Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[P:9]([O-])([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([P:9](=[O:10])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOP(=O)([O-])OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(N)nc1

Procedure:
A mixture of 2-amino-5-bromopyridine (5 g, 0.029 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.), diethyl phosphate (5.02 g, 0.036 mol), triethylamine (4.4 g, 0.043 mol), Pd(OAc)2 (0.78 g, 3.4 mmol), triphenylphosphine (2.28 g, 8.7 mmol) in ethanol (100 mL) was refluxed for 14 hours under nitrogen. TLC (Petroleum ether/ethyl acetate=1:1) indicated that the reaction was complete. The resulting mixture was filtered, and the filtrate was concentrated in vacuo, the residue was purified by prep. HPLC to afford (I-25a) (4.3 g, 64.4%) as a white solid; m/z 231.3 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[CH:40]=[C:39](Cl)[N:38]=[CH:37][N:36]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:34][C:35]2[N:36]=[CH:37][N:38]=[C:39]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:40]=2)[CH:20]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Clc1cc(Oc2cc(Cl)c3[nH]c(C4CCOCC4)nc3c2)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1Nc2ncccc2C2(CCN(c3cc(Oc4cc(Cl)c5[nH]c(C6CCOCC6)nc5c4)ncn3)CC2)O1

Procedure:
49 mg (0.19 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 70 mg (0.19 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole and 70 μL (0.40 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and for 3 h at 40° C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=[CH:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)[CH2:8][CH2:7]1.[C:27]([O:31][C:32]([N:34]1[CH2:42][CH2:41][CH:37]([C:38](O)=[O:39])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>>[C:27]([O:31][C:32]([N:34]1[CH2:42][CH2:41][CH:37]([C:38]([NH:3][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][C:9](=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[CH:16]=[CH:15][C:14]4[CH:23]=[CH:24][CH:25]=[CH:26][C:13]3=4)[CH2:8][CH2:7]2)=[O:39])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: NCCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Aminoethyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene) piperidine dihydrochloride (2.3 g, 6.0 mmol), 1-t-butoxycarbonylisonipecotic acid (1.6 g, 7.2 mmol), triethylamine (3.0 ml, 21.6 mmol) and 1-ethyl-3-(3-dimethlaminopropyl) carbodiimide hydrochloride (1.4 g, 7.2 mmol) were mixed, and the mixture was stirred at room temperature overnight. After evaporating the solvent, the residue was dissolved in 100 ml of dichloromethane, washed with 100 ml of 1 N hydrochloric acid, 100 ml of a 1 N aqueous, sodium hydroxide solution, and 50 ml of a saturated aqueous sodium chloride solution. The solvent was evaporated and the residue was purified by silica gel chromatography to obtain the titled compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:1][CH:2]2[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCC(O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a mixture of 3.0 g (0.03 mole) of 3-hydroxy-1-methylpyrrolidine, 3.1 g (0.03 mole) of triethylamine, and 25 mL of methylene chloride was added 5.6 g (0.03 mole) of 4-methylphenylsulfonyl chloride, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to a residue. The residue was dissolved in ether, the solution filtered, and the filtrate concentrated to give 5.75 g of product as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[NH2:9][N:10]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[NH:12][C:11]1=[O:19]>Cl.C(O)C>[O:19]=[C:11]1[NH:12][C:13]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:14][N:10]1[N:9]=[CH:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)c1cn(N)c(=O)[nH]1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cn(N=Cc2cccnc2)c(=O)[nH]1
Temperature: 25 °C

Procedure:
5.4 g of 3-formylpyridine and three drops of concentrated hydrochloric acid are added to a solution of 7.8 g of 1-amino-2,3-dihydro-2-oxo4-tert-butyl-1H-imidazole in 50 ml of ethanol. The reaction mixture is refluxed for 30 minutes with stirring and then cooled to room temperature, upon which the mixture starts to crystallize. To complete the crystal precipitation process, 100 ml of diethyl ether are added to the mixture. The crystallizate is filtered off with suction, triturated with acetonitrile, again filtered off with suction and then dried. This gives the title compound which melts at 255°-256°.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.Cl>O1CCOCC1.CCOCC>[ClH:21].[NH2:8][CH2:9][CH:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C(CN)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 178.2 %

