Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[Cl:13])=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[N:26]([CH2:30][CH2:31][CH3:32])[C:27]([NH2:29])=[S:28]>>[Cl:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]1[N:29]=[C:27]([N:26]([C:18]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=2[O:16][CH3:15])[CH2:30][CH2:31][CH3:32])[S:28][C:2]=1[CH3:14]
Reactant: COc1ccc(C(=O)C(C)Br)c(Cl)c1
Reactant: CCCN(C(N)=S)c1cc([N+](=O)[O-])ccc1OC
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc([N+](=O)[O-])ccc1OC

Procedure:
By carrying out the procedure according to EXAMPLE 12 and by using 2-bromo-1-(2-chloro-4-methoxyphenyl)propan-1-one (Compound 1-2) and N-(2-methoxy-5-nitrophenyl)-N-propylthiourea, the expected product is obtained in the form of a powder; m.p.=97° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:20]2=3)=[O:18])[CH2:13][CH2:12]1>CN(C=O)C.C(N(CC)CC)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:20]2[N:19]([C:17]([CH:14]3[CH2:13][CH2:12][CH:11]([CH2:10][NH:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:16][CH2:15]3)=[O:18])[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]=2[CH:30]=1
Reactant: CCCCCCBr
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CN)CC1)C2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCNCC1CCC(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E10.2 (2.05 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=458.4
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].BrC[C:14]1[C:15]([C:20]#[N:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.O.[CH2:23]1COCC1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([CH2:23][C:18]1[CH:19]=[CH:14][C:15]([C:20]#[N:21])=[CH:16][CH:17]=1)[C:1]([O:8][CH3:9])=[O:7]
Reactant: N#Cc1ccccc1CBr
Reactant: C1CCOC1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C(Cc1ccc(C#N)cc1)C(=O)OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Dimethyl malonate (10.00 g, 75.7 mmol) was added to a suspension of NaH (60% in oil, 3.33 g, 83.3 mmol) in THF (100 mL) over 20 minutes at room temperature. The mixture was heated at 80° C. for 15 minutes, then a solution of α-bromotolunitrile (14.84 g, 75.69 mmol) in THF (100 mL) was added. Heating was continued at 80° C. for 1 hour, then at 50° C. for 64 hours. Water (30 mL) was added, and the aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phases were dried (MgSO4) and concentrated. Purification of the crude material on silica gel (25% EtOAc/hexanes) gave the title compound as colourless crystals (8.49 g, 45%). 1H NMR (CDCl3) δ 3.27 (d, 2H, J=9.0 Hz), 3.67 (t, 1H, J=9.0 Hz), 3.70 (s, 6H), 7.32 (d, 2H, J=9.0 Hz), 7.58 (d, 2H, J=9.0 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[C:21]([O:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH3:30])[C:31]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH3:13])=[O:11])=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
There are introduced into a reactor, with stirring, 2.13 kg of methyl(2S)-2,3-dihydroindole-2-carboxylate, 1 kg of triethylamine, 30 litres of tetrahydrofuran and then, after 10 minutes' stirring at room temperature, 1.9 kg of N-[tert-butyloxycarbonyl]-(S)-alanine and 2 kg of dicyclohexylcarbodiimide. The heterogeneous mixture is then stirred at room temperature for 6 hours, and is subsequently cooled to 0° C. and filtered.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:9]=2)=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[C:14]([C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[N:3][CH:4]=2)=[N:9][C:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:11][CH:12]=1)#[N:15].[NH2:31][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[N:9]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1cnc(Nc2ccc(F)cc2)nc1-c1ccc(Cl)nc1
Product: COc1ccc(CNc2ccc(-c3nc(Nc4ccc(F)cc4)ncc3C#N)cn2)cc1
