Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH2:24]([O:31][C:32]([N:34]([CH2:36][C:37](O)=[O:38])[CH3:35])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.CC[N+](CCCN(C)C)=C=N.C(N(CC)CC)C>C(Cl)Cl>[CH2:24]([O:31][C:32](=[O:33])[N:34]([CH2:36][C:37](=[O:38])[NH:23][CH2:22][CH:18]1[C:19]2[C:14](=[CH:13][C:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=3)(=[O:11])=[O:10])=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17]1)[CH3:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: CC[N+](=C=N)CCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC(=O)NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21)C(=O)OCc1ccccc1
Yield: 51.1 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.2 gms, 0.56 mmole), (Benzyloxycarbonyl-methyl-amino)-acetic acid (0.15 gms, 0.67 mmole), 1-hydroxybenzotriazole (0.11 gms, 0.84 mmole), 0.16 gms N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.16 gms, 0.84 mmole) and triethylamine (0.50 ml, 3.36 mmole) in 30 mL methylene chloride was stirred at room temperature for 24 hours. The reaction was quenched with 0.2 ml water, and the entire mixture was absorbed on to silica gel and medium pressure chromatography, eluting with ethyl acetate, gave 0.15 gms of ({[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl)-methyl-carbamic acid benzyl ester as an oil.
Reaction SMILES: C12CC(CC1)CC2NC1SC(C)C(=O)N=1.BrC1C=CC=CC=1.[CH3:23][C:24]1([C:43]2[CH:50]=[CH:49][C:46](C#N)=[CH:45][CH:44]=2)[S:28][C:27]([NH:29][C@H:30]([C:32]2C=[CH:36][CH:35]=[CH:34][C:33]=2[C:38](F)(F)F)C)=[N:26][C:25]1=[O:42]>>[CH:35]12[CH2:34][CH:33]([CH2:38][CH2:36]1)[CH2:32][CH:30]2[NH:29][C:27]1[S:28][C:24]([CH3:23])([C:43]2[CH:44]=[CH:45][CH:46]=[CH:49][CH:50]=2)[C:25](=[O:42])[N:26]=1
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Agent: CC1SC(NC2CC3CCC2C3)=NC1=O
Solvent: Brc1ccccc1
Product: CC1(c2ccccc2)SC(NC2CC3CCC2C3)=NC1=O

Procedure:
The title compound was prepared from the reaction of 2-(bicyclo[2.2. 1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one with bromobezene using the procedure described for 2a. MS (ESI, pos. ion) m/z: 301(M+1). % de (chiral LC): 10%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([S:29][CH2:30][CH2:31][OH:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([O:32][CH2:31][CH2:30][S:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OCCSCc1ccccc1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)OCCSCc1ccccc1
Yield: 94 %