Procedure:
A solution of methyl 3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoate (451 mg, 1.44 mmol) in dioxane (6.0 mL) was treated with 4M HCl in dioxane (about 6.0 mL, 23.0 mmol) at room temperature. The mixture was stirred for 18 hours to completion, after which the reaction mixture was diluted with ether to afford a precipitate. The slurry was filtered under nitrogen to afford a white solid, which was washed with ether. The solid was dried under vacuum to afford the methyl 3-amino-2-(4-chlorophenyl)propanoate hydrochloride as a white solid (321 mg, 89%). LCMS (APCI+) m/z 214.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.[C:15]1([S:21]([N:24]([CH2:28][CH2:29]Cl)[CH2:25][CH2:26]Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CCCC)CCCC)CCC>CO>[C:15]1([S:21]([N:24]2[CH2:28][CH2:29][N:1]([C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=4[CH:14]=3)[CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)N(CCCl)CCCl
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1cc2cc(N3CCN(S(=O)(=O)c4ccccc4)CC3)ccc2o1
Temperature: 75 °C
Reaction time: 43 h
Yield: 53.6 %

Procedure:
Methyl 5-aminobenzofuran-2-carboxylate (200 g) and N-benzenesulfonyl-N,N-bis(2-chloroethyl)amine (289 g) were added to tributyl amine (1012 ml) under stifling at 25-30° C. The resulting mixture was heated to 73-77° C., followed by stirring for 43 hours at the same temperature. The reaction mass was cooled to 25-30° C., followed by the addition of methanol (506 ml) and then stirring for 30 minutes at 25-30° C. The resulting mass was filtered, washed with chilled methanol (200 ml) and then dried to produce 220 g of methyl 5-[4-(benzenesulfonyl)-1-piperazinyl]benzofuran-2-carboxylate as a fine powder (Purity by HPLC: 99.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[C:4]=1[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([O:7][CH3:21])=[O:6]
Reactant: COc1cc(OC)c(C(=O)O)c(OC)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(OC)cc(OC)cc1OC
Temperature: 25 °C

Procedure:
2,4,6-trimethoxybenzoic acid (CAS 570-02-5) (5.61 g, 26.42 mmol) was suspended in 20 mL of methanol (CAS 67-56-1). Concentrated sulfuric acid (CAS 7664-93-9) (1 mL) was added to the mixture, and the reaction heated to reflux for 24 hrs. The reaction was cooled to room temperature, and the methanol (CAS 67-56-1) removed in vacuo. The residues were taken up in 50 mL 5% NaHCO3 (CAS 144-55-8) and extracted with hexane (CAS 110-54-3) until all the solids had dissolved. The hexane extract was dried over anhydrous Na2SO4 (CAS 7757-82-6), filtered, and rotovapped to dryness to give the desired product, methyl 2,4,6-trimethoxybenzoate (CAS 29723-28-2), as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](Br)=[CH:4][N:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(N)cc1C
Temperature: 25 °C
Yield: 58.4 %

Procedure:
To a stirred solution of 2-amino-5-bromo-4-methylpyridine (10 g, 54 mmole) in propionitrile (50 mL) was added ethyl acrylate (17 mL, 157 mmole), DIEA (19 mL, 106 mmole), palladium(II) acetate (0.61 g, 2.7 mmole) and tri-o-tolylphosphine (1.64 g, 5.4 mmole). The reaction was purged with argon and heated at reflux for 6 hr, then was cooled to RT and concentrated to dryness under vacuum. The resulting residue was taken up in ethyl acetate and filtered through a pad of silica gel. The filtrate was concentrated and the remaining residue was triturated with 1:1 Et2O/petroleum ether (50 mL), filtered, and dried under vacuum to give the title compound (6.50 g, 59%) as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.66 (d, J=16.0 Hz, 1H), 6.40 (br s, 2H), 6.32 (d, J=16.0 Hz, 1H), 6.28 (s, 1H), 4.15 (q, 2H), 2.24 (s, 3H), 1.24 (t, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[C:7]([C@@H:9]([NH2:11])[CH3:10])[CH:8]=1.C([O:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45](O)=[O:46])=[CH:42][CH:43]=3)[C:38]([CH3:48])=[C:37]2[CH3:49])=[CH:31][CH:30]=1)=[O:22])(C)(C)C>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([F:13])([F:14])[F:15])=[C:7]([C@@H:9]([NH:11][C:45]([C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][CH:42]=2)[N:36]([CH2:35][C:32]2[CH:31]=[CH:30][C:29]([C:24]4[C:23]([C:21]([OH:22])=[O:20])=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:34][CH:33]=2)[C:37]([CH3:49])=[C:38]3[CH3:48])=[O:46])[CH3:10])[CH:8]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cc(F)ccc1C(F)(F)F
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cc(F)ccc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(5-fluoro-2-(trifluoromethyl)phenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 589 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][C:3]=1[C:14]([O:16]C)=[O:15].[H-].[Na+].[CH2:20]([O:27][C:28]1[C:33]([CH2:34]Cl)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:20]([O:27][C:28]1[C:33]([CH2:34][N:9]2[C:8](=[O:13])[C:7]3[C:2]([CH3:1])=[C:3]([C:14]([OH:16])=[O:15])[CH:4]=[CH:5][C:6]=3[O:12][CH2:11][CH2:10]2)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: COC(=O)c1ccc2c(c1C)C(=O)NCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCOc3ccc(C(=O)O)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a solution of methyl 6-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxylate (130e, 0.10 g, 0.45 mmol) in DMF (8 mL) was added NaH (54 mg, 1.36 mmol, 60% in oil) at 0° C. After stirring at 0° C. for 10 minutes, 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 0.20 g, 0.77 mmol) was added. The mixture was stirred at room temperature overnight. To the reaction mixture was added H2O (30 mL). The mixture was extracted with EtOAc (2×20 mL). The aqueous layer was acidified with conc. HCl to pH 3 and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (4×30 mL), dried over Na2SO4, and concentrated under vacuum to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxylic acid (130f, 0.17 g, 84.7%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][C:19](=[O:20])[N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Reactant: O=C(CBr)N1CCc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCc3ccccc3C2)cc1
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
A mixture of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.582 g) in dimethylformamide (8 mL) under argon was treated with 55% sodium hydride (0. 141 g), stirred for 30 minutes and then 2-(2-bromo-1-oxoethyl)-1,2,3,4-tetrahydroisoquinoline (0.762 g) in dimethylformamide (6 mL) was added. The solution was stirred at room temperature for 20 hours and worked up as in Example 20. The crude product was purified by HPLC (ethyl acetate-hexane; 2:3) to yield 0.3 g of 4-[2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethoxy]-alpha-oxobenzeneacetic acid ethyl ester as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=O)=[CH:16][CH:15]=3)=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:30])[CH3:2].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]2)=[CH:16][CH:15]=3)=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:30])[CH3:2]
Reactant: OCCN1CCNCC1
Reactant: CCc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCc1ccc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 90.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-ethyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (87.6 mg, 0.217 mmol) was dissolved in acetonitrile (7 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (113 mg, 0.868 mmol), acetic acid (0.248 mL, 4.34 mmol) and sodium triacetoxyborohydride (184 mg, 0.868 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-ethyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (102 mg, yield 91%).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:13][C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=P(Cl)(Cl)Oc1ccc(Br)cc1

