Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:9]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[CH3:10])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:39]=[CH:38][S:37][CH:36]=1)CCC.[F-].[K+]>C1(C)C=CC=CC=1.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>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:39]=[CH:38][S:37][CH:36]=3)=[CH:3][CH:4]=2)[CH:9]([N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])[CH3:10])=[CH:24][CH:25]=1
Reactant: CC(C(Cc1ccc(Cl)cc1)c1ccc(Br)cc1)N1C(=O)c2ccccc2C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C(Cc1ccc(Cl)cc1)c1ccc(-c2ccsc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
113 mg of N-{(1RS, 2RS)-2-(4-bromophenyl)-3-(4-chlorophenyl)-1-methylpropyl}phthalimide prepared in the same manner as in Example 114, was dissolved in 3 ml of toluene, and 99 mg of tributyl(3-thienyl)tin and 14 mg of tetrakis(triphenylphosphine)palladium (0) were added thereto. The mixture was refluxed under heating for 3 hours in a light-shielding nitrogen atmosphere. The reaction solution was left to cool to room temperature. Then, 2 ml of a 5% potassium fluoride aqueous solution was added thereto, and the mixture was stirred for 30 minutes. Insoluble matters were separated by filtration. Then, ethyl acetate and water were added to the filtrate for liquid separation. The organic layer was collected by separation, washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=100/1→30/1) to obtain 83 mg of N-[(1RS, 2RS)-3-(4-chlorophenyl)-1-methyl-2-{4-(3-thienyl)phenyl}propyl]phthalimide
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[C:5]([CH3:11])[CH:4]=1)=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN(C=O)C.C(OCC)(=O)C>[CH3:11][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[C:8]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:10]
Reactant: CN1CCNCC1
Reactant: Cc1cc(C=O)[nH]c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C=O)[nH]c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (306.3 mg, 2 mmol) in DMF 5 mL was added HOBt (324.3 mg, 2.4 mmol), EDC (460.1 mg, 2.4 mmol) and then 1-methylpiperazine (0.27 mL, 2.4 mmol). The mixture was stirred at room temperature under nitrogen for overnight. The reaction was diluted with ethyl acetate and washed with sodium bicarbonate. The aqueous layer was extracted several times with ethyl acetate. The combined organic layer was washed with brine, dried, concentrated and column chromatographed (MeOH/DCM) to give 310 mg (66%) of 4-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde as a light yellow foam solid. 1H NMR (360 MHz, DMSO-d6) 12.20 (br s, 1H, NH), 9.47 (s, 1H, CHO), 6.80 (s, 1H), 3.58 (m, 4H, 2×CH2), 3.44 (m, 4H, 2×CH2), 2.03 (s, 3H, CH3).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[CH2:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1)[CH3:9].CI>C(OCC)C.O>[CH2:8]([N:10]([CH3:3])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1)[CH3:9]
Reactant: CCNc1ccccc1-c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CI
Product: CCN(C)c1ccccc1-c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under ice-cooling, 60% sodium hydride (54 mg) was added to an N,N-dimethylformamide (3.0 mL) solution of methyl 4-(2-(ethylamino)phenyl)-2-nitrobenzoate (0.27 g), followed by stirring at the same temperature for 5 minutes and then at room temperature for 15 minutes. Methyl iodide (0.083 mL) was added to the reaction mixture under ice-cooling, followed by stirring at room temperature for 1 hour and then at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and then methyl iodide (0.11 mL) was added thereto, followed by stirring at 40 to 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then water and diethyl ether were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-95% hexane/ethyl acetate] to obtain 0.12 g of methyl 4-(2-((ethyl)(methyl)amino)phenyl)-2-nitrobenzoate as a yellow oily substance.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][CH2:13][C:14]1[C:15]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[N:16][CH:17]=[CH:18][CH:19]=1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][CH2:13][C:14]3[C:15]([N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(c1ncccc1CN)S(C)(=O)=O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
