Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CCOC(C)=O>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccnc1NC1CCN(Cc2ccccc2)CC1
Yield: 36.6 %

Procedure:
To a solution of 1.64 g 2-chloro-3-nitropyridine and 1.37 g of 1-benzyl-piperidin-4-ylamine in 20 mL THF was added diisopropylethylamine. The reaction was refluxed for 6 hours. The reaction was cooled down, diluted with 50 mL of EtOAc and washed with 30 mL of saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×30 mL of EtOAc. The combined organic phases were washed with 15 mL of brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 25% EtOAc in hexane, then 50% EtOAc in hexane and 100% EtOAc to give 823 mg of the title compound as a yellow solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][C:24]1[C:28]([C:29]([OH:31])=O)=[C:27]([CH2:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:26][N:25]=1.C(N(C(C)C)C(C)C)C.[C:50]1([C:56]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C.C(Cl)(Cl)Cl>[OH:62][C:56]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:61][CH2:60][N:59]([C:29]([C:28]2[C:24]([CH3:23])=[N:25][O:26][C:27]=2[CH2:32][C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:40])=[O:31])[CH2:58][CH2:57]1
Reactant: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(CC(=O)c2ccccc2)c1C(=O)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of TBTU (0.48 g, 1.5 mmol, 1.5 eq.) in DMF (2 mL) was added to a mixture of 3-methyl-5-(2-oxo-2-phenylethyl)isoxazole-4-carboxylic acid (0.24 g, 1 mmol, 1 eq), N-ethyl-N-isopropylpropan-2-amine (0.18 mL, 1 eq) and 4-phenylpiperidin-4-ol (0.18 g, 1 eq) in DMF (1 mL). The resulting solution was stirred at room temperature. Chloroform (25 mL) was added and the solution was washed with water and 1 M HCl, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2 1:2 heptane/EtOAc) to afford the title compound. MS (ESI, POS. ION) M/Z Calcd for C24H24N2O4: 404.1736, found 404.1732.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])=[N:9][C:8]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[N:7][C:6]=2[C@@H:5]1[CH3:33])(=[O:3])[CH3:2].C(NC(NC1C=CC(C2N=C(N3CCOC[C@@H]3C)C3CCNC(C)C=3N=2)=CC=1)=O)C.CN(C)C=O.C(N(CC)C(C)C)(C)C.C(Cl)(=O)C>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])=[N:9][C:8]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[N:7][C:6]=2[C@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)[C@H]3C)cc1
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3C)cc1
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)[C@@H]3C)cc1
Reaction time: 2 h

Procedure:
and 1-(4-((S)-7-acetyl-8-methyl-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (wr2): 1-Ethyl-3-(4-(8-methyl-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.172 g, 0.419 mmol) in dry N,N-Dimethylformamide (2.00 mL, 25.8 mmol) was added N,N-Diisopropylethylamine (0.219 mL, 1.26 mmol) followed by Acetyl chloride (0.0448 mL, 0.630 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was purified by HPLC and the diastereomers were separated by SFC. R-Diastereomer (wr1): 1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.18 (d, J=8.6, 2H), 7.48 (d, J=8.6, 2H), 6.21 (s, 1H), 3.99 (s, 1H), 3.88 (d, J=12.3, 2H), 3.71 (d, J=10.8, 1H), 3.58 (dd, J=23.8, 11.1, 2H), 3.13 (dd, J=13.5, 6.4, 2H), 3.06-2.91 (m, 3H), 2.71 (t, J=14.7, 1H), 2.38 (d, J=39.3, 1H), 2.12 (d, J=6.4, 3H), 1.58 (d, J=6.8, 1H), 1.47-1.42 (m, 3H), 1.13 (t, J=7.2, 3H), 1.06 (t, J=7.1, 3H). LC/MS-m/z+453.2 (M+H)+; and
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:22]=[C:21]([O:23][C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[Br:15][C:16]1[CH:22]=[C:21]([O:23][C:24]([F:26])([F:27])[F:25])[CH:20]=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1Br

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-bromo-4-trifluoromethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]2[N:6]3[CH2:11][CH2:10][CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[K+].[Br-]>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]2[N:6]3[CH2:11][CH2:10][CH2:9][C:7]3=[N:8][C:4]=2[C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cc2c(cc1Br)nc1n2CCC1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc2c(nc3n2CCC3)c([N+](=O)[O-])c1Br

