and washed with H2O (2×30 mL) and brine H2O (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (1-4% EtOAc/DCM) to give 1.85 g (84%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C13H16BrNO3, 314.0 (M+H). found 314.2.
Reaction SMILES: [I-:1].[Na+].CC1C=CC(S(OCCC[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)(=O)=O)=CC=1.[CH3:26][C:27]([CH3:29])=O>>[I:1][CH2:26][CH2:27][CH2:29][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18]1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccccc23)cc1
Reactant: CC(C)=O
Agent: [Na+]
Product: ICCCn1ccc2ccccc21

Procedure:
Sodium iodide (827 mg, 5.52 mmol, 2 equiv) was added to a solution of 3-(1H-indol-3-yl)propyl 4-methylbenzenesulfonate (909 mg, 2.76 mmol, 1 equiv) in acetone, and the mixture was refluxed for 16 h. Upon cooling the reaction, it was evaporated under reduced pressure and the residue was taken into dichloromethane. The organic layer was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.7, gradient—5%-30% ethyl acetate in hexanes) to afford the title compound as an oil (789 mg, quant); 1H NMR (400 MHz, DMSO-d6): δ 2.07-2.14 (m, 2H); 2.78 (t, 2H, J=7.6 and 6.8 Hz); 3.29 (t, 2H, J=6.8 Hz); 6.95-6.99 (m, 1H); 7.04-7.08 (m, 1H); 7.14 (d, 1H, J=2 Hz); 7.32-7.34 (m, 1H); 7.52 (d, 1H, J=8 Hz); 10.81 (s, 1H); MS for C11H12IN m/z 285.12 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][CH2:6][P:7](CC[Si](C)(C)C)(CC[Si](C)(C)C)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])[CH3:3].[OH2:32].O.O.[Rh:35](Cl)(Cl)Cl.[CH2:39]=O.[OH-].[K+]>C(O)C>[CH2:39]=[O:32].[Rh:35].[CH3:4][Si:2]([CH2:5][CH2:6][P:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:1])[CH3:3].[CH3:4][Si:2]([CH2:5][CH2:6][P:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:1])[CH3:3].[CH3:4][Si:2]([CH2:5][CH2:6][P:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:1])[CH3:3]
Reactant: O
Reactant: C[Si](C)(C)CCP(CC[Si](C)(C)C)(CC[Si](C)(C)C)(c1ccccc1)c1ccccc1
Reactant: Cl[Rh](Cl)Cl
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCP(c1ccccc1)c1ccccc1
Product: [Rh]

Procedure:
To a vigorously stirred, refluxing, nitrogenated solution of 11.44 g (40 mmole) of tris-(trimethylsilylethyl) diphenyl phosphine of Example 1 in 400 ml of ethanol, a hot solution of 1.04 g (0.4 mmole) of rhodium trichloride trihydrate in 80 ml ethanol was added at once. After a delay of 15 seconds, 40 ml warm aqueous (37%) formaldehyde solution and, immediately thereafter, 80 ml hot ethanolic solution of 3.2 g of potassium hydroxide were added. The resulting clear orange liquid reaction mixture was refluxed for 10 minutes. During the heating, the color changed to deep orange.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[C:21]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH3:22].Br[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH3:42])[CH:37]=2)[N:32]=1>O1CCCC1.CCOCC>[CH3:26][C:25]([O:24][C:21](=[O:23])[CH2:22][CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH3:42])[CH:37]=2)[N:32]=1)([CH3:28])[CH3:27]
Reactant: COc1ccc2nc(CBr)ccc2c1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: COc1ccc2nc(CCC(=O)OC(C)(C)C)ccc2c1
Temperature: 10 °C
Reaction time: 0.2 h
Yield: 33.8 %