N-{3-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.4302 mmol) and N-(3-aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide (102.0 mg, 0.4738 mmol) in a manner analogous to Example 2d. Product isolated as a tan solid (0.056 g, 35%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=4.6 Hz, 1H), 8.11 (d, J=6.5 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.40-7.32 (m, 2H), 6.93 (t, J=7.5 Hz, 1H), 6.26 (d, J=7.9 Hz, 1H), 4.62 (d, J=6.3, 2H), 3.24 (s, 3H), 3.16 (s, 3H). MS=367, 369 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.Cl>C(Cl)Cl>[ClH:28].[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH2:32])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{(R)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester (3.0 g) was dissolved in 60 mL DCM. 25 mL of 4N HCl (in dioxane) was added and the mixture stirred at room temperature for 2.5 hours. The mixture was concentrated and DCM added and mixture concentrated again. The resulting solid was dried under vacuum to provide 2.6 g. LCMS: m/z 489.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N+:5]([O-])=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12.P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][C:3]=12
Reactant: [O-][n+]1c(SC2CCCC2)cc(Cl)c2c1CCC2
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: Clc1cc(SC2CCCC2)nc2c1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 4-chloro-2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.160 g, 0.59 mmol) in methylene chloride (10 mL) was added phosphorous trichloride (0.1 mL, 0.89 mmol). The mixture stirred at rt for 2 h. After this time, the mixture was quenched with a saturated solution of NaHCO3 and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.137 g, 91%) as a clear oil. MW=253.79. 1H NMR (CDCl3, 500 MHz) δ 6.96 (s, 1H) 3.98-3.90 (m, 1H), 3.02 (t, J=7.5 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.22-2.08 (m, 4H), 1.83-1.72 (m, 2H), 1.68-1.58 (4H); APCI MS m/z 254 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][CH:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[CH:20]4[OH:35])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:38]([O:40][C:41]([CH3:43])=[CH2:42])=[O:39]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:32])[CH3:33])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:38]([O:40][C:41]([CH3:43])=[CH2:42])=[O:39])=[O:17])[CH2:15][C@@:7]3([OH:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)OC(=O)Cl
Reactant: CC1=C[C@@H]2[C@H](C(C)C)CCC(C)[C@]2(O)[C@@H](OC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)C1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)OC(=O)O[C@@H]1C(C)=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@H]1OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To (1S,4aS,5S,8aR)-2,8a-dihydroxy-3,8-dimethyl-5-(1-methylethyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 144, 50 mg, 0.096 mmol) and 4-dimethylaminopyridine (35 mg, 0.29 mmol) in dichloromethane (5 ml) at 0° C. under nitrogen was added isopropenyl chloroformate (17.4 mg, 0.144 mmol) and the resulting mixture stirred at 0° C. for 30 minutes and at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (25 ml) and washed with citric acid solution (3×15 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (5 g) eluting with hexane:ethyl acetate (1:1). The pure fractions were combined and concentrated in vacuo to give the title product (56 mg, 96%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[O:11].O>CO>[CH3:1][O:2][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: C[O-]
Reactant: O=C(CCCCCBr)N1CCCc2ccccc21
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCCCC(=O)N1CCCc2ccccc21

Procedure:
Sodium methoxide (0.8 g) was added to a solution of 1-(6-bromohexanoyl)-1,2,3,4-tetrahydroquinoline (2.1 g) in methanol (50 ml). The mixture was refluxed for 8 hours, then poured into water and extracted with ether. The extract was dried and evaporated and the residue chromatographed on silica gel, eluting with 98:2 methylene chloride:methanol, so as to obtain the product 1-(6-methoxyhexanoyl)-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].[H-].[Na+].CS(O[CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=O)=O.O>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([C:12]2[CH:13]=[CH:14][N:15]([CH2:24][CH2:25][NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:16]=2)=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])#[N:7]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCn1ccc(-c2ccc(C#N)c([N+](=O)[O-])c2)n1