Product: N#Cc1cnc(Nc2ccc(F)cc2)nc1-c1ccc(N)nc1

Procedure:
5-cyano-N-(4-fluorophenyl)-4-[2-(4-methoxybenzylamino)pyridin-5-yl]-pyrimidine-2-amine was prepared in a similar manner to the title compound of Example 7 from 4-(2-chloropyridin-5-yl)-5-cyano-N-(4-fluoro-phenyl)pyrimidine-2-amine (764 mg, 2.3 mmol) and p-methoxybenzyl-amine (644 mg, 4.6 mmol) as a yellow solid (432 mg). δH (d6 DMSO) 10.35 (1H, s), 8.82 (1H, s), 8.77 (1H, d, J 2.3 Hz), 8.04 (1H, dd, J 8.9, 2.3 Hz), 7.84 (1H, t, J 5.6 Hz), 7.77-7.74 (1H, m), 7.28 (2H, d, J 8.6 Hz), 7.21 (2H, t, J 8.9 Hz), 6.90 (2H, d, J 8.6 Hz), 6.66 (1H, d, J 8.9 Hz), 4.51 (2H, s) and 3.73 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[C:5]([C:6]([NH:8][CH:9]([CH2:14][OH:15])[C:10]([O:12][CH3:13])=[O:11])=O)=[CH:4][N:3]=1.CCN(S(F)(F)F)CC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:15][CH2:14][CH:9]([C:10]([O:12][CH3:13])=[O:11])[N:8]=2)=[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])[CH:17]=1
Reactant: COC(=O)C(CO)NC(=O)c1cnc(Cl)cc1NC(C)C
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C1COC(c2cnc(Cl)cc2NC(C)C)=N1
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 2-(6-chloro-4-(isopropylamino)nicotinamido)-3-hydroxypropanoate (36) (100 mg, 0.317 mmol) in DCM (15 mL), DAST (0.317 mmol) was added at −78° C. and stirred for 4 h. K2CO3 (0.633 mmol) was added to the reaction mixture and stirred for 3 h. The reaction mixture was diluted with DCM and washed with water (twice) followed by brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by flash chromatography using silica gel and EtOAC:pet ether as eluent to afford the title compound, methyl 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-4,5-dihydrooxazole-4-carboxylate. 1H NMR: 400 MHz, DMSO-d6: δ 1.20-1.21 (m, 6H), 3.73 (s, 3H), 3.84-3.89 (m, 1H), 4.51-4.59 (m, 2H), 5.07-5.12 (m, 1H), 6.83 (s, 1H), 8.36 (s, 1H), 8.80 (d, J=7.60 Hz, 1H).
Reaction SMILES: [N+](C1C=C(C(N=[N+]=[N-])=O)C=C([N+]([O-])=O)C=1)([O-])=O.C(#N)C.[N+:21]([C:24]1[CH:25]=[C:26]([N:33]=[C:34]=[O:35])[CH:27]=[C:28]([N+:30]([O-:32])=[O:31])[CH:29]=1)([O-:23])=[O:22].[CH3:36][CH:37]([CH3:44])[C:38]([O:40][CH2:41][CH2:42][OH:43])=[O:39]>ClCCl.O>[C:38]([O:40][CH2:41][CH2:42][O:43][C:34](=[O:35])[NH:33][C:26]1[CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=1)(=[O:39])[CH:37]([CH3:44])[CH3:36]
Reactant: O=C=Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(C)C(=O)OCCO
Agent: [N-]=[N+]=NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC(C)C(=O)OCCOC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
19.5 g (0.0822 mol) of 3,5-dinitrophenyl carbonyl azide was placed, in a nitrogen current, in a 0.3-l four-necked flask equipped with a nitrogen inlet tube, a dropping funnel, a reflux condenser, a thermometer and a mixing blade. Thereto was added acetonitrile for dissolution and the total amount was made 50 ml. The flask contents were heated for refluxing to obtain 50 ml of an acetonitrile solution containing 3,5-dinitrophenyl isocyanate (compound 7). While the flask was being cooled with ice water, 12.0 g (0.0909 mol) of 2-hydroxyethyl 2-methylpropionate was dropwise added to the flask contents with stirring. After the dropwise addition, stirring was conducted at room temperature for 2 hours; 50 ml of water was added; and stirring was conducted for several minutes. Then, dichloromethane was added. All the flask contents were transferred into a separating funnel for separation of the aqueous layer. The organic layer taken out was returned to the separating funnel. Thereto was added a 5% aqueous sodium carbonate solution, followed by mixing. The lower layer (organic layer) was taken out and dried over anhydrous magnesium sulfate. From the dried solution was removed dichloromethane by distillation by the use of an evaporator, whereby a solid was separated. The solid was recrystallized from butanol to obtain 2-(3,5-dinitrophenylcarbamoyloxy)ethyl isobutyrate (compound 8) as a yellow powder. Yield: 14.4 g (50%) Melting point: 94-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:24][N:25]([CH:32]([CH3:34])[CH3:33])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH:32]([CH3:34])[CH3:33])[CH3:24])[CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: Clc1ccc(Nc2ncnc3oc4c(c23)CCNC4)cc1Cl
