Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].I[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Reactant: CCCCCCCI
Product: CCCCCCCNc1c(F)c(C)c(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Yield: 45.6 %

Procedure:
Substantially the same manner as that in Example 107 (2) was repeated except that 650 mg (1.61 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one obtained in Example 107 (1) and 0.53 mL (3.22 mol) of 1-iodoheptane were used, to give 369 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(1-heptylamino)-7-methyl-4H-1-benzopyran-4-one (yield: 46%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][N:3]=1.[NH2:19][NH2:20]>C1COCC1>[NH:19]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][N:3]=1)[NH2:20]
Reactant: NN
Reactant: CCOC(=O)c1cnc(Cl)nc1-c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1-c1ccccc1
Yield: 91 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of ethyl 2-chloro-4-phenylpyrimidine-5-carboxylate (0.09 g, 0.34 mmol) and hydrazine (0.06 g, 1.7 mmol) in THF resulting in a 91% yield (0.08 g); m.p. 74°-75° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:23][CH2:24][C@@H:25]([C@H:27]2[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]2)[OH:26])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.B(O)O.C(=O)(O)[O-].[Na+].[CH2:42](O)[CH3:43]>C1(C)C=CC=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([C:5]5[N:6]([CH3:8])[N:7]=[CH:43][CH:42]=5)[CH:3]=[C:4]([NH:23][CH2:24][C@@H:25]([C@H:27]5[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]5)[OH:26])[C:5]4=[N:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:20][CH2:19]1
Reactant: CCO
Reactant: CC1(C)OC[C@H]([C@@H](O)CNc2cc(Cl)nn3c(-c4ccc(C(=O)NC5CC5)cc4)cnc23)O1
Agent: O=C([O-])O
Agent: OBO
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1nccc1-c1cc(NC[C@H](O)[C@H]2COC(C)(C)O2)c2ncc(-c3ccc(C(=O)NC4CC4)cc3)n2n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a mixture of 52 mg (94 mot) 4-[6-chloro-8-({(2S)-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl}amino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropylbenzamide which was prepared according to intermediate example 192a, 33 mg 1-methyl-1H-pyrazol-5-yl) boronic acid, 6.5 mg tetrakis(triphenylphosphin)palladium in 1 mL of ethanol and 1 mL of toluene was added 0.26 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then the mixture was filtered, the solvent was removed and the residue was purified by chromatography to give 36 mg of the title compounds.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.C1COCC1.[Cl:28][CH2:29][C:30]([C:32]1[CH:33]=[C:34]2[C:38](=[C:39]([Cl:41])[CH:40]=1)[NH:37][C:36](=[O:42])[CH2:35]2)=[O:31]>C1COCC1>[Cl:41][C:39]1[C:38]2[C:34](=[CH:35][C:36](=[O:42])[N:37]=2)[CH:33]=[C:32]([C@H:30]([OH:31])[CH2:29][Cl:28])[CH:40]=1
Reactant: O=C1Cc2cc(C(=O)CCl)cc(Cl)c2N1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: O=C1C=c2cc([C@H](O)CCl)cc(Cl)c2=N1
Reaction time: 1 h

Procedure:
To a solution of (S)-Methyl-CBS-oxazaborolidine (1M in toluene, 0.745 mL, 0.745 mmol) and BH3-THF (8 mL, 8 mmol) is added at the same time a solution of BH3-THF (19 mL, 19 mmol) and a solution of the 5-Chloroacetyl-7-chlorooxindole (37.98 mmol) in 19 mL of THF. Both solutions are added dropwise over 30 minutes. The solution is stirred for 1 hour and quenched with the slow addition of methanol (50 mL). The solution is concentrated and the residue chromatographed over a short silica gel column (1:1 hexane/ethyl acetate).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[F:30])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH3:42])=[C:34]1[C:43](O)=[O:44].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH3:42])=[C:34]1[C:43]([NH:1][C@H:2]([C:6]([NH:8][CH:9]([CH:18]([OH:31])[CH2:19][O:20][C:21]1[C:22]([F:30])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27])[CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:44]
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Reactant: Cc1c(C(=O)O)n(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc2c(F)c(F)cc(F)c2F)C(C)C)n(C)c2ccccc12
Yield: 71.6 %