Procedure:
To a solution of diisopropylamine (7.4 mL, 52.8 mmol) in 70 mL of tetrahydrofuran cooled to -78° C. was added a solution of 1.6M n-butyllithium in hexanes (31.4 mL, 50.2 mmol). After being stirred for 12 minutes, the resulting solution of lithium diisopropylamide was treated with a solution of t-butyl acetate (4.81 g, 41.4 mmol) in 70 mL of tetrahydrofuran, added slowly through an addition funnel. The reaction mixture was allowed to warm gradually to 10° C. over 3.75 hr, and then recooled to -78° C. whereupon a solution of 2-(bromomethyl)-6-methoxyquinoline from the preceding example (3.46 g, 13.7 mmol) in 40 mL of tetrahydrofuran was added and the reaction was allowed to stir overnight at room temperature. The resulting solution was worked-up with ether in the usual manner. Flash chromatography of the crude product on 360 g of silica gel, eluting with hexane-ethyl acetate (4:1) afforded 1.31 g (33.8 %) of the title compound as an orange oil.
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C1C=CC2N(O)N=[N:17]C=2C=1.C(Cl)CCl.[NH4+].[OH-]>CC#N>[CH3:1][C:2]1([C:8]([NH2:17])=[O:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: On1nnc2ccccc21
Reactant: CC1(C(=O)O)CCOCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: ClCCCl
Product: CC1(C(N)=O)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A mixture of 4-methyltetrahydro-2H-pyran-4-carboxylic acid (2.60 g, 18.0 mmol), HOBt (2.76 g, 18.0 mmol) and EDC (4.49 g, 23.4 mmol) in MeCN (75 mL) was stirred at RT for 3 h, treated with NH4OH (˜15M, 7 mL, ˜105 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, and the residue was partitioned between satd. brine (40 mL) and DCM (100 mL). The aqueous was extracted with THF (50 mL) and DCM (5×30 mL). The combined organics were washed with 10% aq K2CO3 (50 mL), dried over Na2SO4 and concentrated in vacuo to afford 4-methyltetrahydro-2H-pyran-4-carboxamide (1.83 g, 70%). 1H NMR (400 MHz, DMSO-d6): δ 7.14 (s, 1H), 6.86 (s, 1H), 3.60 (dt, J=11.7, 4.5 Hz, 2H), 3.36 (m, 2H), 1.91-1.89 (m, 2H), 1.30 (m, 2H), 1.08 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11]Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([NH:16][C:17]1[C:18]([I:33])=[C:19]([N:28]([C:30](=[O:32])[CH3:31])[CH3:29])[C:20]([I:27])=[C:21]([C:24]([O-:26])=[O:25])[C:22]=1[I:23])(=[O:15])[CH3:14].[Cs+].[I-].[Na+]>CN(C=O)C>[C:13]([NH:16][C:17]1[C:18]([I:33])=[C:19]([N:28]([C:30](=[O:32])[CH3:31])[CH3:29])[C:20]([I:27])=[C:21]([C:24]([O:26][CH2:11][O:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:25])[C:22]=1[I:23])(=[O:15])[CH3:14]
Reactant: O=C(Cc1ccccc1)OCCl
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OCOC(=O)Cc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Reaction time: 4 h

Procedure:
Chloromethyl phenylacetate (1.0 2 g, 5.5 mmol) (Intermediate 4) in dry DMF (50 ml) is added dropwise at 50° C. to a solution of cesium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (3.80 g, 5.0 mmol) and sodium iodide (37 mg, 0.25 mmol) in dry DMF (70 ml). The precipitate is removed by filtration after stirring for 4 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (50 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][C@@H:11]2[CH3:29])=[O:9])=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32].CO>C(O)(C)C>[ClH:1].[CH3:30][N:31]([CH3:32])[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][C@@H:11]2[CH3:29])=[O:9])=[CH:6][N:7]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccc(Cl)nc1
Reactant: CNC
Solvent: CC(C)O
Solvent: CO
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccc(N(C)C)nc1
Product: Cl
Temperature: 120 °C

