Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:22]2[CH:23]=[N:24][C:19]([N:16]3[CH2:15][CH2:14][N:13]([C:10]4[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=4)[CH2:18][CH2:17]3)=[N:20][C:21]2=[O:25])=[CH:29][CH:28]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
To an N,N-dimethylformamide solution (170 mL) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (8.48 g, 30.8 mmol) synthesized in Reference Synthesis Example 3, 4-chlorobenzyl bromide (6.32 g, 30.9 mmol) and potassium carbonate (5.11 g, 37.0 mmol) were added and the resultant mixture was stirred at 50° C. for 1 hour and at 70° C. for 3 hours. To the reaction solution, 4-chlorobenzyl bromide (1.90 g, 9.25 mmol) and potassium carbonate (2.13 g, 15.4 mmol) were added and the resultant reaction solution was stirred at 70° C. further for 2 hours. After the completion of the reaction, water was added to the reaction solution and a resultant solid was filtered and was dried under reduced pressure. The resultant solid was suspended in ethyl acetate and the suspension was stirred at room temperature for 10 minutes. The solid was filtered and was dried under reduced pressure. These operations from suspending of the solid to the second drying of the solid were performed twice to obtain the title compound (6.49 g, yield: 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90.5 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate (27 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 36 mg of the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 3.22-3.30 (m, 4H), 3.75-3.78 (m, 3H), 4.08-4.13 (m, 4H), 6.89-6.96 (m, 3H), 7.19-7.44 (m, 5H), 7.64-7.80 (m, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[NH2:16][C:17]([NH:19][C:20]1[NH:21][C:22]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=2)=[CH:23][C:24]=1[C:25]([NH2:27])=[O:26])=[O:18].C(=O)([O-])O.[Na+]>CN(C)C=O.O.C(O)(=O)C>[NH2:16][C:17]([NH:19][C:20]1[NH:21][C:22]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][OH:11])=[CH:32][CH:33]=2)=[CH:23][C:24]=1[C:25]([NH2:27])=[O:26])=[O:18]
Reactant: NC(=O)Nc1[nH]c(-c2ccc(C=O)cc2)cc1C(N)=O
Reactant: OCCNCc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1[nH]c(-c2ccc(CN(CCO)Cc3ccccc3)cc2)cc1C(N)=O
Yield: 36 %

Procedure:
Acetic acid (30 μl N-benzylethanolamine (79 μL, 0.55 mmol) and sodium cyanoborohydride (35 mg, 0.55 mmol) were added to a solution of 2-aminocarbonylamino-5-(4-formylphenyl)pyrrole-3-carboxamide (Compound No. 14-1, 50 mg, 0.18 mmol) in N,N-dimethylformamide (3 mL) and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate (10 mL) and water (10 mL) were added to the reaction solution, extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, the obtained residue was purified by silica gel column chromatography to give the target compound (26 mg) as a colorless solid (Yield 36%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:11]O>Cl>[CH3:11][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=1
Reactant: CO
Reactant: O=C(O)c1cncc(Br)c1
Agent: Cl
Product: COC(=O)c1cncc(Br)c1
Reaction time: 60 h

Procedure:
5-Bromo-nicotinic acid (5,00 g, 24.7 mmol) was dissolved in methanol (50 mL) and saturated with hydrochloric acid gas. The reaction mixture was allowed to stand for 2.5 days and then filtered. The filtrate was concentrated under reduced pressure and methylene chloride was added. The solution was washed with saturated sodium bicarbonate solution. The aqueous wash was back-extracted with methylene chloride (2×). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford 5-bromo-nicotinic acid methyl ester (4.72 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[CH2:14][CH2:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[CH2:10][CH2:11][N:12]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:13][CH2:14]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C2(CCO)CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1
Solvent: ClCCl
Product: Cc1cccc(C2(CCOS(C)(=O)=O)CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 0 °C