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2c(oc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 41A (100 mg, 0.30 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (81 mg, 0.42 mmol) to yield 86 mg (61%).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:27].C([Li])CCC.CCCCCC.[CH3:39][S:40]SC>C(OCC)C>[F:27][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:2]=1[S:40][CH3:39])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)N1CCC([C@H]2C[C@H]2COCc2ccc(Br)c(F)c2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1ccc(COC[C@@H]2C[C@@H]2C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
tert-butyl 4-((1R,2R)-2-(((4-bromo-3-fluorobenzyl)oxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step A product, 7.7 g, 17.4 mmol) was dissolved in Diethyl ether (70 ml) and cooled to −78° C. The mixture was stirred for 5 min, then n-Butyllithium in hexane (2.5 M, 7.66 ml, 19.15 mmol) was added dropwise. The mixture was stirred at −78° C. for 10 min and dimethyl disulfide (1.85 ml, 20.9 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and TLC showed the SM was almost consumed. The mixture was quenched with sat. NH4Cl at −78° C., extracted with EtOAc (2×). The EtOAc phase was washed with brine, dried over MgSO4, and concentrated to afford 7.13 g (100%) of the designed product. This crude product was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]([OH:18])[C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:3].COC.[C:24]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:27])[CH2:25]O.O1CCCC1>CS(O)(=O)=O.CCCCCC>[CH3:17][N:15]([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:7]2[CH:19]=[CH:20][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[O:18][CH2:25][C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:10][CH:11]=1
Reactant: O=C(CO)OCc1ccccc1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Agent: COC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)c1ccc(C(OCC(=O)OCc2ccccc2)c2ccc(N(C)C)cc2)cc1

Procedure:
A solution of 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether (11.0 g, 0.039 mole), benzyl glycolate (6.6 g, 0.039 mole), 90 ml of tetrahydrofuran, 200 ml of hexane, and 10 drops of methanesulfonic acid was refluxed for 6 hours, replacing solvent as distillate was removed; then, 10 drops of tetramethylguanidine was added to discharge the color and the reaction mixture was filtered hot and cooled. A white solid formed which was filtered, washed with petroleum ether and then recrystallized from 4/1 hexane/acetone. The resulting white crystalline product had a mp 101.8°-103° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].CS(O[CH2:15][C:16]1[C:17]2[CH:25]=[C:24]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[S:23][C:18]=2[N:19]=[C:20]([CH3:22])[N:21]=1)(=O)=O.Cl>O.CN(C=O)C.C1COCC1>[CH:26]1([C:24]2[S:23][C:18]3[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([CH2:15][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]4=[O:7])[C:17]=3[CH:25]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=C1CCCCN1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCCCC3)sc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(CN2CCCCC2=O)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.6 %

Procedure:
