Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CC1C[N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[CH:39](O)([CH3:41])[CH3:40]>C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH:23]4[CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:21]([CH2:40][CH2:39][CH3:41])[N:22]4[OH:35])[CH2:9][CH2:8]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: CC(C)O
Reactant: c1ccc2c(c1)CCNC2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: CCCC1c2ccccc2CC(N2CCC(c3noc4cc(F)ccc34)CC2)N1O

Procedure:
A mixture of N-[3-(2,3-epoxy)propyl]-4-(6-fluoro-1,2-benzisoxaz-3-yl)piperidine (3.56 g, 12.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.06 g, 15.4 mmol) in isopropyl alcohol (150 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was removed. The residual oil was purified by flash chromatography over a silica gel column (SiO2, 45 g, eluted with 1% CH3OH: 99% methylene chloride). The product thus purified as a light oil, weighed 4.15 g. The oil was treated with a solution of fumaric acid (1.98 gm, 17 mmol) in ethanol. The white crystals so obtained were recrystallized in a large volume of hot ethanol (~150 ml). The recrystallized crystals weighed 2.75 g, m.p. 179°-181° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[Cl:11].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[Cl:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][S:19][C:17]1[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: COc1ccc(CBr)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(CSc2nc(C)cc(O)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A mixture of 1-(bromomethyl)-2-chloro-4-methoxybenzene (1.0 g, 4.2 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (550 mg, 3.9 mmol), and triethylamine (585 μL, 4.2 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The product was recovered by filtration, washed with water (2×20 mL) and diethyl ether (2×20 mL), and dried in vacuo, affording the title compound (929 mg, 81% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 3.76 (s, 3H), 4.41 (s, 2H), 6.00 (s (br), 1H), 6.89 (dd, 1H, J=2.5 Hz, 8.6 Hz), 7.07 (d, 1H, J=8.6 Hz), 7.52 (d, 1H, J=8.6 Hz); M+297.
Reaction SMILES: Br.[NH2:2][C@@H:3]([CH2:7][CH2:8][Br:9])[C:4]([OH:6])=[O:5].S(Cl)([Cl:12])=O.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:12].[CH2:14]([O:5][C:4](=[O:6])[C@@H:3]([NH2:2])[CH2:7][CH2:8][Br:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1
Reactant: N[C@@H](CCBr)C(=O)O
Agent: Br
Product: Cl
Product: N[C@@H](CCBr)C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-amino-4-bromo-butyric acid hydrobromide (2 g, 7.6 mmol) in benzyl alcohol (10 ml), at 0° C., was added thionyl chloride (1.11 ml, 15.21 mmol). The solution was stirred at 70° C. for 2 hour, cooled and concentrated in vacuo. Heptane was added and the mixture was concentrated. The oil was dissolved in toluene, ether added and initial precipitate filtered. The filtrate was allowed to stand overnight and the second precipitate filtered and dried in vacuo to provide (S)-2-amino-4-bromo-butyric acid benzyl ester hydrochloride as an off white solid (630 mg).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:14]1[CH2:16][CH:15]1[CH2:17]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[CH:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:17][CH:15]3[CH2:16][O:14]3)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1CCC(CN2CCNCC2)CC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Product: C1CCC(CN2CCN(CC3CO3)CC2)CC1
Yield: 92 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from 1-cyclohexylmethyl piperazine and (±)-3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after flash chromatography the title compound as a yellow oil in a 92% yield.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(O)(C)C.[CH2:17]([O:35][CH2:36][CH:37]1[O:39][CH2:38]1)[CH2:18][CH2:19][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].[ClH:40]>O>[ClH:40].[OH:39][CH:37]([CH2:36][O:35][CH2:17][CH2:18][CH2:19][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])[CH2:38][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCCOCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Yield: 39.5 %

Procedure:
L-arginine (17.4 g, 0.1 mols) was dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 32.6 g (0.1 mols) of octadecylglycidyl ether (made by Sakamoto Yakuhin Kogyo Co., Ltd.) were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that octadecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 21.2 g of N-(2-hydroxy-3-octadecyloxypropyl)-L-arginine hydrochloride (yield 42.3%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6](Cl)[C:5]=2[N:15]=1.[NH3:26]>CO>[NH2:18][CH2:17][CH2:16][N:3]1[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:26])[C:5]=2[N:15]=[C:2]1[NH2:1]
Reactant: N
Reactant: CC(C)(C)OC(=O)NCCn1c(N)nc2c(Cl)nc3ccccc3c21
Solvent: CO
Product: NCCn1c(N)nc2c(N)nc3ccccc3c21
Temperature: 150 °C