Procedure:
(2S)-1-[(6-Chloro-3-pyridinyl)carbonyl]-2-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 26) (67 mg, 0.15 mmol) was weighed into a microwave vial, suspended in isopropanol (0.75 ml) and treated with dimethylamine, 2M in methanol (0.75 ml, 1.50 mmol). The mixture was heated in the microwave to 120° C. for 18 h with stirring. LCMS analysis showed clean conversion to the product. The reaction mixture was concentrated to give the crude material as a pale yellow gum/solid. This was purified by MDAP (High pH system) to give the free base of the title compound as a colourless gum (61 mg).
Reaction SMILES: [C:1]1([C:10]2C(=[CH:15][CH:16]=[CH:17][CH:18]=2)C(O)=O)[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:3](O)=[O:4].[C:19](Cl)(=O)[C:20]([Cl:22])=[O:21].C(Cl)[Cl:26]>CN(C)C=O>[C:1]1([C:10]2[C:19](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]([Cl:22])=[O:21])[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:3]([Cl:26])=[O:4]
Reactant: ClCCl
Reactant: O=C(O)c1ccccc1-c1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1-c1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
24.2 g of diphenic acid (biphenyl-2,2'-dicarboxylic acid) were dissolved in 200 ml of methylene chloride and 1 ml of N,N-dimethylformamide, and 27.9 g of oxalylchloride were dropped in the resultant solution under stirring at room temperature over 30 minutes. After the dropping, the resultant solution was reacted at room temperature for one hour, and the reaction solution was thickened in aspirator vacuum. Methylene chloride and an excessive amount of oxalylchloride were removed from the thickened solution to obtain an oily matter of diphenic acid chloride.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH2:6][O:7][P:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])([OH:10])=[O:9])([CH3:4])[CH3:3].FC(F)(F)C(O[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=O.N1C(C)=CC=CC=1C.C(OCC)C>CN(C)C=O>[CH3:1][N+:2]([CH2:5][CH2:6][O:7][P:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:18])([O-:10])=[O:9])([CH3:4])[CH3:3]
Reactant: C[N+](C)(C)CCOP(=O)(O)OCCCCCC(=O)O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Product: C[N+](C)(C)CCOP(=O)([O-])OCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 80.3 %

Procedure:
A sample of 505 mg (1.7 mmol) of 6-phosphocholinehexanoic acid in 11 ml of dimethylformamide was stirred at room temperature for 5 min. To this mixture, 1.3 g (5.5 mmol) of p-nitrophenyl trifluoroacetate was added. While stirring the resulting mixture, 0.43 ml (3.7 mmol) of 2,6-lutidine was added and the mixture was stirred until the 6-phosphocholinehexanoate completely dissolved. The reaction mixture was stirred at room temperature for an additional 6 hours. Afterwards, a 150 ml aliquot of ethyl ether was added to the reaction mixture to precipitate p-nitrophenyl 6-(O-phosphocholine)hydroxyhexanoate from solution. The supernatant was decanted and the oily product was dissolved in 5 ml of acetonitrile and precipitated again with ether. After the removal of solvent traces, 571 mg of p-nitrophenyl 6-(O-phosphocholine)hydroxyhexanoate was obtained at a yield of about 80%. The overall synthesis produced a yield of about 27%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:21]([OH:23])[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:23][CH2:21][CH3:22])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCOc1cc(Br)cc(C#N)c1
Yield: 44 %