Procedure:
A solution of 245 mg (0.97 mmol) of 23 in a 5 mL mixture of fuming nitric acid and concentrated sulphuric acid (4:1) was stirred in an ice bath for 10 min. The completed reaction was poured over cracked ice and the pH of resulting solution adjusted to 6.5 with aqueous sodium bicarbonate. Extraction of this solution with 3×50 mL portions of chloroform, drying the extracts (sodium sulfate), and then concentration afforded a yellow solid, 165 mg (57%). Recrystallization from chloroform/hexane afforded analytically pure material: mp 201°-203° C.; TLC (chloroform/methanol, [95:5]) Rf =0.61; IR(KBr pellet) 1537, 1517, 1449, 1413, 1383, 1374, 1342, 1297, 884, 860 cm-1 ; 1H NMR (dimethyl sulfoxide-d6) δ7.77 (1 H, s, aromatic proton), 4.15 (2 H, t, J~Hz, C(1) methylene), 2.99 (2 H, t, J~7 Hz, C(3) methylene), 2.67 (2 H, quintet, J~7 Hz, C(2) methylene); 2.52 (3 H, s, 7-methyl); mass spectrum (EI mode) m/z 295 and 297 (P+, 79Br and 81Br), 249 and 251 (P+ -NO2) Anal. Calcd for C11H10BrN3O2 : C, 44.60; H, 3.40; N, 14.18. Found: C, 44.83; H, 3.31; N, 14.07.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=23)=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: CC(C)Oc1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(isopropyloxy)phenyl]-1-propanol (0.46 g, 1.5 mmol) and 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.34 g, 1.8 mmol) in acetonitrile (20 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol), and the mixture was stirred at room temperature for 5 hrs. To the reaction solution was added water (100 ml), and the mixture was extracted with- ethyl acetate (100 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the objective substance (0.55 g, 77%) as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16][CH3:17])=[C:11]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[C:11]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(OCc2ccccc2)cc1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)c1ccc(OCc2ccccc2)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 7 %

Procedure:
1-{4-(Benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml) to prepare a solution. A sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The reaction solution was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (15 mg, yield 7%).
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[CH3:9][N:10]([CH2:12][C:13]1[S:17][C:16]([CH2:18][S:19][CH2:20][CH2:21][NH2:22])=[CH:15][CH:14]=1)[CH3:11]>C(O)C>[N+:5]([NH:4][C:3]([NH:22][CH2:21][CH2:20][S:19][CH2:18][C:16]1[S:17][C:13]([CH2:12][N:10]([CH3:9])[CH3:11])=[CH:14][CH:15]=1)=[NH:8])([O-:7])=[O:6]
Reactant: CN(C)Cc1ccc(CSCCN)s1
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNC(=N)N[N+](=O)[O-])s1
Yield: 52.2 %

Procedure:
A suspension of N-nitrocarbamimidothioic acid methyl ester (1.05 g) and 2-[[[5-(N,N-dimethylaminomethyl)2-thienyl]methyl]thio]ethanamine (1.6 g) in ethanol (10 ml) was heated at 45° for 10 min. The resultant solid was recrystallised from ethyl acetate to give the title compound as white crystals (1.15 g) m.p. 118°-118.5°. TLC silica/methanol, Rf 0.40.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:26][C:27]([F:35])([F:34])[C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>>[F:32][C:28]([F:33])([C:27]([F:35])([F:34])[F:26])[C:29]([O:31][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:30]
Reactant: ON=C1CCCCC1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: O=NC1(OC(=O)C(F)(F)C(F)(F)F)CCCCC1

Procedure:
1-Nitrosocyclohexyl 2,2,3,3,3-pentafluoropropanoate was prepared from cyclohexanone oxime, lead tetraacetate and pentafluoropropionic acid using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 2.35-2.31 (2H, m), 1.77-2.00 (4H, m), 1.49-1.72 (4H, m).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+:18]>CO.O>[NH2:2][C@H:3]([CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:4]([O-:6])=[O:5].[Na+:18]
Reactant: CCOC(=O)[C@H](N)CCC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N[C@H](CCC1CCCCC1)C(=O)[O-]
Reaction time: 1 h

