Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:28]=[C:27](Br)[CH:26]=2)=[CH:17][C:16]=1[CH3:41]>CN(C=O)C.C(N(CC)CC)C.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.[Cu]I>[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:28]=[C:27]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:26]=2)=[CH:17][C:16]=1[CH3:41]
Reactant: C#Cc1ccc(Cl)cc1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(Cl)cc3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-chloro-4-ethynyl-benzene (240 mg, 1.76 mmol), (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (106 mg, 0.207 mmol, example 6), Pd(PPh3)4 (23 mg, 0.021 mmol), CuI (11 mg, 0.058 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 120 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/THF mixtures to give (4-{3-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 63 mg (54%) yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]12[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH:10]1[CH2:9][O:8][NH:7]2.[C:21]([N:29]=[C:30]=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:21]([NH:29][C:30]([N:7]1[C:6]2([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH:10]2[CH2:9][O:8]1)=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2cccs2)C1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CON(C(=S)NC(=O)c3ccccc3)C2(c2cccs2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 6a-(2-thienyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (7.16 g, 24.2 mmol) in THF (161 mL) is added benzoyl isothiocyanate (3.94 g, 24.2 mmol). The reaction is stirred for 1 hour at room temperature, concentrated under reduced pressure, and triturated with hexane/ethyl acetate (1:1) to give the title compound. ES/MS (m/e): 459 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[CH2:24][C:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:28]=2[O:27][CH:26]=1.Cl>CN(C=O)C.O>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][O:10][CH2:24][C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:28]=3[O:27][CH:26]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c(CCl)coc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c(COCCC(c3ccccc3)c3ccccc3)coc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
3,3-diphenyl-1-propanol (550 mg) was dissolved in DMF (5 ml) and the obtained solution was cooled to 0° C. To this solution, potassium t-butoxide (291 mg) was added and the solution was stirred at 0° C. for 10 minutes. To the reaction solution, 3-chloromethyl-7-methoxybenzofuran (339 mg) solution in DMF (4 ml) was added dropwise and the resulting solution was stirred at 0° C. for 30 minutes. After neutralizing the reaction solution with 1N hydrochloric acid, the solution was poured into water layer (50 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=9/1) using silica gel to obtain the desired compound (547 mg, yield: 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:22]([OH:39])[CH:23]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:35]([O:34][C:32]([NH:31][CH:23]([CH:22]([OH:39])[CH:21]([NH:20][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)CCCCCNC(=O)OCc1ccccc1

Procedure:
N-(6-(Benzyloxycarbonylamino)hexanoic acid was coupled to the resultant compound of Example 11 using the mixed anhydride procedure of Example 54A to give the desired compound after silica gel chromatography using 75% ethyl acetate in chloroform.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].CCCCCC>C(#N)C>[Cl:8][C:7]1[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Product: CN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A mixture of 2,3-dichloropyrazine (5.0 g, 34 mmol), N-methylpiperazine (5.1 g, 51 mmol) and potassium carbonate (7.0 g, 51 mmol) in acetonitrile (100 mL) was stirred at ambient temperature for 2 h. Addition of hexane, followed by filtration and concentration of the filtrate gave 7.3 g of the crude product as an orange liquid. Purification by filtration through silica using heptane/EtOAc (3:1) followed by EtOAc/acetone (1:1) gave 4.1 g (57%) of the title compound as a yellow oil which solidified upon cooling. HPLC purity: 100%. MS m/z 213 (M+H)+. *Reported in WO 00/76984, Example 169, Step 1.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2[CH2:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([Li:18])CCC>CCCCCC>[F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2([Li:18])[CH:11]=[CH:10][CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CC2=CC=CC2)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]C1(Cc2ccc(F)cc2)C=CC=C1
Temperature: 0 °C
Yield: 90 %

Procedure:
7 g of 4-fluorobenzylcyclopentadiene (40 mmoles) and 50 ml of hexane are charged, in an argon atmosphere, into a tailed test-tube equipped with magnetic stirring. The solution is cooled to 0° C. and 16 ml of a 2.4M solution of butyllithium in hexane are added. The temperature is then allowed to rise to room temperature and the mixture is left under stirring for a night. A precipitate is formed which is filtered, washed twice with 10 ml of hexane and finally dried. 6.5 g of the desired salt are obtained with a yield of 90%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][NH:25][C:24]4=[O:29])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:30]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][N:25]([CH3:30])[C:24]4=[O:29])=[CH:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCNC4=O)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCN(C)C4=O)cc3)CC2)c(C)c1

Procedure:
Using 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}tetrahydropyrimidin-2-one (78 mg) described in Example 446 and methyl iodide (14 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (49 mg) was obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13](=O)[CH:14](Br)[CH3:15])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.Cl.C(OCC)(=O)C>[CH2:11]([O:10][C:8]([C:6]1[N:7]=[C:3]([NH:2][CH3:1])[S:4][C:5]=1[C:13]1[N:25]=[C:22]2[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]2[C:14]=1[CH3:15])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1nc(NC)sc1C(=O)C(C)Br
Reactant: Cc1ccc(N)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(NC)sc1-c1nc2ccc(C)cn2c1C
Yield: 57.4 %