Procedure:
Another embodiment of the invention provides a method of preparing d4T-5′-(para-bromophenyl methoxyalaninyl phosphate) in a single reaction vessel without purification of the intermediates formed. Phosphorous oxychloride is reacted with a para-bromophenol moiety to form para-bromophenyl phosphorodichloridate. Without purification, the para-bromophenyl phosphorodichloridate is contacted with alanine methyl ester to produce para-bromophenyl methoxyalaninyl phosphorochloridate. Without purification, the para-bromophenyl methoxyalaninyl phosphorochloridate is reacted with d4T.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:45])[C@@H:14]([NH:30][C:31](=[O:44])[C@@H:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:33]([CH3:35])[CH3:34])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:17]=2)[NH:8]1)=[O:6].C(=O)(O)[O-].[Na+].[I:53][C:54]1[CH:55]=[C:56]([CH:59]=[CH:60][CH:61]=1)[CH2:57][NH2:58].C(OCC)(=O)C>O1CCCC1>[C:40]([O:39][C:37](=[O:38])[NH:36][C@H:32]([C:31](=[O:44])[NH:30][C@@H:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si:23]([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:25])[CH3:24])[CH:17]=1)[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5](=[O:6])[NH:58][CH2:57][C:56]2[CH:59]=[CH:60][CH:61]=[C:54]([I:53])[CH:55]=2)[NH:8]1)=[O:45])[CH:33]([CH3:34])[CH3:35])([CH3:41])([CH3:43])[CH3:42]
Reactant: NCc1cccc(I)c1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)NCc2cccc(I)c2)N1
Reaction time: 8 h
Yield: 34 %