Procedure:
3.8 ml of methanesulfonyl chloride are added dropwise to 21 g of 4-(2-hydroxyethyl)-4-(3-methylphenyl)-N-tritylpiperidine (prepared according to scheme 5) dissolved in 200 ml of methylene chloride, cooled to 0° C. The reaction mixture is left for half an hour at room temperature, washed twice with water, dried over MgSO4 and concentrated under vacuum.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][O:11][CH3:12].[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>ClCCl>[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:10]([O:11][CH3:12])[CH3:9])=[O:17]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccc1F
Reaction time: 0.17 h
Yield: 674.6 %

Procedure:
Triethylamine (5.32 mL, 37.84 mmol) was added dropwise to a solution of N,O-dimethylhydroxylamine hydrochloride (2.768 g, 28.38 mmol) in anhydrous dichloromethane (45 mL) at 0° C. After stirring for 10 min, 2-fluorobenzoyl chloride (0.303 mL, 2.52 mmol) in anhydrous dichloromethane (15 mL) was added dropwise. The reaction mixture was returned to room temperature and stirred for 5 h. The reaction mixture was quenched with water (60 mL) and the products were extracted with dichloromethane (2×60 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 93:7 to 60:40) afforded 2-Fluoro-N-methoxy-N-methyl-benzamide (3.116, 17 mmol) in a 90% yield.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[CH:1]1([CH:7]=[C:8]2[N:12]([CH3:22])[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NC(=CC2CCCCC2)C(=O)N1c1ccccc1F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1C(=O)N(c2ccccc2F)C(=O)C1=CC1CCCCC1
Yield: 80.5 %

Procedure:
The 5-cyclohexylmethylene-3-(2-fluorophenyl)imidazolidine-2,4-dione (2.25 g, 7.81 mmol), cesium carbonate (2.6 g, 8.0 mmol) and methyl iodide (1.66 g, 11.7 mmol) were stirred overnight in DMF (25 mL). The solution was diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine (saturated, 2×). dried (over MgSO4), filtered and concentrated. Purification by column chromatography afforded 1.9 grams of 5-cyclohexylmethylene-3-(2-fluorophenyl)-1-methylimidazolidine-2,4dione, a white solid, m.p. 131°-137° C.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.CCCCCC.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35]Br)=[CH:29][CH:28]=1.[Cl-].[NH4+]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH2:35][CH2:34][CH2:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: Fc1ccc(CCCBr)cc1
Reactant: N#Cc1ccc(Cn2ccnc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C(CCCc2ccc(F)cc2)n2ccnc2)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1-(4-cyanobenzyl)-imidazole (1 g, 0.0054 mol) is dissolved into dry tetrahydrofuran (30 ml) and cooled to -70° C. n-BuLi in hexane (0.0054 mol) is added dropwise into the reaction mixture. After stirring for additional 30 min at -70° C. 3-(4-fluorophenyl)propyl bromide (1.5 g, 0.0069 mol) in THF (10 ml) is added to the mixture and stirig is continued for 2 hours. Then the mixture is allowed to warm to room temperature. Saturted aqueous ammonium chloride solution is added to the mixture, shaked and then the layers are separated. THF-phase is dried and evaporated to dryness. The residue is crystalizd from isopropanol as hydrogen chloride salt. The filtrate is purified by flash chromatography.
Reaction SMILES: C(Cl)C[Cl:3].[N:5]1[C:10]2[NH:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[CH:8]=[C:7]([CH:16]=[CH:17][C:18]([OH:20])=O)[CH:6]=1.[CH3:21][NH:22][CH2:23][C:24]1[O:25][C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]=1[CH3:29].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C.O>[ClH:3].[CH3:21][N:22]([CH2:23][C:24]1[O:25][C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]=1[CH3:29])[C:18](=[O:20])[CH:17]=[CH:16][C:7]1[CH:6]=[N:5][C:10]2[NH:11][CH2:12][CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1
Reactant: CNCc1oc2ccccc2c1C
Reactant: O=C(O)C=Cc1cnc2c(c1)OCCCN2
Reactant: ClCCCl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)C=Cc2cnc3c(c2)OCCCN3)oc2ccccc12
Temperature: 10 °C
Reaction time: 23 h
Yield: 69.1 %