Procedure:
A solution of 34.7 g of 2-[4-(3,5-dichloro-2-pyridyloxy)-phenoxy]-propionyl chloride in 80 ml of toluene was added dropwise at 0° to 10° C. to a solution of 16.8 g of 2-benzylthioethanol and 10.1 g of triethylamine in 100 ml of toluene whilst stirring. After the addition was completed, the mixture was stirred further at 30° to 40° C. for 1 hour. The mixture was washed successively with a 1% aqueous solution of sodium hydroxide and water, and dried. Upon distilling off the toluene under reduced pressure, there were obtained 44.9 g of 2-benzylthioethyl 2-[4-(3,5-dichloro-2-pyridyloxy)-phenoxy]-propionate in the form of a colorless viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:3]=1.Cl[CH2:34][S:35](Cl)(=[O:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[C:22]([O:21][C:20](=[O:26])[NH:19][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([C:5]3[C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:3][C:2]4[NH:1][S:35](=[O:37])(=[O:36])[CH2:34][O:8][C:7]=4[N:6]=3)=[CH:14][CH:13]=2)[CH2:18][CH2:17][CH2:16]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3[nH]c(=O)c(N)cc3-c3ccccc3)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NS(=O)(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
In a 40 mL reaction tube was added tert-butyl 1-(4-(5-amino-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl)phenyl)cyclobutylcarbamate (500 mg, 1.159 mmol) in anhydrous pyridine (5 mL) to give a yellow solution. After stirring at room temperature for 15 minutes, chloromethanesulfonyl chloride (126 μl, 1.390 mmol) was added and the resulting solution stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and redissolved in anhydrous methanol (5 mL), followed by the addition of potassium carbonate (641 mg, 4.63 mmol) and heating to 60° C. overnight. The reaction mixture was allowed to cool to room temperature and concentrated to dryness under reduced pressure. The residue was redissolved in ethyl acetate (5 mL) and washed with 50:50 water:brine (2×5 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a brown oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate:dichloromethane:methanol, gradient elution from 80:10:10:0 to 0:90:10:0 then to 0:90:10) to give the desired product as an off-white solid (330 mg, 56% yield). 1H-NMR (500 MHz, d6-Acetone) δ 7.35 (1H, s), 7.23-7.32 (7H, m), 7.16-7.32 (2H, m), 5.39 (2H, s), 2.30-2.60 (4H, m), 2.00-2.12 (1H, m), 1.75-1.88 (1H, m), 1.05-1.40 (9H, br m). LCMS (Method A) RT=6.68 min, M+H+=508.01.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH:16]1([C:19]2[O:23][N:22]=[C:21]([NH:24][CH2:25][CH2:26][NH2:27])[N:20]=2)[CH2:18][CH2:17]1.ClCCl>ClCCl.C(OCC)(=O)C.CN(C=O)C>[CH:16]1([C:19]2[O:23][N:22]=[C:21]([NH:24][CH2:25][CH2:26][NH:27][C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[N:20]=2)[CH2:18][CH2:17]1
Reactant: NCCNc1noc(C2CC2)n1
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/C(F)(F)F)NCCNc1noc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (17 mg, 0.12 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (11 μl, 0.12 mmol) and the solution was stirred at room temperature for 10 minutes. This solution was added to a solution of N-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)ethane-1,2-diamine (17 mg, 0.1 mmol) and TEA (42 μl, 0.3 mmol) in a mixture of anhydrous dichloromethane (1 ml) and anhydrous DMF (1 ml) and the resulting mixture was stirred at room temperature. After one hour, additional acid chloride (0.12 mmol as prepared above) was added and stirring was continued for one hour. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 5% to 100% acetonitrile) to yield 8 mg of a solid (0.019 mmol, 19%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7](=[CH:20][C:17]1[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=1)[C:6]2=[O:13]
Reactant: O=Cc1ccncc1
Reactant: COc1ccc2c(c1)C(=O)CCO2
Product: COc1ccc2c(c1)C(=O)C(=Cc1ccncc1)CO2

Procedure:
By the method of Example 1, 6-methoxy-4-chromanone (26.7 g, 0.15 mol) and pyridine-4-carbaldehyde were converted to present title product, 13.5 g; m.p. 170-171.5° C.; IR (KBr) 1675, 1616, 1598, 1552 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCl)cn1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Agent: Cl
Product: Cc1ccc(Cn2cc(C#Cc3cccc(Cl)c3)nc2C)cn1

Procedure:
The title compound, MS: m/e=322.5 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 5-chloromethyl-2-methyl-pyridine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:18]=1.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[C:8]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:7][C:6]=2[CH:18]=1
Reactant: NCc1cccnc1
Reactant: CN1c2ccc(Cl)cc2NC(=S)c2ccccc21
Solvent: CCOCCO
Product: CN1c2ccc(Cl)cc2N=C(NCc2cccnc2)c2ccccc21
Yield: 38.2 %