Procedure:
The procedure of Example 77 was followed using N-(valinyl)-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (213.9 mg, 0.47 mmol), 1,3-dimethylindole-2-carboxylic acid (107 mg, 0.57 mmol), NMM (0.3 ml, 2.8 mmol), HOBt (151 mg, 0.99 mmol), and EDAC (198 mg, 1.04 mmol) in methylene chloride to prepare the titled product (210 mg, 71%).
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:18]([O:20][C:21](=[O:22])[C:13]=12)=[O:19]>C1COCC1>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:18]([C:14]2[C:13]([C:21]([OH:20])=[O:22])=[N:12][CH:17]=[CH:16][CH:15]=2)=[O:19])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)cc1
Reactant: O=C1OC(=O)c2ncccc21
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cccnc2C(=O)O)cc1
Reaction time: 1 h

Procedure:
Iodine (catalytic amount) was added to a THF (30 ml) suspension of magnesium (2.4 g) in a nitrogen atmosphere at room temperature with stirring, and then a THF (20 ml) solution of 4-bromotoluene (17.1 g) was dropwise added thereto and stirred for 1 hour. The resulting mixture was added to a THF (50 ml) solution of 2,3-pyridinedicarboxylic acid anhydride (12.7 g) at 0°-5° C. with stirring, and this was stirred for additional 30 minutes as it was and then for 1 hour at room temperature. The solvent was removed from the reaction mixture by distillation, and water (30 ml) was added to the residue, which was then adjusted the pH to 1.0 with hydrochloric acid. The mixture was extracted with dichloromethane, washed with water and dried. Then, the solvent was removed by distillation. Dichloromethane (about 10 ml) was added to the residue, and then isopropyl ether (about 70 ml) was added thereto. This was stirred for 16 hours at room temperature, and 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid was obtained as colorless crystals (5.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[N:19]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[O:21])[C:17](=[O:29])[N:16]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)[C:15]=3[CH3:40])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[I:41][CH3:42]>>[I-:41].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[N:19]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][N+:26]([CH3:42])([CH3:27])[CH3:28])=[O:21])[C:17](=[O:29])[N:16]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=4)[C:15]=3[CH3:40])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CI
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)nc(C(=O)NCCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)nc(C(=O)NCCC[N+](C)(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Product: [I-]
Yield: 24 %

Procedure:
6-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-N-[3-(dimethylamino)propyl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide was reacted with iodomethane using an analogous method to that described in Step 2 of Example 4 to afford the title compound (26 mg, 24%) as a white solid; 1H NMR (500 MHz, DMSO) δ 1.91-1.83 (2H, m), 1.93 (3H, s), 3.01 (9H, s), 3.30-3.23 (4H, m), 6.77 (1H, d), 7.69 (2H, d), 7.78 (1H, d), 7.92-7.87 (3H, m), 7.99-7.93 (3H, m), 8.93 (1H, t); APCI-MSm/z: 564 [M+]
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[NH2:23][C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.CN1CCC(N)CC1>C(O)(=O)C>[CH3:24][N:23]1[CH2:3][CH2:2][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CN1CCC(N)CC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CN1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 33.8 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 1-methylpiperidin-4-amine (0.124 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 47.3 mg (0.15 mmol, 33.8% yield) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.OS(O)(=O)=O.O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=[O:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A solution of 17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"methoxycyclohexyl)-1'-methylvinyl]-14-t-butyl-dimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (Example 4) (30 gm, 0.0331 mol) in acetone (200 ml) was cooled to 0° C. To the solution was added 16.5 mL of Jones reagent (prepared by dissolving 26.72 g CrO3 in 23 mL of concentrated H2SO4, then diluting the solution to 100 mL with H2O) (The reaction was monitored by TLC 20% acetone/hexanes). After 60 minutes, the reaction was complete and excess oxidant was destroyed by slow addition of 10 mL of 2-propanol. After 10 min., the mixture had become bright green, and the reaction mixture was diluted with 800 mL of water and 1 L of ether. The layers were separated and the aqueous layer was washed with four equal portions of ether. Each ether layer was sequentially washed with two equal portions of water, then twice with 1 M KHCO3 solution, then with brine (Virtually all of the green color was removed following the KHCO3 washes). MS: 796 (M+7). The ether layers were combined, dried over MgSO4, and concentrated to a pale yellow gum that was lyophilized from benzene to afford 26.8 g (89%) of the title compound as a white solid. MS 796 (M+7).
Reaction SMILES: [OH:1][CH:2]([CH2:19]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[CH:13][N:12]([CH3:17])[C:11]1=[O:18].[BrH:21].[C:22]([OH:25])(=O)[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:22]([O:1][CH:2]([CH2:19][Br:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH:14]=[CH:13][N:12]([CH3:17])[C:11]1=[O:18])(=[O:25])[CH3:23]
Reactant: CC(=O)O
Reactant: Br
Reactant: Cn1ccc(=O)n(CCCCCCCC(O)CO)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(CBr)CCCCCCCn1c(=O)ccn(C)c1=O
Yield: 97 %