Procedure:
A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (987 mg, 1.337 mmol) in tetrahydrofuran (20 mL) was treated with sodium bicarbonate (337 mg, 4.011 mmol) and 3-Iodo-benzylamine (467 mg, 2.005 mmol). After overnight stirring, ethyl acetate and silica were added and the volatiles removed in vacuo. The product was purified by silica gel chromatography using iso-hexanes/ethyl acetate, 1:0 then 1:2 to afford the title compound (374 mg, 34%) as a white solid. 1H NMR (300 MHz, CDCl3) δ0.17 (s, 3H), 0.18 (s 3H), 0.81 (d, J=6.9 Hz, 3H), 0.86 (d, J=7.1 Hz, 3H), 0.97 (s, 9H), 1.46 (s, 9H), 1.61-1.70 (m, 2H), 1.73-1.83 (m, 1H), 1.84-1.94 (m, 1H), 1.96-2.05 (m, 1H), 2.53-2.66 (m, 1H), 2.81-3.01 (m, 3H), 3.34-3.45 (m, 1H), 3.74 (t, J=6.0 Hz, 1H), 3.98-4.09 (m, 1H), 4.31-4.51 (m, 2H), 4.79-4.88 (m, 1H), 5.75 (q, J=8.7 Hz, 1H), 6.38-6.49 (m, 1H), 6.67-6.73 (m, 1H), 6.74-6.78 (m, 1H), 6.84 (d, J=7.6 Hz, 1H), 7.03-7.15 (m, 2H), 7.31 (s, 1H), 7.33-7.43 (m, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.67 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:17])[O:11][CH2:10][CH2:9][C@H:8]2[N:5]1[C:6](=[O:16])[C@@H:7]2[C:12]([OH:15])([CH3:14])[CH3:13].S(OC)(O[CH3:22])(=O)=O.C(O)(=O)C>CN(C)C=O>[CH3:3][C:4]1([CH3:17])[O:11][CH2:10][CH2:9][C@H:8]2[N:5]1[C:6](=[O:16])[C@@H:7]2[C:12]([O:15][CH3:22])([CH3:13])[CH3:14]
Reactant: CC(C)(O)[C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(C)(C)[C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (38.1 mg, 50% in mineral oil) in N,N-dimethylformamide (1.14 ml) was added dropwise a solution of (6R, 7S)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]-octan-8-one (84.6 mg) in N,N-dimethylformamide (25.4 ml) at 0° C. After stirring for 30 minutes at 0° C., thereto was added a solution of dimethyl sulfate (75.13 μl) in N,N-dimethylformamide (0.676 ml), and the resultant mixture was stirred for 3 hours at 0° C. and for additional 1.5 hours at ambient temperature. Acetic acid (0.046 ml) was added to the mixture, and the solvent was distilled off in vacuo. The residue was diluted with ethyl acetate (20 ml) and then washed with an aqueous sodium chloride, 10% aqueous sodium bicarbonate, and a saturated aqueous sodium chloride in turn. The aqueous washings were extracted with ethyl acetate, and this extract was washed with an aqueous sodium chloride. The combined extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The residue (92.9 mg) was chromatographed on silica gel (2.5 g) eluting with a mixture of ethyl acetate and methylene chloride (1:100 to 1:3) to give (6R, 7S)-2,2-dimethyl-7-(1-methoxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]-octan-8-one (69.1 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1ccc(Br)nc1
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: Cc1ccc(-c2ccc(Cl)cn2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Bromine (18.0 ml, 353.7 mmol) is slowly added to a soln. of 2-amino-5-chloropyridine (15.0 g, 116.7 mmol) in 47% aq. HBr (75.0 ml) at −10° C. An aq. soln. of NaNO2 (28.1 g, 407.3 mmol) is slowly added. The mixture is stirred for 1 h at −10 to −5° C., then for 1 h at 5° C. The mixture is neutralised with 5M aq. NaOH soln. maintaining the temperature below 25° C. The precipitate is filtered and recrystallized from pentane to give 2-bromo-5-chloropyridine. 2-Bromo-5-chloropyridine (5.0 g, 26.0 mmol), p-tolylboronic acid (4.0 g, 29.4 mmol) and tetrakis(triphenylphosphine)palladium (1.44 g, 1.2 mmol) are dissolved in toluene:EtOH 9:1 (1375 ml). A 2M aq. Na2CO3 soln. (62.5 ml) is added to the reaction mixture. The mixture is stirred at 90° C. for 24 h, cooled to rt and filtered over celite. The toluene layer is separated and washed with brine. The aq. layers are extracted with AcOEt. The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown solid which is purified by FC (silica gel, eluent toluene) to give 5-chloro-2-p-tolyl-pyridine. (R)-3-Quinuclidinol (2.97 g, 23.4 mmol) is added to a suspension of NaH (0.96 g of a 60% dispersion in mineral oil, 22.8 mmol) in DMF (90 ml). The mixture is stirred for 1 h at rt. 5-Chloro-2-p-tolyl-pyridine (4.00 g, 19.6 mmol) is added and the mixture is heated for 135 h at 135° C. The reaction mixture is diluted with toluene and washed with 1M aq. NaOH soln. and brine. The aq. layers are re-extracted with toluene (3×). The combined organic extracts are dried over MgSO4 and filtered. The filtrate is evaporated to give a brown oil which is purified by FC (silica gel, eluents: AcOEt, then AcOEt/MeOH/NEt3 87:10:3) and recrystallized from CH3CN to give (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane; mp° C.: 110-112; [α]Drt=+21.2° (0.50, MeOH), M+H+ 295.2.