Procedure:
EDC (108 mg, 0.56 mmol) was added to a solution of 3-(6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocyclohepten-3-yl)-acrylic acid (95 mg, 0.43 mmol), methyl-(3-methyl-benzofuran-2-ylmethyl)-amine (100 μL, 0.52 mmol), HOBt.H2O (64 mg, 0.47 mmol) and DIPEA (225 μL, 1.29 mmol) in dry DMF (4 mL). After stirring for 23 hr, the mixture was cooled (10° C.) and treated with water (50 mL). The precipitated crude product was separated by decantation and purified by chromatography (silica, EtOAc). The clean fractions of the free base were collected, concentrated to 10 mL and treated with HCl (0.7 mL, 1.4 mmol, 2M in Et2O). The resulting precipitate was collected by filtration, washed with EtOAc and hexanes to afford the title compound (123 mg, 57%). 1H NMR (300 MHz, DMSO-d6, 8): 8.07 (m, 2H), 7.58-7.41 (m, 3H), 7.36-7.15 (m, 3H), 4.99 and 4.77 (rotamers, 2s, 2H), 4.28 (m, 2H), 3.57 (m, 2H), 3.16 and 2.90 (rotamers, 2s, 3H), 2.25 (s, 3H), 2.11 (m, 2H). MS (ESI): m/e 378 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20]Br.C(OCC)(=O)C>CS(C)=O.CCCCCC>[C:3]1([C:13]2([C:14]#[N:15])[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCCBr
Reactant: N#CCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#CC1(c2cccc3ccccc23)CCCC1
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 5.24 g, 131.6 mmol) in dimethyl sulfoxide (50 mL) was added dropwise a mixture of naphthalen-1-yl-acetonitrile (337) (10.0 g, 59.8 mmol) and 1,4-dibromobutane (12.91 g, 59.8 mmol) dissolved in dimethyl sulfoxide-ether (1:1; 120 mL) at 0° C. and stirred for 30 min at the same temperature and then stirred at room temperature for 4 h (silica TLC, 10% ethyl acetate in hexane, Rf=0.65). The reaction mixture was quenched with HCl [1N; 20 mL] at 0° C. Ethyl acetate (400 mL) was added and the mixture was washed with water (500 mL) and brine (2×200 ml) and dried and concentrated in vacuo to get a crude mass which was purified by CombiFlash using a gradient eluent; mixture of ethyl acetate and hexane to get pure 1-naphthalen-1-yl-cyclopentanecarbonitrile (338) (8.4 g, 63%) as a white solid.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]=1[OH:28])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:24]([C:20]1[CH:21]=[C:22]([C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[OH:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(-c2ccc(C#N)c(C#N)c2)cc(C(C)(C)C)c1O
Reaction time: 72 h

Procedure:
To a stirred solution of 4-nitrophthalonitrile (8 g, 0.05 mol) was added 2,6 di-tert-butylphenol (11.44 g, 0.06 mol), potassium carbonate (9 g, 0.07 mol) and DMF (50 ml), producing a deep red colour. The reaction mixture was stirred under a nitrogen atmosphere for 72 h. Water (300 ml) was added and the mixture extracted with ethyl acetate (3×100 ml), the organic layer was further washed with water (3×75 ml) and dried over MgSO4. Evaporation of the solvent under reduced pressure yielded the crude product. Recrystallisation from ethanol yielded the pure product 4-(3,5-di-tert-butyl-4-hydroxyphenyl)phthlonitrile (1) as colourless, prismatic crystals (18.70 g, 81.70%), m.p. 209-210° C.; IR (KBr) 3416 (OH), 2231 (CN) cm- 1; (Found C, 79.55%; H, 7.50%; N, 8.20%. C22H24N2O requires C, 79.47%; H, 7.28%; N, 8.43%.); MS (EI) m/e 332 (M+); δH (200 MHz, solvent CDCl3): 1.51 (18H, s), 5.55 (1H, s), 7.39 (2H, s), 7.75-8.00 (3H, m).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14](O)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].[P:29](Cl)(OC1C=CC=CC=1)([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:27])[C@@H:14]([PH:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@H](C(=O)OCCOC(=O)C(C)C)[PH](=O)Oc1ccccc1
Yield: 91 %