Procedure:
A mixture of 3-(8,9-dihydroxynonyl)-1-methyluracil (2.15 g, 7.6 mmol) and a 30% solution of hydrogen bromide in acetic acid (4.5 mL, 23 mmol) were stirred for 6 hours. The reaction mixture was added slowly to a mixture of sodium bicarbonate (8.4 g, 0.1 mol), water (30 mL), and dichloromethane (30 mL). The layers were separated, and the aqueous layer extracted with dichloromethane (3×40 mL). The combined organic layers were washed with aqueous saturated salt solution (20 mL) and dried over sodium sulfate. The solvent was removed under vacuum to yield 2.89 g (97% yield) 3-(8-acetoxy-9-bromononyl)-1-methyluracil (inventive compound no. 1801) as a thick, slightly orange oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([O:11][C:12](=[O:14])[CH3:13])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[CH2:19][CH2:20][CH3:21]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[C:7]([O:11][C:12](=[O:14])[CH3:13])([C:8](=[O:9])[CH3:10])[CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(OC(C)=O)(C(C)=O)C(=O)OC(C)(C)C
Yield: 75.4 %

Procedure:
According to the general alkylation method, tert-butyl-2-acetoxy-aceto-acetate (219a) (1.08 g, 5.00 mmol), NaH (156 mg, 6.5 mmol) and butylbromide (538 μL, 685 mg, 5.00 mmol) were reacted in DMF (10 mL) to give 2-acetoxy-2-acetyl-hexanoic-acid-tert-butylester (250i) (1026 mg, 3.77 mmol, 75%) as a slightly yellow oil. Then, 250i (731 mg, 2.68 mmol) and 51 mg (0.27 mmol) p-TsOH.H2O were stirred in 9.0 mL benzene according to decarboxylation method A. Kugelrohr distillation at 1.0 mbar and 60° C. gave 251i (415 mg, 2.41 mmol, 90%) as a colorless oil.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C-]#N.CO[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1.Cl>CO.C1(C)C=CC=CC=1>[OH:19][C:12]1[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:14][C:9]([CH2:8][C:1]#[N:2])=[CH:10][C:11]=1[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: COCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)c1cc(CC#N)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Sodium cyanide (2.94 g; 50 mmol) was slurried in methanol (20 mLs) in a 100 mL round bottom flask and the slurry was heated to a gentle reflux. To the cyanide slurry, a solution of 4-methoxymethyl-2,6-di-t-butyl phenol (12.5 g; 50 mmol), toluene (20 mLs) and methanol (25 mLs) was added dropwise over a period of time of 55 minutes. The resultant black reaction mixture was refluxed an additional 35 minutes after complete addition of the 4-methoxymethyl-2,6-di-t-butyl phenol. Upon cooling to ambient temperature, 2N hydrochloric acid (40 mLs) was added to the reaction flask. A yellow slurry which resulted was extracted with diethyl ether. The ether extract was dried (MgSO4) and concentrated in vacuo to afford 11.74 grams of 4-hydroxy-3,5-di-t-butylphenylacetonitrile as identified by NMR. Analysis by VPC indicated a 95% yield of 4-hydroxy-2,6-di-t-butylphenylacetonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)CO.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C(O)(C)C>[Cl:1][C:2]1[C:7]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccc1
Reactant: Nc1ccnc(Cl)c1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Nc1ccnc(Cl)c1Sc1ccccc1
Reaction time: 24 h
Yield: 91 %