Procedure:
2-Nitro-4-(1H-pyrazol-5-yl)benzonitrile (1.0 g), DMF (10 ml) and sodium hydride (60% in oil, 0.24 g) were stirred for 30 min at RT. 2-(tert-Butoxycarbonyl-amino)ethyl methanesulfonate (1.45 g) in DMF (3.3 ml) was added and the mixture was microwaved for 30 min at 160° C. (Biotage Initiator Sixty operating at 2.45 GHz). After pouring the mixture to water, it was extracted with EtOAc. Combined organic phases were washed with water and brine, dried with Na2SO4 and evaporated. The product was triturated with IPA and filtered. Yield 0.92 g. 1H-NMR (400 MHz; d6-DMSO): δ 1.35 (s, 9H), 3.38 (m, 2H), 4.24 (t, 2H), 6.92 (m, 1H), 7.06 (d, 1H), 7.85 (d, 1H), 8.19 (d, 1H), 8.33 (dd, 1H), 8.70 (d, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].CO[C:10]([C:12]1([CH3:34])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[NH:16][C:15]=2[CH:14]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[NH:13]1)=[O:11]>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6](=[O:7])[N:13]2[CH:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)[C:15]3[NH:16][C:17]4[C:22]([C:23]=3[CH2:24][C:12]2([CH3:34])[C:10]1=[O:11])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][CH:18]=4
Reactant: O=C=NCCCCl
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(OC)cc23)C(c2cccc(O)c2)N1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCCCl)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared analogously to the procedure described for example 22, using chloro propyl isocyanate and (1RS,3SR)-1-(3-hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-betacarboline-3-carboxylic acid methyl ester. MS: m/z (MH+)=454.0
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:37]4[CH2:38][CH2:39][C@@H:35]([F:34])[CH2:36]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: F[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CC[C@@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.75 (m, 1H), 7.55 (2H), 7.05 (1H), 5.43-5.56 (1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 426 [M+H]
Reaction SMILES: C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([O-:15])=O.[K+].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:30]2[O:31][C:32](=O)[C:33]([CH:36]([CH3:38])[CH3:37])(C)[N:34]=2)[CH3:29])=[CH:24][CH:23]=1.Cl>O.C(#N)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]([CH3:29])[C:30]([NH:34][C:33]([CH3:32])([CH:36]([CH3:38])[CH3:37])[C:13](=[O:15])[CH2:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])=[O:31])=[CH:26][CH:27]=1
Reactant: CC(C1=NC(C)(C(C)C)C(=O)O1)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)C(C)(NC(=O)C(C)c1ccc(Cl)cc1)C(C)C
Yield: 47.4 %

Procedure:
0.73 g (0.00722 mole) of triethylamine and 0.41 g (0.0043 mole) of magnesium chloride were added, at room temperature, to a solution of 0.73 g (0.0043 mole) of monopotassium ethyl malonate dissolved in :10 ml of acetonitrile, followed by stirring. Thereto was added 0.8 g (0.00287 mole) of 2-[1-(4-chlorophenyl)ethyl]-4-isopropyl-4-methyl-1,3-oxazol-5-one. The mixture was stirred at 60° C. for 5 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled. Thereto were added 50 ml of water and diluted hydrochloric acid to adjust the mixture to a pH of 4 or less. The mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated. The concentrate was subjected to separation by column chromatography to obtain 0.5 g (0.00136 mole) of ethyl 4-[2-(4-chlorophenyl)propanoylamino]-4,5-dimethyl-3-oxohexanoate (yield=48%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[CH2:6]1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[CH2:6]1
Reactant: CN1CC(CCCl)Cc2ncccc2C1=O
Reactant: CNc1ccccc1
Agent: Cl
Product: CN1CC(CCN(C)c2ccccc2)Cc2ncccc2C1=O

Procedure:
A solution of 8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one hydrochloride in excess N-methylaniline is heated to about 95° C. for 2 days. Excess N-methylaniline is removed at reduced pressure and the residue is taken up in chloroform. The chloroform layer is washed with dilute aqeuous base, decolorized with activated carbon and dried over sodium sulfate, filtered and concentrated. The residue is dissolved in a suitable solvent and purified by high pressure liquid chromatography using a silica gel column and ethyl acetate. The product is recrystallized from ethyl acetate.