Procedure:
In analogy to the procedure described in WO2007060448, the reaction of 3-bromo-5-fluorobenzonitrile with ethanol using sodium bis(trimethylsilyl)amide as the base yielded the title compound as a light brown oil (yield: 44% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]([CH3:26])([CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:18]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl.CO.C1COCC1>[CH3:16][C:17]([CH3:26])([CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(C)(CO)CN1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(C2(C#N)CCOCC2)cc1)CN1CCCC1
Yield: 6.9 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (1.29 g, 6.4 mmol), 2,2-dimethyl-3-pyrrolidin-1-yl-propan-1-ol (0.8 g, 5.1 mmol), PPh3 (1.67 g, 6.4 mmol), THF (16 ml) and DIAD (1.25 ml, 6.4 mmol) were reacted together according to general procedure H. The crude material was subjected to chromatography on silica eluting with DCM:MeOH (98:2). The resulting solid was slurried in TBME:heptanes (1:2, 1 ml) to provide the title compound (120 mg, 5%) as a white solid. 1H NMR (400 MHz, CDCl3), δ 7.37 (d, 2H), 6.94 (d, 2H), 4.12-4.03 (m, 2H), 3.89 (td, 2H), 3.71 (s, 2H), 2.57 (br s, 4H), 2.47 (s, 2H), 2.15-1.99 (m, 4H), 1.70 (brs, 4H), 1.00 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[C:3]([CH:12]=O)=[N:2]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:12]1[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[NH:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]=3)[CH:5]=2)[NH:1][N:2]=1
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccc2[nH]nc(C=O)c2c1
Product: c1ccc2[nH]c(-c3ccc4[nH]nc(-c5nc6ccccc6[nH]5)c4c3)nc2c1

Procedure:
The title compound was synthesized from 1H-Indazole-3,5-dicarbaldehyde and 1,2-diaminobenzene using the methods described in Example 4 except that an excess of 1,2-diaminobenzene was used. LC/MS m/z 351.2 (MH+), Rt 2.03 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].I[CH2:13][CH2:14][CH3:15].[O-:16]I(=O)(=O)=O.[Na+]>CN(C=O)C.O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:13][CH2:14][CH3:15])=[O:16])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1ccc(S)cc1Br
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)c1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-bromo-4-methyl-benzenethiol (1.27 g; 6.25 mmol) in anhydrous DMF (12.5 ml) was treated with sodium hydride (300 mg; 7.5 mmol). Then reaction mixture was stirred at RT for 15 minutes, then the treated with 1-iodopropane (0.73 ml; 7.5 mmol). The reaction was stirred for 24 hours, before being quenched by dropwise addition of water. EtOAc was added and the layers separated. The organic layer was washed with brine, dried on MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (13 mL), cooled to 0° C. and treated with a 0.5 M solution of sodium (meta)periodate in water (12.5 ml; 6.24 mmol). After stirring for 24 hours at RT, EtOAc and water were added and the phases separated and the organic phase was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a yellow sticky solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[H-].[Na+].F[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1>CN(C=O)C>[CH:29]([C:28]1[CH:31]=[CH:32][C:25]([O:1][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:26][CH:27]=1)=[O:30]
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2O)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)c1
Temperature: 70 °C

Procedure:
A solution was prepared of 9.8 g (35 mmol) of 1-hydroxy-2-(3-methoxyphenyl)-6-methoxynaphthalene in 490 mL of DMF under a nitrogen atmosphere and to this solution was slowly added 1.47 g (36.8 mmol) of 60% NaH in mineral oil. After ten minutes, 7.5 mL (70 mmol) of 4-fluorobenzaldehyde was added and the reaction mixture was heated to 70° C. for sixty-four hours. The reaction mixture was evaporated to dryness and the residue partitioned between water and EtOAc. The EtOAc layer was dried with Na2SO4 and chromatographed on a silica gel column eluted with EtOAc-hexane (1:9)(v/v). The final product was further purified by crystallization from MeOH. This yielded 2.4 g of the title compound as a tan solid, mp 145-146° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11]([O:13]CC)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[OH-].[Na+].O.Cl>O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:11]([OH:13])=[O:12])=[C:5]([C:7]([F:9])([F:8])[F:10])[N:6]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(Cl)nc1C(F)(F)F
Yield: 73.5 %