Procedure:
To a 250 mL round flask was added 2-chloro-3-iodo-4-aminopyridine (5.0 g, 19.6 mmol), thiophenol (2.16 g, 19.6 mmol), CuI (0.187 g, 0.98 mmol), ethylene glycol (2.5 g, 39 mmol), potassium carbonate (5.4 g, 39 mmol), and 150 mL of isopropanol. The reaction was heated to reflux and stirred under a nitrogen atmosphere for 24 h. After cooling, the mixture was purified by a silica gel column. Yield (91%) of 2-chloro-3-phenylthio-4-aminopyridine was 4.2 g.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CN1CCCC1=O.[CH2:17]([C@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1)[CH3:18].[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[N:40]=[C:39]3[C:35]([N:36]=[C:37](Cl)[N:38]3[CH2:41][C:42]([F:45])([F:44])[F:43])=[C:34]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[N:33]=2)=[CH:28][N:27]=1>O>[CH2:17]([C@@H:19]1[NH:20][CH2:21][CH2:22][N:23]([C:37]2[N:38]([CH2:41][C:42]([F:43])([F:45])[F:44])[C:39]3[C:35]([N:36]=2)=[C:34]([N:47]2[CH2:48][CH2:49][O:50][CH2:51][CH2:52]2)[N:33]=[C:32]([C:29]2[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=2)[N:40]=3)[CH2:24]1)[CH3:18]
Reactant: CC[C@H]1CNCCN1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Temperature: 100 °C
Reaction time: 96 h
Yield: 81.9 %

Procedure:
Diisopropylethylamine (1.48 ml, 8.49 mmol) was added to an N-methyl-2-pyrrolidone suspension (4 ml) of 2-(S)-ethylpiperazine 2 hydrochloride (529 mg, 2.83 mmol) and 2-(2-aminopyrimidin-5-yl)-8-chloro-6-(morpholin-4-yl)-9-(2,2,2-trifluoroethyl)-9H-purine (391 mg, 0.94 mmol) and the resulting mixture was stirred at 100° C. for 4 days. Water was added to the reaction mixture and the resulting mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform:methanol=97:3 to 90:10) to give the title compound (379 mg) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cu][C:15]#[N:16].CN1CCCC1=O>O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:15]#[N:16])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(C#N)cc(C)c1N
Temperature: 120 °C

Procedure:
Methyl 2-amino-5-bromo-3-methylbenzoate (100 g, 0.393 mol, 96% of quantitative NMR), copper(I) cyanide (36.3 g, 0.401 mol) and N-methyl-2-pyrrolidinone (NMP) (206 g, 200 mL, 2.084 mol) are heated to 170° C. for 4 hours under agitation. The reaction batch is cooled down to 120° C., 350 mL of H2O (90° C.) are added dropwise in the course of 30 minutes and the suspension obtained is filtered. The solid obtained is washed twice with ammonia (200 g, 12% in H2O) and 2 times with 100 ml of water. Following drying in a vacuum drying cabinet at 50° C., methyl 2-amino-5-cyano-3-methylbenzoate is obtained as a grey solid. Yield: 69.0 g, 88.2% of theory, purity: 95.6% quantitative NMR, 1500 ppm Cu).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].Cl[S:33]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])(=[O:35])=[O:34]>O1CCCC1.CN(C)C=O.O>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH:4]2[N:3]([S:33]([CH2:36][CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])(=[O:35])=[O:34])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[CH:29][CH:28]=1)#[N:27]
Reactant: COC(=O)CCCS(=O)(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 70 mg, 0.18 mmol) in a mixture of tetrahydrofuran (1.5 mL) and N,N-dimethylformamide (150 μL) is treated with sodium hydride (60% in mineral oil, 28 mg, 0.7 mmol) and stirred at room temperature for 5 min Methyl 4-(chlorosulfonyl)butanoate (106 mg, 0.53 mmol) is added, and the mixture is stirred at 50° C. over night. The mixture is diluted with water and N,N-dimethylformamide and purified by reversed phase HPLC (Wate7rs SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 48 mg; ESI mass spectrum [M+H]+=562; Retention time HPLC: 0.95 min (Z018_S04).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH2:17])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].Cl[S:19]([C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][N:28]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:29]2)=[CH:24][CH:23]=1)(=[O:21])=[O:20].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([NH:17][S:19]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:32](=[O:37])[C:33]([F:36])([F:34])[F:35])[CH2:29]3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reactant: COC(=O)C1(N)CCN(c2ccncc2)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C1(NS(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)CCN(c2ccncc2)CC1

Procedure:
To a solution of 4-amino-1-(pyridin-4-yl)piperidine-4-carboxylic acid methyl ester (330 mg) in chloroform (5 ml) were added 7-chlorosulfonyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (Journal of Medicinal Chemistry, vol. 23, No.8, p. 837 (1980)) (500 mg) and pyridine (0.23 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, water was added, and the mixture was extracted with chloroform and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (627 mg).