Procedure:
Following the general procedure for phosphorylation of Description 23, (2-methylpropanoyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-hydroxy-butanoate (29) (1.0 g, 2.4 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 1.46 mL (1.9 g, 7.0 mmol) of diphenyl chlorophosphate [(PhO)2POCl] in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) (0.17 g, 1.4 mmol) and triethylamine (TEA) (0.97 mL, 0.71 g, 7.0 mmol). The reaction was monitored by TLC. After aqueous work-up, the crude material was further purified by silica gel column chromatography using ethyl acetate (EtOAc) as eluent to provide 1.2 g (80% yield) of the title compound (49a) as a colorless oil. Rf=0.55 (EtOAc). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.15 (m, 12H), 1.40-1.46 (2d, J=5.6, 5.6 Hz, 3H), 1.85 (s, 3H), 2.01-2.08 (m, 2H), 2.45-2.55 (m, 1H), 3.13-3.17 (m, 2H), 3.28-3.33 (m, 2H), 3.97-4.04 (m, 2H), 4.84-4.88 (2d, J=7.2, 7.6 Hz, 1H), 6.32-6.36 (br. m, 1H), 6.88-6.93 (m, 1H), 7.18-7.26 (m, 6H), 7.31-7.38 (m, 4H) ppm. MS (ESI) m/z 658.25 (M+H)+. The analytical data was consistent with proposed structure.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@H:4]2[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)([O-:41])=[O:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:39]([C:42]1[CH:43]=[CH:44][C:45]([C:46]([O:1][C@@H:2]2[CH2:19][N:5]3[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@H:4]3[CH2:3]2)=[O:47])=[CH:49][CH:50]=1)([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@H](O)C[C@@H]2C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@@H]2C1
Temperature: -78 °C

Procedure:
tert-Butyl (8R,9aR)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (50 mg, 0.185 mmol, 1.0 equivalent, Part D), triphenylphosphine (60.6 mg, 0.231 mmol, 1.25 equivalents), and 4-nitrobenzoic acid (46.4 mg, 0.277 mmol, 1.5 equivalents) were dissolved in tetrahydrofuran (1.0 mL), and the resulting solution was cooled to −78° C. Diisopropyl azodicarboxylate (0.043 mL, 0.222 mmol, 1.2 equivalents) was dissolved in tetrahydrofuran (0.5 mL), and the resultant solution was added to the reaction mixture. The reaction mixture was removed from the cooling bath and warmed to room temperature for 0.5 hour. After the addition of 1 drop of saturated sodium bicarbonate, the tetrahydrofuran solution was loaded directly onto 2 sequentially linked 4 g silica gel cartridges, eluted with 50-100% ethyl acetate/heptanes over 20 minutes. The titled compound co-eluted with triphenylphosphine oxide and was used without additional purification (225 mg combined material). 1H NMR (400 MHz, CDCl3) δ ppm 8.28 (d, J=8.9 Hz, 2H), 8.15 (d, J=8.9 Hz, 2H), 5.52 (t, J=4.0 Hz, 1H), 4.53-3.94 (m, 4H), 3.73 (dd, J=14.1, 4.2 Hz, 1H), 3.02 (br s, 1H), 2.78-2.59 (m, 3H), 2.55 (dt, J=13.7, 7.0 Hz, 1H), 2.03-1.91 (m, 1H), 1.47 (s, 9H); MS (ESI+) m/z 419.8 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:19]=O.Br[C:22]1[CH:29]=CC(Br)=C[C:23]=1C=O.NC1C=CC(Br)=CC=1C(OC)=O.NC1C=CC(Br)=C(C=1)C(OC)=O.BrC1(OC(F)(F)F)C=CC(C2C=CC=CC=2)=CC1C[CH2:69][C:70]1[CH:87]=[CH:86][C:73]([C:74]([NH:76][CH2:77][CH2:78][C:79]([O:81]C(C)(C)C)=[O:80])=[O:75])=[CH:72][CH:71]=1>>[F:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[C:3]3[C:2]([CH2:23][CH2:22][CH2:29][CH:19]3[CH2:69][C:70]3[CH:87]=[CH:86][C:73]([C:74]([NH:76][CH2:77][CH2:78][C:79]([OH:81])=[O:80])=[O:75])=[CH:72][CH:71]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1cc(Br)ccc1Br
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CCC2C=C(c3ccccc3)C=CC2(Br)OC(F)(F)F)cc1
Reactant: O=Cc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1Br
Agent: COC(=O)c1cc(Br)ccc1N
Agent: COC(=O)c1cc(N)ccc1Br
Product: O=C(O)CCNC(=O)c1ccc(CC2CCCc3ccc(-c4ccc(OC(F)(F)F)cc4)cc32)cc1