Procedure:
Ethyl (2R)-2-amino-4-cyclohexylbutanoate hydrochloride (4.00 g, 18.75 mmol) was dissolved in MeOH/Water (10/5 ml). Sodium hydroxide (1.50 g, 37.50 mmol) was added. The reaction mixture was stirred for 1 h and concentrated to give the title compound as a colourless solid (containing 100 mol % of sodium chloride). 1H NMR [(CD3)2SO), 400 MHz] δ0.83-0.97 (m, 2H), 1.10-1.33 (m, 6H), 1.48-1.78 (m, 7H), 3.15 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:11])[CH2:9][CH3:10])=[N:6][CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)#[N:13].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:11][CH:8]([C:5]1[N:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]#[N:13])=[CH:3][CH:4]=1)[CH2:9][CH3:10]
Reactant: CCC(O)c1ccc(Br)cn1
Reactant: N#Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(O)c1ccc(-c2ccccc2C#N)cn1
Temperature: 100 °C
Yield: 19.4 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)propan-1-ol (0.7 g, 3.2 mmol) in toluene (15 mL) and ethanol (8 mL) was added 2-cyano phenyl boronic acid (0.57 g, 3.8 mmol) and a 2M solution of aq. Na2CO3. The reaction mixture was degassed with argon, Pd(PPh3)4 (0.187 g, 0.162 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and the reaction heated to 100° C. for 3 h. The reaction mixture was evaporated under vacuum to remove ethanol, diluted with water (40 mL), extracted with ethyl acetate (200 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by a Biotage Isolera® One column (using 20% ethyl acetate and hexane) to give 2-(6-(1-hydroxypropyl)pyridin-3-yl)benzonitrile. (0.150 g, 19.4% yield). 1H NMR (400 MHz DMSO-d6): δ 8.67 (s, 1H), 8.02-7.97 (m, 2H), 7.82 (t, 1H), 7.69 (d, 1H), 7.63-7.60 (m, 2H), 1.83-1.68 (m, 2H), 0.89 (t, 3H): LC-MS m/z calcd for [M+H]+ 239.11. found 239.0.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].C(OCC)(=O)C>C1COCC1.O>[Cl:24][C:23]([Cl:26])([Cl:25])[CH2:22][O:21][C:19](=[O:20])[NH:11][C:7]1[N:8]([CH3:10])[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: Cn1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of 5-tert-butyl-2-methyl-2H-pyrazol-3-ylamine (0.50 g, 3.26 mmol) and pyridine (0.27 mL, 3.29 mmol) in THF (THF, 10 mL) is added 2,2,2-trichloroethyl chloroformate (0.44 mL, 3.29 mmol). The reaction mixture is stirred at 0° C. for 30 min and then warmed to room temperature for 2 hours. Then the reaction mixture is distributed between ethyl acetate (100 mL) and water (100 mL). The aqueous phase is extracted with ethyl acetate (50 mL). The combined organic phases are washed with saturated NaCl (2×50 mL) and dried over anhydrous magnesium sulfate. After removal of solvent, the residue is purified on a silica gel chromatography by washing with ethyl acetate to provide a white solid (0.83 g, 78%, ES+(m/z) 329.9 [M+H]).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[CH2:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][CH2:13][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:15])=[CH:7]2
Reactant: C=Cc1nc([C@H](C)Nc2ncnc3c2ncn3Cc2ccc(OC)cc2)cc2cccc(Cl)c12
Reactant: C1COCCN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(CCN5CCOCC5)n4)ncnc32)cc1
Temperature: 25 °C