Procedure:
tert-Butyl 2-(2-amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)ethylcarbamate (3.5 g, 9.7 mmol) and ammonia (approximately 100 mL of a 7 N solution in methanol) were added to a pressure vessel, which was sealed and heated at 150° C. overnight. The volatiles were removed under reduced pressure, and the residue was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 1.5:28.5:70) to provide 840 mg of 1-(2-aminoethyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine as a dark grey solid.
Reaction SMILES: [CH3:1][C:2]1[N:23]([CH3:24])[C:5]2[CH:6]=[C:7]([C:20](O)=[O:21])[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1.[CH3:25][NH2:26].O>O1CCCC1.CN(C)C=O>[CH3:25][NH:26][C:20]([C:7]1[C:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:12][C:13]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:23]([CH3:24])[C:5]=2[CH:6]=1)=[O:21]
Reactant: CN
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)N3
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a suspension of 1.0 g (3.1 mmol) 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-h]quinoline-5-carboxylic acid in 10 ml tetrahydrofuran and 5 ml N,N-dimethylformamide were added 1.0 g (6.2 mmol) N,N′-carbonyldiimidazole. After 1 h at 60° C., the solution was cooled down and 15.6 ml (31.2 mmol) methylamine (2M in tetrahydrofuran) were added. The mixture was stirred 2 h at ambient temperature and then poured into 50 ml water. The precipitate was collected, washed with water and dried at 50° C. to yield 0.87 g (84%) of the title compound. m.p. 259° C.
Reaction SMILES: CN(C)[S:3]([C:6]1[C:7](Cl)=[N:8][CH:9]=CC=1)(=O)=O.[CH2:14]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH2:17][NH:16][CH2:15]1.[Na].C(O)(C(F)(F)F)=O>C1COCC1.O>[S:3]1[CH:6]=[CH:7][N:8]=[C:9]1[N:16]1[CH2:15][CH:14]=[C:19]([C:20]([OH:22])=[O:21])[CH2:18][CH2:17]1
Reactant: O=C(O)C1=CCNCC1
Reactant: CN(C)S(=O)(=O)c1cccnc1Cl
Agent: [Na]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)C1=CCN(c2nccs2)CC1

Procedure:
A solution of 2-chloro-pyridine-3-sulfonic acid dimethylamide (1.18 mmol) and isoguvacine, sodium salt (2.19 mmol) in THF (0.5 mL) and water (2 mL) was stirred at 90° C. for 22 hours, acidified (pH˜1) with TFA, and extracted with CH2Cl2. The organic layer was dried (Na2SO4), concentrated, and purified by flash chromatography (5% MeOH/CH2Cl2) and trituration (Et2O) to provide as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.47 (dd, J=1.7, 4.8 Hz, 1H), 8.22 (dd, J=1.7, 7.8 Hz, 1H), 7.22 (dd, J=4.8, 7.8 Hz, 1H), 7.03 (sept, J=1.7 Hz, 1H), 3.99 (q, J=3.0 Hz, 2H), 3.40 (t, J=5.6 Hz, 2H), 2.73 (s, 6H), 2.56 (m, 2 H).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:16]=2)[CH:12]=[N:11]1)[CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)#[N:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:5]1([CH:4]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:27])=[CH:29][CH:30]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:3][C:1]#[N:2])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CN1CCNCC1
Reactant: N#CCC(C1CCCC1)n1cc(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc(Nc3nccc(-c4cnn(C(CC#N)C5CCCC5)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)benzoic acid (30 mg, 0.07 mmol), 1-methyl-piperazine (8.3 μL, 0.074 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.4 mg, 0.089 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (31 μL, 0.18 mmol). The reaction was stirred at room temperature for 1 h, quenched with water, purified on HPLC to give the desired product as a racemic mixture (28 mg, 82%). LCMS (M+H) 485.5.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([Sn](C)(C)C)[S:17][C:10]=12>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[S:17][C:10]=12
Reactant: Brc1cncnc1
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Solvent: Cc1ccccc1
Product: Clc1ccnc2cc(-c3cncnc3)sc12
Temperature: 25 °C
Yield: 50.5 %