Procedure:
The compounds in TABLE 1 were prepared using the chemistry described in EXAMPLES 1, 4, 5 and 6 or with following modifications: 1) EXAMPLES 47 to 50 (where R1=R21) were prepared as described in EXAMPLE 1 substituting 4-bromo-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde with 2,5-dibromobenzaldehyde; 2) EXAMPLES 117 to 133 were prepared as described in EXAMPLE 1 substituting methyl 2-amino-5-bromobenzoate with methyl 5-amino-2-bromobenzoate; 3) EXAMPLES 111 to 113 were prepared from the intermediate from EXAMPLE 1 Step H using the procedure described in EXAMPLE 42A/42B.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]([NH:11][NH:12][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Into a stirred solution of 6.65 g (0.040 mol) of N-[(phenylmethoxy)carbonyl]hydrazine in 40 ml of dimethylformamide was dropped a solution of 8.58 g (0.044 mol) of t-butyl bromoacetate in 20 ml of dimethylformamide followed by a solution of 8.2 ml (0.048 mol) of N,N-diisopropylethylamine in 8 ml of dimethylformamide. After the mixture had been stirred at room temperature for one day, the solvent was distilled off in vacuo and the residue was taken up in ether and water. The organic layer was washed three times with water, dried (magnesium sulfate) and evaporated in vacuo to leave an oil (10.6 g), which was purified by column chromatography on silica gel eluting with ethyl acetate/toluene (1:1). The appropriate fractions were evaporated in vacuo and the residue was stirred with petroleum ether yielding 6.0 g of the title compound, melting point 61°-62° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]1([P:20]([C:27]2C=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:33](Cl)(Cl)Cl>>[Cl-:1].[C:7]1([CH2:6][CH2:5][CH2:4][C:3]([C:2]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[P+:20]([CH3:33])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClC(Cl)Cl
Reactant: O=C(CCl)CCCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1C(=O)CCCc1ccccc1
Product: [Cl-]

Procedure:
A solution of 1-chloro-2-oxo-5-phenylpentane (6.55 g.) in dry chloroform (30 ml.) was added to a solution of triphenylphosphine (8.7 g.) in dry chloroform (30 ml.) and heated at reflux in an atmosphere of dry nitrogen for 4 hours. The solution was then evaporated under reduced pressure and the residual oil was triturated with a mixture of light petroleum ether (b.p. 40°-60° C.) and diethyl ether, to give a white solid. Recrystallisation of this material from a mixture of dichloromethane and diethyl ether gave 4-phenylbutanoylmethyltriphenylphosphonium chloride (11.2 g.) in the form of a white crystalline solid. m.p. 192-195° C. (Elemental analysis: C, 76.0; H, 6.2%; C29H28ClOP requires: C, 75.9; H, 6.2%; νmax 1110 cm-1, 1445 cm-1, 1490 cm-1, 1695 cm-1).