Procedure:
Compound 2 was then converted to compound 4 in two steps: To a stirred mixture of (S)—N-(1-(8-chloro-1-vinylisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 2 (200 mg, 0.42 mmol, 1 eq) in EtOH (50 mL) at RT, morpholine (183 mg, 2.1 mmol, 5 eq) and triethylamine (213 mg, 2.1 mmol, 5 eq) were added sequentially. The resulting mixture was stirred at reflux for 4 h. The mixture was allowed to cool to RT and then concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 3. The PMB group was then subsequently deprotected using Method L to provide compound 4. ESI-MS m/z: 438.8 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.[C-:12]#[N:13].[K+]>CN(C=O)C.O.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:12]#[N:13])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: [C-]#N
Reactant: CCc1cc(Br)ccc1CBr
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(Br)ccc1CC#N
Temperature: 45 °C
Yield: 81.9 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-ethyl-benzene (2.0 g, 7.25 mmol) in DMF/H2O (30 mL/6 mL) was added potassium cyanide (471 mg, 7.25 mmol). The reaction mixture was heated to 45° C. for 3 hours before it was cooled to room temperature. The mixture was diluted with Et2O and washed with H2O, brine and dried over MgSO4. The solvent was removed in vacuo to obtain the desired product (1.33 g, 80% yield). 1H NMR (300 MHz, CDCl3): δ 1.26 (t, J=7.5 Hz, 3H), 2.60-2.67 (m, 2H), 3.66 (s, 2H), 7.23-7.26 (m, 1H), 7.35-7.36 (m, 1H), 7.38-7.40 (m, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1>Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Product: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of 4.6 g (14.1 mmol) of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate in 100 ml of 6M hydrochloric acid was refluxed for four hours. The solution was cooled to room temperature and the solids were filtered, washed with water, and dried to give 3.9 g of the title compound, mp 234°-235° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.[CH2:12]([C:14]1[S:15][C:16]([CH2:19][CH3:20])=[N:17][N:18]=1)[CH3:13]>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:12]([C:14]1[S:15][C:16]([C:19]([CH3:20])=[CH:10][C:3]2[N:2]([CH3:1])[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=2)=[N:17][N:18]=1)[CH3:13]
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: CCc1nnc(CC)s1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCc1nnc(C(C)=Cc2ncc([N+](=O)[O-])n2C)s1
Yield: 34.6 %

Procedure:
4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde, which has been dissolved in 80 ml of acetic acid and 35 ml of acetic anhydride, is dripped into 17.1 g of 2,5-diethyl-1,3,4thiadiazole, which has been dissolved in a mixture of 60 ml of acetic acid, 25 ml of acetic anhydride and 0.5 g of zinc chloride, over a period of 5 hours at reflux temperature. After being heated for a further 24 hours at reflux temperature the reaction mixture is concentrated by removing the solvent and water is added. The precipitated reaction product is then subjected to sublimation and recrystallized from propanol. 2.9 g of product, corresponding to 35% of the theory, is obtained. The compound melts at 125° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=2)[N:22]([NH2:33])[CH:21]=1)[CH3:19].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=2)[N:22]([NH:33][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])[CH:21]=1)[CH3:19]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: CCc1cn(N)c2ccc(C(F)(F)F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2C)c2ccc(C(F)(F)F)cc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (232 mg, 1.0 mmol) and 3-ethyl-5-trifluoromethyl-indol-1-ylamine (228 mg, 1 mmol) in DMF (5 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (276 mg, 1 mmol) and stirred at 50° C. for 2 h. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 5 min. The precipitate is collected by filtration and dried in vacuo to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-ethyl-5-trifluoromethyl-indol-1-yl)-amide (240 mg, 54%). MS: 443 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.24 (s, 1H), 8.34 (d, 1H), 8.26 (d, 1H), 8.19 (s, 1H), 7.58 (m, 2H), 7.42 (m, 3H), 2.84 (q, 2H), 2.78 (s, 3H), 1.31 (t, 3H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].O[C@@H:10]1[CH2:15][O:14][C@@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]34[CH2:29][CH2:28][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:26][CH2:27]3)[CH2:24][CH2:23]4)=[CH:18][CH:17]=2)[CH2:12][O:11]1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:8][C@@H:10]1[CH2:15][O:14][C@@H:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]34[CH2:29][CH2:28][C:25]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:26][CH2:27]3)[CH2:24][CH2:23]4)=[CH:20][CH:21]=2)[CH2:12][O:11]1)(=[O:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCC/C=C/C(=O)O
Reactant: CCCCCC12CCC(c3ccc([C@H]4CO[C@H](O)CO4)cc3)(CC1)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)O[C@@H]1CO[C@@H](c2ccc(C34CCC(CCCCC)(CC3)CC4)cc2)CO1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N,N-dicyclohexylcarbodiimide (0.18 g, 0.8 mmol) in dichloromethane (10 cm3) is added to a solution of (E)-hex-2-enoic acid (0.07 g, 0.7 mmol), 1-[4-(trans-5-hydroxydioxan-2-yl) phenyl]-4-pentylbicyclo[2.2.2]octane (0.25 g, 0.7 mmol), 4-(dimethylamino) pyridine (0.04 g) in dichloromethane (20 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture is stirred overnight, filtered to remove precipitated material and the filtrate was evaporated down under reduced pressure. The crude product is purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C.)/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield the desired ester.