Procedure:
A solution of 329 mg (1.2 mmol) of 8-chloro-5-methyl-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588 (1967)) in 10 mL of 2-ethoxyethanol was treated with 0.3 mL (2.4 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product as an oil. Chromatography on silica gel, eluting with CHCl3 /MeOH (98/2) gave 160 mg (38.4% yield) of the product as a golden solid foam. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =349.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:34]1([C:40]([OH:42])=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[Br:43][C:44]1[CH:53]=[CH:52][C:47]2[N:48]=[C:49]([NH2:51])[S:50][C:46]=2[CH:45]=1>C(Cl)Cl>[Br:43][C:44]1[CH:53]=[CH:52][C:47]2[N:48]=[C:49]([NH:51][C:40]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)=[O:42])[S:50][C:46]=2[CH:45]=1
Reactant: O=C(O)C1CCCCC1
Reactant: Nc1nc2ccc(Br)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nc2ccc(Br)cc2s1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
A mixture of Hunig's base (286 μl, 1637 μmol), HATU (830 mg, 2182 μmol) and cyclohexanecarboxylic acid (147 mg, 1146 μmol) was dissolved in 2.0 mL CH2Cl2 and stirred at room temperature for 10 min. 6-bromobenzo[d]thiazol-2-amine (250 mg, 1091 μmol) was added, and stirring was continued overnight. The solids were filtered and washed with CH2Cl2. The filtrate was concentrated, dissolved in CH2Cl2 and purified by silica gel chromatography using 100% CH2Cl2 to provide N-(6-bromobenzo[d]thiazol-2-yl)cyclohexanecarboxamide (290 mg, 78% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C14H15BrN2OS: 339.3/341.3. found 339.0/341.0.
Reaction SMILES: [N+:1](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-:2].[CH3:9][CH:10]([OH:13])[C:11]#[CH:12].[C:14]1(C)C=CC=CC=1>>[OH:13][CH:10]([CH3:9])[CH2:11][C:12]1[NH:2][N:1]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:14]=1
Reactant: Cc1ccccc1
Reactant: C#CC(C)O
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)c1cc(CC(C)O)[nH]n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Into a flask containing ethyl diazoacetate (52.63 mmol, 6 g) in toluene (100 ml), 3-butyn-2-ol (78.94 mmol, 6.6 g) was added at RT and stirred at 100° C. for 5 h. The solvent was evaporated and the crude was purified by flash-chromatography. Yield 697 mg. 1H-NMR (400 MHz; CDCl3): δ 1.22-1.28 (m, 3H), 1.39 (t, 3H), 2.72-2.78 (m, 1H), 2.82-2.91 (m, 1H), 4.10-4.17 (m, 1H), 4.38 (q, 2H), 6.64 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.Cl.[CH3:16][O:17]CN.CCN=C=NCCC[N:28]([CH3:30])C.Cl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.O>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([N:28]([O:17][CH3:16])[CH3:30])=[O:7]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1F
Reactant: COCN
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(OC(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
3-Fluoro-4-(1-methylethoxy)benzoic acid (100 mg, 0.505 mmol) was dissolved in dichloromethane (2.5 mL). The resultant mixture was added with methoxymethylamine hydrochloride (99 mg, 1.01 mmol), WSC-HCl (106 mg, 0.555 mmol), triethylamine (422 μL, 3.03 mmol), and HOBt-H2O (34 mg, 0.252 mmol) sequentially, and stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. 3-Fluoro-4-(1-methylethoxy)-N-methoxy-N-methylbenzamide (117 mg, yield 96%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[F:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([F:14])[CH3:12]
Reactant: CC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(F)(F)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Yield: 24 %

Procedure:
3-Bromo-7-(1,1-difluoroethyl)imidazo[1,2-α]pyrimidine (130 mg, 0.50 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 5′-[7-(1,1-difluoroethyl)imidazo[1,2-α]pyrimidin-3-yl]-2′-fluorobiphenyl-2-carbonitrile (45 mg, 24%) as a white powder: δH (400 MHz, CDCl3) 2.15 (3H, t, J 21), 7.34 (1H, d, J 7), 7.43 (1H, t, J 9), 7.53-7.74 (5H, m), 7.86 (1H, dd, J 8 and 1), 7.99 (1H, s), 8.95 (1H, d, J 7); m/z (ES+) 379 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19]Cl)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COc1c(Cl)cnc2[nH]c(-c3ccc(OCCCl)cc3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1c(Cl)cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc12
Temperature: 100 °C
Yield: 7.1 %

Procedure:
6-Chloro-2-[4-(2-chloroethoxy)phenyl]-7-methoxy-3H-imidazo[4,5-b]pyridine (0.27 g, 0.8 mmol), morpholine (0.22 ml, 2.52 mmol) and Hünig's base (1.42 ml, 8.15 mmol) were dissolved in NMP (20 ml) and the mixture was heated at 100° C. for 9 h. The NMP was partly removed by evaporation, after which water was added. The precipitated crude material was purified by column chromatography (dichloromethane/methanol 95:5), giving the title product (0.022 g, 7%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C@H:12]1[C@@H:17]([SH:18])[CH2:16][CH2:15][CH2:14][O:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:3]([O:10][CH2:11][C@H:12]1[C@@H:17]([S:18][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:16][CH2:15][CH2:14][O:13]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: S[C@H]1CCCO[C@H]1COCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCS[C@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
0.27 g of a 55% w/w suspension of sodium hydride in mineral oil was suspended in 2 ml of dimethylformamide. To the suspension was added dropwise a solution of 1.210 g of dl-cis-2-benzyloxymethyl-3-mercaptotetrahydropyran (prepared as described in Preparation 16) in 5 ml of dimethylformamide, whilst ice-cooling the mixture. The reaction mixture was stirred at 60° C. for 1 hour, after which it was cooled to room temperature. A solution of 1.86 g of hexadecyl bromide in 3 ml of dimethylformamide was then added, and the mixture was stirred at room temperature for 1 hour. It was then poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 40 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 3:97 to 10:90 by volume was collected to give 2.284 g of the title compound as a solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]=[C:7]([NH:20][C:21](=[O:30])[C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=O.[NH2:31][C:32]([NH2:34])=[S:33].FC1C=CC=C(F)C=1C(NC1SC(C2C=CC=C(C(F)(F)F)C=2)=C(C2N=C(C)SC=2)N=1)=O>>[NH2:34][C:32]1[S:33][CH:2]=[C:3]([C:5]2[N:6]=[C:7]([NH:20][C:21](=[O:30])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[S:8][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:31]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: Cc1nc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)cs1
Product: Nc1nc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)cs1