Procedure:
A mixture of 116 g (0.4468 mole) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate, 18 g (0.45 mole) of sodium hydroxide, 200 ml. of water, 400 ml. of tetrahydrofuran was stirred at room temperature for 16 hours and made acidic with 50 ml. of concentrated hydrochloric acid. The reaction mixture was extracted twice with 200 ml. of ether. The ether-tetrahydrofuran solution was dried (MgSO4) and concentrated under reduced pressure. The residual oil was treated with benzene and the benzene solution was concentrated under reduced pressure to remove the last trace of water. The residual solid was recrystallized from hexane-benzene to give 76 g (73.4%) of 2-chloro-4-trifluoromethyl-5-thiazolecarboxylic acid, m.p. 131°-131.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][C:35]=1[C:41]([F:44])([F:43])[F:42].O>CS(C)=O.[Cl-].[Na+].O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([F:33])=[C:35]([C:41]([F:44])([F:42])[F:43])[CH:36]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 9.3 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (54 mg, 0.20 mmol) and 1,1′-Carbonyldiimidazole (36 mg, 0.22 mmol) in 3.0 mL DMSO was stirred at rt for 5 minutes, and then heated at 60° C. for 25 minutes. Then 4-fluoro-3-(trifluoromethyl)aniline (0.051 mL, 0.40 mmol) was added, and the reaction heated at 80° C. for 46 hours. Next, an additional 2 small drops of 4-fluoro-3-(trifluoromethyl)aniline was added and the reaction heated at 160° C. for 1.5 hours. Upon cooling to rt, the reaction mixture was added to a solution of 35 mL H2O plus 5 mL brine, and the resulting precipitate filtered and rinsed with H2O and hexane/EtOAc. The precipitate was chromatographed using CHCl3/MeOH, and the resulting solid chromatographed again using EtOAc/MeOH to give the title compound as a yellow solid (8 mg, 9%). 1H NMR (Acetone-d6) δ: 9.77 (br. s., 1H), 8.31 (dd, J=6.4, 2.6 Hz, 1H), 8.10-8.17 (m, 2H), 7.62-7.64 (m, 1H), 7.35-7.44 (m, 3H), 7.24-7.28 (m, 1H), 5.79 (br. s., 2H), 4.35 (s, 2H), 3.70 (t, J=5.9 Hz, 2H), 2.80-2.86 (m, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])C.ClC(Cl)(O[C:25](=[O:31])OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:25](=[O:31])[N:16]([C:17]2[CH:18]=[CH:10][CH:9]=[CH:8][CH:13]=2)[C:19]2[CH:20]=[CH:3][CH:2]=[CH:1][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(N(c1ccccc1)c1ccccc1)N(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A solution of diphenylamine (3.05 g, 18 mmol) and triethylamine (6 mL, 43 mmol) in THF (62 mL) was added dropwise to a stirred solution of triphosgene (1.99 g, 6.7 mmol) in THF (37 mL) at room temperature. The reaction mixture was heated to reflux overnight. Then, a solution of diphenylamine (3.1 g, 18 mmol) and triethylamine (5.8 mL, 42 mmol) in THF (37 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 tetraphenylurea as a yellow solid. Yield: 6.0 g (91%). Oxalyl chloride (1.8 mL, 21 mmol) was added to a stirred solution of the urea (6.0 g, 16 mmol) in diethyl ether (65 mL). The reaction mixture was evaporated to dryness after stirring for 2 days at reflux. A solution of ammonia in methanol (5 mL, 35 mmol, 7 M) was added. The reaction mixture was heated to reflux overnight and evaporated to dryness. The product was neutralized and purified from ammonium chloride by several treatments with aqueous sodium hydroxide solutions. The organic layer was extracted and dried over sodium sulfate. Crystallization from diethyl ether at low temperature yielded the desired guanidine as a white solid. Yield: 2.0 g (33%). 13C NMR (CDCl3, 75 MHz): δ 121.4, 126.7, 128.6, 140.3, 164.5 ppm.