Procedure:
Tereakis(triphenylphosphine)palladium (17 mg) was added to a solution of 5-bromopyrimidine (0.057 g, 0.36 mmole) and 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.119 g, 0.36 mmole) in toluene (10 ml). The reaction mixture was stirred at 90□ C. overnight. After cooling to room temperature, the mixture was filtered, washed with CH2Cl2 and was partitioned between H2O (20 ml) and CH2Cl2 (2×20 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 0-1% MeOH in CH2Cl2 to give white solid (0.045 g, 51%); 1H NMR (300 MHz, C6D6) δ9.25 (1H, s), 9.10 (2H, s), 8.64 (1H, d, J=5.1 Hz), 7.89 (1H, s), 7.34 (1H, d, J=5.1 Hz); ESIMS (MH+): 248.00.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])=[O:8].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])=[O:8])=[N+:20]=[N-:21]
Reactant: O=C(CCCCCBr)Nc1ccccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCC(=O)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A mixture of 2 (28.4 g, 90 mmol) and sodium azide (12 g, 184 mmol) in DMF (200 mL) was stirred overnight at room temperature. The reaction mixture was poured into ice-water (500 mL) and extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water (4×100 mL) and brine (50 mL). After removal of the solvent the crude product was passed through a silica gel pad (100 g) and washed with 1:2 mixture of hexane and diethyl ether. Concentration of the appropriate fractions gave 22.5 g of 3 as a pale yellow oil. LC-MS (M++Na) 300
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][CH2:26][NH2:27])=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCc1ccc(F)cc1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccc(F)cc3)cc2F)cn1
Yield: 39.1 %

Procedure:
Using a method similar to Example 405, using 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.040 g, 0.154 mmol) and 4-fluorophenethylamine (0.021 g. 0.154 mmol) gives the title compound (0.0231 g, 39.2%): TOF MS ES+ 384.2 (M+H)+, HRMS calcd for C21H20N3O2F2 384.1524 (M+H)+. found 384.1509, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.8 min 100% purity.
Reaction SMILES: [K+].[C:2]([C:4]1[N:5]=[C:6]([C:17]([O-:19])=O)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)#[N:3].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][CH:63]([C:66]2[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([C:73]3[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=3)[CH:67]=2)[CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl.CCOC(C)=O>[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][CH:63]([C:66]2[CH:71]=[CH:70][C:69]([NH:72][C:17]([C:6]3[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:8]=[C:4]([C:2]#[N:3])[N:5]=3)=[O:19])=[C:68]([C:73]3[CH2:78][CH2:77][CH2:76][CH2:75][CH:74]=3)[CH:67]=2)[CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCCCC3)c2)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (3.34 g, 10.9 mmol) (as prepared in Example 3, step (d)) in 20 mL DCM was added DIEA (3.8 mL, 21.8 mmol) and PyBroP (5.6 g, 12.0 mmol), and the reaction stirred at 25° C. for 15 min. A solution of 4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 10.9 mmol) (as prepared in Example 13, step (d)) in 10 mL DCM was added and the reaction stirred for 8 h at 25° C. The reaction was diluted EtOAc (60 mL) and washed with NaHCO3 (2×60 mL) and brine (100 mL) and the organic layer was dried over Na2SO4 and then concentrated. The title compound was purified by flash chomatography (silica gel, 2% EtOAc/DCM) to give 5.5 g (85%) of the title compound as a yellow oil. Mass spectrum (ESI, m/z): Calcd. for C33H47N5O4Si, 606.2 (M+H), found 606.2.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH:6]([OH:14])[C:7]([C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)=O)[O:3][CH:2]=1.[N:15]#[C:16][NH2:17].[O-]CC.[Na+].O>C(O)C>[NH2:17][C:16]1[O:14][C:6]([C:4]2[O:3][CH:2]=[CH:1][CH:5]=2)=[C:7]([C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)[N:15]=1
Reactant: N#CN
Reactant: O=C(c1ccco1)C(O)c1ccco1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccco2)c(-c2ccco2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
Furoin (0.50 g, 2.60 mmol) was dissolved in ethanol (15 mL). Cyanamide (218.8 mg, 5.20 mmol) and sodium ethoxide (530.8 mg, 7.80 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=1:1→1:2) to give the title compound (175.0 mg, 31.1%) as a dark brown crystal.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:11](=[CH:16][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42](O)=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:11](=[CH:16][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1C(=O)OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1C(=O)OC
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a stirred solution of dimethyl (S)-4-(2-pyrrolidinylmethoxy)phthalate (212 mg, 0.72 mmol) in DMF (8 mL) was added pentafluorophenyl ester of the 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (346 mg, 0.72 mmol) and Et3 N (120 ml, 0.86 mmol), and the mixture was stirred overnight. The resulting mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated off in vacuo to give 413 mg (97%) dimethyl (S)-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]phthalate as an oil. 1H-NMR (CDCl3) δ 1.92–2.12 (m, 4 H), 2.29 (br s, 3 H), 3.51–3.64 (m, 7 H), 3.87 (s, 3 H), 3.89 (s, 3 H), 4.10–4.19 (m, 2 H), 4.44 (m, 1 H), 6.73–8.02 (series of m, total 12 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:3]=1.O.[NH2:15][NH2:16]>C(O)C>[NH:15]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:3]=1)[NH2:16]
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)ncn1
Solvent: O
Solvent: CCO
Product: NNc1cc(N2CCOCC2)ncn1
Temperature: 25 °C