Procedure:
Compound 87 was prepared from Compound 85 and thiourea similarly as described for the preparation of Compound 86.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH:28]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:29]([C:39](=O)[CH:40]([CH3:42])[CH3:41])[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:23][CH:22]=1.CC(O)C>CCCCCCC.C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:1]([CH2:2][CH2:3][C@H:4]3[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]3)[C:39]([CH:40]([CH3:42])[CH3:41])=[C:29]([C:30]([NH:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[C:28]=2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:25][CH:26]=1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: CCCCCCC
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Temperature: 25 °C

Procedure:
A solution of (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl) -2,2-dimethyl-1,3-dioxane-4-acetate, (Example 2) 1.36 g (4.97 mmol), and (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide mixture of [R-(R*,R*)], [R-(R*,S*)], [S-(R*,R*)], and [S-R*,S*)] isomers, (Example 3) 1.60 g (3.83 mmol), in 50 mL of heptane:toluene (9:1) is heated at reflux for 24 hours. The solution is cooled slightly and 15 mL of 2-propanol added. The mixture is allowed to cool to 25° C. and filtered to give 1.86 g of (4R-cis)-1,1-dimethylethyl 6-[2[2-(4-fluorophenyl)-5-(1-methyl-ethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate as a yellow solid.
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:45])[NH:40][C:39](=[O:46])[C:38]2=[CH:47]OC.[NH2:50][CH2:51][C:52]1[CH:53]=[C:54]([OH:59])[CH:55]=[CH:56][C:57]=1[I:58]>>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:45])[NH:40][C:39](=[O:46])[C:38]2=[CH:47][NH:50][CH2:51][C:52]1[CH:53]=[C:54]([OH:59])[CH:55]=[CH:56][C:57]=1[I:58]
Reactant: NCc1cc(O)ccc1I
Reactant: COC=C1C(=O)NC(=O)c2ccc(-c3ccco3)cc21
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: O=C1NC(=O)c2ccc(-c3ccco3)cc2C1=CNCc1cc(O)ccc1I
Yield: 77 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-Furan-2-yl-4-methoxymethylene-4H-isoquinoline-1,3-dione (400 mg, 1.5 mmol) and 3-Aminomethyl-4-iodo-phenol (400 mg, 1.61 mmol) in 77% yield: MS (ESI): 485.1 (M−1)−1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Si:13]([O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Cl:1])=[N:3][CH:4]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cnc(Cl)c2ccccc12
Product: CC(C)(C)[Si](C)(C)Oc1cnc(Cl)c2ccccc12

Procedure:
1-Chloroisoquinolin-4-ol was treated with tert-butyldimethylsilyl chloride to produce 4-{[tert-butyl(dimethyl)silyl]oxy}-1-chloroisoquinoline. Halogen exchange gave 4-{[tert-butyl(dimethyl)silyl]oxy}-1-iodoisoquinoline, which was treated with copper iodide and methyl difluoro(fluorosulfonyl)acetate to produce 1-(trifluoromethyl)isoquinolin-4-ol.
Reaction SMILES: [CH2:1]([N:19]=[C:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:22]([CH2:47][CH2:48][OH:49])([C:25]([C:28]([C:31]([C:34]([C:37]([C:40]([C:43]([F:46])([F:45])[F:44])([F:42])[F:41])([F:39])[F:38])([F:36])[F:35])([F:33])[F:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23]>>[CH2:1]([NH:19][C:20]([O:49][CH2:48][CH2:47][C:22]([C:25]([C:28]([C:31]([C:34]([C:37]([C:40]([C:43]([F:44])([F:45])[F:46])([F:41])[F:42])([F:38])[F:39])([F:35])[F:36])([F:33])[F:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Octadecyl isocyanate (29.5 g, 0.1 moles) and C8F17CH2CH2OH (46.4 g, 0.1 moles) were mixed under nitrogen and heated with stirring to 90° C. for 8 hours. An infrared spectrum showed no --NCO absorption, indicating completion of the reaction. The product is a white wax melting at 72°-75° C. NMR showed proton resonances at 4.7 ppm (1 proton NH), 4.4 ppm (2 proton CH2OCO--), 3.2 ppm (2 protons CH2CH2NH), 2.5 ppm (2 protons C8F17CH2), 1.3 pm (32 protons CH3 (CH2)16) and 0.8 ppm (3 protons CH3 (CH2)16).