Reaction SMILES: C([O:4][C@@H:5]1[C@:9]([CH:18]=[CH2:19])([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:7][C@H:6]1[N:29]1[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31])(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@:9]1([CH:18]=[CH2:19])[C@@H:8]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:7][C@@H:6]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[C@@H:5]1[OH:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 42 h
Yield: 97.3 %

Procedure:
To a stirred solution of nucleoside 23 (3.90 g, 7.7 mmol) in anhydrous methanol (40 cm3) was added sodium methoxide (0.83 g, 15.4 mmol). The mixture was stirred at room temperature for 42 h and then neutralised with dilute aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2×150 cm3), and the combined extract was washed with saturated aqueous sodium hydrogencarbonate (3×100 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure to give nucleoside 24 as a white foam (3.48 g, 97%). δH (CDCl3) 8.89 (1H, br s, NH), 7.60 (1H, d, J 0.9, 6-H), 7.36-7.26 (10H, m, Bn), 6.23 (1H, d, J 7.8, 1′-H), 5.98 (1H, dd, J 11.2, 17.7, 1″-H), 5.66 (1H, d, J 17.7, 2″-Ha), 5.55 (1H, d, J 11.5, 2″-Hb), 4.75-4.37 (6H, m, 2′-H, 4′-H, Bn), 3.84 (1H, dd, J 2.7, 10.8, 5′-Ha), 3.58 (1H, d, J 11.2, 5′-Hb), 3.23 (1H, d, J 10.6, 2′OH), 1.50 (3H, s, CH3). δC (CDCl3) 163.7 (C-4), 151.3 (C-2), 138.0, 136.9 (Bn), 136.0 (C-6), 131.2 (C-1″), 128.8, 128.6, 128.3, 127.8, 127.7, 127.3 (Bn), 120.7 (C-2″), 111.3 (C-5), 87.3 (C-1′), 84.6 (C-3′), 81.4 (C-4′), 78.0 (C-2′), 73.7 (C-5′), 70.0, 66.4 (Bn), 11.8 (CH3). Found: C, 66.8; H, 6.2; N, 5.9; C26H28N2O6 requires C, 67.2; H, 6.1; N, 6.0%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:10][CH2:11][C@H:12]([CH2:16][N:17]2[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[NH:19][C:18]2=[O:25])[C@H:13]([OH:15])[CH3:14])=[CH:5][CH:4]=1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:52]([N:55]([CH:69]([CH3:71])[CH3:70])[P:56](N(C(C)C)C(C)C)[O:57][CH2:58][CH2:59][C:60]#[N:61])([CH3:54])[CH3:53]>ClCCl>[CH:69]([N:55]([CH:52]([CH3:54])[CH3:53])[P:56]([O:57][CH2:58][CH2:59][C:60]#[N:61])[O:15][C@H:13]([CH3:14])[C@@H:12]([CH2:16][N:17]1[CH:22]=[C:21]([CH3:23])[C:20](=[O:24])[NH:19][C:18]1=[O:25])[CH2:11][O:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:71])[CH3:70]
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: COc1ccc(C(OC[C@H](Cn2cc(C)c(=O)[nH]c2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H](Cn2cc(C)c(=O)[nH]c2=O)[C@@H](C)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a stirred solution of 34 (0.95 g, 1.79 mmol) in 25 ml of anhydrous dichloromethane was added diisopropylammonium tetrazolide (0.25 g) followed by 0.7 g (2.32 mmol) of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite. After being stirred at room temperature for 18 hrs the reaction was concentrated, and the residue portioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude phosphoramidite was precipitated twice by re-dissolving in small (˜15 ml) amount of ethyl acetate, diluting with hexane (100 ml), allowing to settle as an oil and decanting the liquid. Drying in vacuo afforded 0.95 g (72%) of 35 as an amorphous white solid. 31P NMR (DMSO-d6): δ 145.81, 144.94.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichlorobenzoyl chloride (5 g, 23.9 mmol) in 50 mL of dichloromethane at 0° C. was added N,O-dimethylhydroxylamine hydrochloride (2.56 g, 26.3 mmol) and pyridine (4.3 mL, 52.6 mmol). The cold bath was removed and the mixture stirred at ambient temperature for 16 hours, diluted with water and extracted with two portions of dichloromethane. The combined organic layers were dried over magnesium sulfate, concentrated in vacuo, and the residue purified by flash column chromatography (SiO2, 20% ethyl acetate/hexanes) to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ: 7.61 (d, J=1.9 Hz, 2H); 7.50 (d, J=1.9 Hz, 1H); 3.60 (s, 3H); 3.40 (s, 3H).