To a mixture of piperidin-2-one (100 mg), THF (4 mL), and DMF (1 mL) was added NaH (60% oil, 40 mg), followed by stirring at room temperature for 30 minutes, and then (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl methanesulfonate (150 mg) was added thereto, followed by further stirring at room temperature for 1 hour. To the reaction mixture were added water and 1 M hydrochloric acid, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain 1-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]piperidin-2-one (13 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=1)[CH2:5][CH:6]=[CH2:7].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][NH:15][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:12][CH:13]=1)[CH2:5][CH:6]=[CH2:7]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCC(C(=O)OC)c1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCC(C(=O)OC)c1ccc(CNS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred solution of 2-(4-aminomethyl-phenyl)-pent-4-enoic acid methyl ester (1.67 g, 6.55 mmol) in dichloromethane (50 cm3) at ambient temperature under an atmosphere of dry nitrogen was added triethylamine (4.56 cm3, 32.8 mmol) followed by dropwise addition of methanesulfonyl chloride (1.52 cm3, 19.7 mmol) over 5 minutes. The mixture was stirred for 4 hours at ambient temperature and the filtrate volatile fractions removed in vacuo to afford a crude yellow oil. The oil was dissolved in ethyl acetate (100 cm3), washed with saturated sodium bicarbonate (2×50 cm3), brine (25 cm3), dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to a crude yellow oil. The oil was purified by column chromatography (silica, eluting with hexane-ethyl acetate 4:1 to 1:1) to afford the title compound as a pale yellow viscous oil (1.85 g, 100%) with a positive ion ESI (M+H)+296.2.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=O)=[CH:9][CH:8]=1)[CH3:2].CO.[CH3:28][NH:29][NH2:30]>>[CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:29]([CH3:28])[N:30]=[C:15]3[C:16]4[C:21]([CH2:22][CH:14]23)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(CC)CCOc1ccc(C=C2Cc3ccccc3C2=O)cc1
Reactant: CNN
Solvent: CO
Product: CCN(CC)CCOc1ccc(C2C3Cc4ccccc4C3=NN2C)cc1

Procedure:
A solution of 26.4 g (0.08 mole) of 2-[[4-[2-(diethylamino)ethoxy]phenyl]methylene]-2,3-dihydro-1H-inden-1-one in 250 ml of methanol containing 3.7 g (0.08 mole) of methyl hydrazine is heated at reflux for 4 hours. After cooling, 9.1 g starting material is recovered.
Reaction SMILES: [Mg].BrCCBr.Br[CH2:7][CH2:8][CH2:9][CH2:10]Br.[CH3:12][C:13](=[C:21]([CH3:23])[CH3:22])[CH2:14][CH2:15][C:16]([O:18]CC)=O.[Cl-].[NH4+]>C(OCC)C>[CH3:12][C:13](=[C:21]([CH3:22])[CH3:23])[CH2:14][CH2:15][C:16]1([OH:18])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: BrCCCCBr
Reactant: CCOC(=O)CCC(C)=C(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: CCOCC
Product: CC(C)=C(C)CCC1(O)CCCC1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
Magnesium turnings (9.53 g, 0.39 mol) were covered with dry diethyl ether (50 ml) at room temperature under nitrogen. 1,2-Dibromoethane (0.5 ml) was added in one portion. As soon as a visible reaction had started (bubbling), magnetic stirring was switched on and a solution of 1,4-dibromobutane (50 g, 0.225 mol) in dry diethyl ether (360 ml) was added at a rate such as to maintain a constant reflux (1 hour). The reaction was further refluxed for 1 hour before cooling in an ice-water bath. Ethyl 4,5-dimethyl-4-hexenoate (26.5 g, 0.156 mol) in dry diethyl ether (30 ml) was added dropwise. Then the reaction was warmed up to room temperature and the reaction was refluxed for 1 hour. It was recooled in an ice-water bath before adding a saturated aqueous ammonium chloride solution (250 ml, slowly). After warming up to room temperature and shaking vigorously, the phases were separated. The organic phase was washed with aqueous saturated bicarbonate (250 ml) and water (500 ml). Each aqueous phase was re-extracted with diethyl ether (250 ml). Combined extracts were dried over anhydrous sodium sulfate. The product was purified by column chromatography on silica gel (eluting with heptanes/ethyl acetate 11:1 to 3:1) followed by bulb-to-bulb distillation (110° C./1 mbar). 