Procedure:
53.0 g (0.27 mol) of 4-(6-chloropyrimidin-4-yl)morpholine are initially charged in 260 ml of ethanol. 132.9 g (2.7 mol) of hydrazine hydrate are added, and the mixture is stirred under reflux for 16 h. The mixture is cooled to RT, and half of the solvent is removed by distillation. The mixture is then cooled to 0° C., and the solid formed is filtered off. The solid is washed with cold ethanol and initially air-dried and then dried under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](Br)=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].Cl.O1CCOC[CH2:16]1>CC(=O)OCC.[CH3-].[CH3-].[Zn+2]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:16])=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1ccc(Br)c(C)n1
Agent: Cl
Agent: [CH3-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl zink (4.58 g, 48.0 mmol) is added to a solution of 5-bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (11.7 g, 48.0 mmol, see preparation of 5-isobutyl-6-methyl-pyridine-2-carboxylic acid) and Pd(dppf) (392 mg, 0.48 mmol) in dioxane (40 mL). The mixture becomes warm and is stirred at rt for 1 h. Another portion of dimethyl zink (4.58 g, 48.0 mmol) is added. The mixture is stirred at 100° C. for 2 h, then at 80° C. for 72 h before it is cooled to rt, and diluted with EA (250 mL) and ice-water (150 mL). The mixture is acidified with 2 N aq. HCl, the org. phase is separated and the aq. phase is extracted with EA (3×100 mL) and DCM (2×75 mL). The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel (heptane:EA gradient) to give 5,6-dimethyl-pyridine-2-carboxylic acid ethyl ester (434 mg) as a brownish oil; LC-MS: tR=0.61 min, [M+1]+=179.98, 1H NMR (CDCl3): δ 1.45 (t, J=7.0 Hz, 3H), 2.37 (s, 3H), 2.62 (s, 3H), 4.48 (q, J=7.3 Hz, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])=[N:6][CH:7]=1
Reactant: Nc1cnc(C(=O)O)cn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc(C(=O)OCc2ccccc2)cn1
Reaction time: 22 h

Procedure:
5-aminopyrazine-2-carboxylic acid (493 mg, 3.54 mmol; Ark Pharm, Inc., Libertyville, Ill.) was stirred in dry N,N-dimethylformamide (3.0 mL) at room temperature under nitrogen. Solid potassium carbonate (742 mg, 5.37 mmol) was added, followed by benzyl bromide (0.43 mL, 3.6 mmol). The mixture was stirred for 22 hours and then diluted with ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica chromatography using a 40 g pre-packed column, eluting with ethyl acetate. The product fractions were combined, evaporated, and dried under high vacuum to afford (I-22a) (161.2 mg, 0.70 mmol, 20%): m/z 229.9 (M+H)+.