22.62 g of the title compound (99.6% pure, 0.122 mol, 78%) were obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[CH:8](OC(=O)C)[O:7][C@@H:6]1[C:18]1[CH:22]=[C:21]([CH2:23][CH3:24])[O:20][N:19]=1)(=[O:3])[CH3:2].[Cl:25][C:26]1[N:34]=[C:33]2[C:29]([NH:30][CH:31]=[N:32]2)=[C:28]([Cl:35])[N:27]=1.N12CCCN=C1CCCCC2.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[C:11]([O:10][C@@H:9]1[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:6]([C:18]2[CH:22]=[C:21]([CH2:23][CH3:24])[O:20][N:19]=2)[O:7][C@H:8]1[N:32]1[CH:31]=[N:30][C:29]2[C:33]1=[N:34][C:26]([Cl:25])=[N:27][C:28]=2[Cl:35])(=[O:13])[CH3:12]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCc1cc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Temperature: 60 °C
Reaction time: 21 h

Procedure:
(2R,3R,4R)-4,5-bis(acetyloxy)-2-(5-ethylisoxazol-3-yl)tetrahydrofuran-3-yl acetate isomer 1 (193 mg) was dissolved in acetonitrile (5 ml) and treated sequentially with 2,6-dichloropurine (213 mg), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.186 ml) and trimethylsilyl trifluoromethanesulphonate (TMSOTf) (0.225 ml) via a syringe over 5 min. The clear yellow solution was stirred at 22° C. for 40 h, at 60° C. for 21 h, and at 80° C. for 6 h. The mixture was cooled to room temperature and more DBU (0.186 ml) and TMSOTf (0.225 ml) were added. After stirring at 22° C. for 36 h the yellow mixture was heated at 60° C. overnight and at 80° C. for 6 h. The solvents were removed in vacuo and the resultant brown oily solid taken up in ethyl acetate and washed with water (20 ml, 3:1). The aqueous layer was extracted with ethyl acetate and the combined organic layers dried (MgSO4) and evaporated in vacuo to afford a brown oily solid. The residue was triturated with dichloromethane and a white solid removed by filtration. Evaporation of the filtrate afforded a tan solid. Purification by flash chromatography on silica gel eluting with ether:cyclohexane (1:1) afforded the title compound as a white solid (161 mg).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[C:5](Cl)=[CH:4][N:3]=1.Cl[C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].O.[N:22]1[CH:27]=[CH:26][CH:25]=CC=1>C1CCCCC1.O1CCOCC1.[OH-].[Na+]>[CH:27]1([N:22]2[C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14](=[O:15])[NH:8][C:7]3[C:6]([CH3:9])=[CH:5][CH:4]=[N:3][C:2]2=3)[CH2:25][CH2:26]1
Reactant: c1ccncc1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Cc1c(Cl)cnc(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 90.0 g (0.508 mole) of 2,5-dichloro-4-methyl-3-aminopyridine in 225ml of cyclohexane, 220ml of pyridine, and 50ml of 1,4-dioxane was added in portions over 15 minutes a solution of 100.7g (0.571 mole) of 2-chloronicotinic acid chloride in 200 ml of 1,4-dioxane. At the end of the addition, the reaction temperature reached 50° C. The mixture was stirred at room temperature for 2 days. The wet filter cake was heated at mild reflux overnight in 1l of water containing 25ml of 1N NaOH solution. (The crude product contained 8%-10% of the di-adduct, which is readily hydrolyzed in dilute sodium hydroxide solution to the required product.) The product was collected by filtration and was washed with cold water. The pure product was dried at 60° C. under vacuum to yield 60g (37.3%) (mp:168° C.-171° C.) of 2,6-dichloro-3-(2'-chloro-3'-nicotinyl) carboxamido-4-methylpyridine.