Procedure:
A solution of ethyl 2-methylamino-5-(2-bromopropionyl)-4-thiazolecarboxylate (2.2 g) and 5-methyl-2-aminopyridine (2.6 g) in acetonitrile (80 ml) was refluxed for 2 hours. The reaction mixture was evaporated to afford a residue, which was dissolved in a mixture of 5% hydrochloric acid and ethyl acetate. The separated aqueous solution was adjusted to pH 8.0 with 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diethyl ether to give 2-(4-ethoxycarbonyl-2-methylaminothiazol-5-yl)-3,6-dimethylimidazo[1,2-a]pyridine (1.3 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[Zn](CC)[CH2:14][CH3:15]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:14]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])[CH3:15]
Reactant: COc1cc(C(=O)O)ccc1Br
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCc1ccc(C(=O)O)cc1OC
Temperature: 70 °C

Procedure:
A mixture of 4-bromo-3-methoxy-benzoic acid (2.49 g, 10.9 mmol) and Pd(dppf)Cl2 (158 mg, 0.216 mmol) were stirred in dioxane (25 mL) and Et2Zn (22 mL, 1M in hexanes, 22 mmol) was added. The reaction mixture was heated at 70° C. for 1 h. The mixture was cooled to room temperature and was quenched with MeOH (1.1 mL). The solution was diluted with ethyl acetate (20 mL) and was washed with 1N HCl (10 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated to dryness to give 4-ethyl-3-methoxybenzoic acid. ESI-MS m/z calc. 180.1. found 179.1 (M−1)−; Retention time: 1.77 minutes (3 min run).
Reaction SMILES: N1C=CC=CC=1.[C:7]([Br:11])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([CH2:44][CH:45]([CH2:48][CH:49]2[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]2)CO)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(OCC)C>[C:58]([O:57][C:55]([N:52]1[CH2:51][CH2:50][CH:49]([CH2:48][CH:45]([CH2:7][Br:11])[CH2:44][CH:41]2[CH2:42][CH2:43][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:39][CH2:40]2)[CH2:54][CH2:53]1)=[O:56])([CH3:61])([CH3:60])[CH3:59]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CC(CO)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CC(CBr)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
After pyridine (0.090 ml; 1.1 mmol), carbon tetrabromide (716 mg; 2.2 mmol) and triphenylphosphine (567 mg; 2.2 mmol) were added to a solution in diethyl ether (5 ml) of 2,2-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]ethyl alcohol (476 mg; 1.1 mmol) synthesized by the above process under ice cooling, the ice bath was removed, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 465 mg (yield: 86%) of 1,3-bis(1-tert-butoxycarbonyl-4-piperidinyl)-2-(bromomethyl)propane as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16][O:17][CH3:18])[C:7]=2[CH:6]([CH2:5][C:4]([OH:20])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(COC)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of (1,6-dihydroxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.20 g, 0.67 mmol) in THF (6 mL) and H2O (2 mL) was added LiOH (0.130 g) at 0° C. The resulting mixture was stirred at room temperature for 2 hours then cooled to 0° C. and acidified to pH 3 with 6N HCl. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give (1,6-dihydroxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid (0.120 g, 71%). 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.42 (s, 1H), 9.10 (s, 1H), 6.99 (s, 1H), 6.82 (s, 1H), 5.46 (m, 1H), 3.28 (s, 3H), 3.03 (m, 1H), 2.02 (m, 1H). MS (ESI) m/z: 251 [M−1]−. HPLC purity: 97.87% (220 nm), 98.47% (Maxplot).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CCC(Oc1ccc(O)cc1)C(=O)NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(Oc1ccc(OCc2cccc(F)c2)cc1)C(=O)NC

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide with 3-fluoro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(3-fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide as a white solid; MS: m/e=318 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.Cl[CH2:11][O:12][CH3:13]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:11][O:12][CH3:13])[CH:7]=1
Reactant: COCCl
Reactant: Oc1cc(Br)ccc1F
Product: COCOc1cc(Br)ccc1F

Procedure:
Starting from commercially available 5-bromo-2-fluoro-phenol and 1-chloro-1-methoxy-methane prepared according to literature (Stadlwieser, J. Synthesis 1985, 490) the title compound is obtained as colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])=[CH:9][CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17][C@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:44])=[O:5])=[CH:12][CH:11]=2)=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (255 mg, 0.397 mmol) was treated with 50% TFA/methylene chloride (10 mL) overnight. Removal of solvent and treating the residue with acetonitrile and water gave a white solid after filtration and drying. 236 mg.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[H-].[Na+].[CH2:10]([O:12][C:13](=[O:16])[CH2:14][CH3:15])[CH3:11]>C1COCC1>[CH2:10]([O:12][C:13](=[O:16])[C@@H:14]([N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7])[CH3:15])[CH3:11]
Reactant: O=c1cccc[nH]1
Reactant: CCOC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)n1ccccc1=O
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A stirred solution of 1H-Pyridin-2-one (500 mg, 5.26 mmol) in anhydrous THF (50 ml) at room temperature was treated portionwise with 60% NaH (231 mg, 5.78 mmol). The reaction mixture was kept for 10 min then added over 5 min to a solution of (R)-2-trifluoromethanesulfonyloxy)-propionic acid ethyl ester (1315 mg, 5.26 mmol) in anhydrous THF (2.5 ml) at room temperature. The resulting mixture was stirred for 2 h, then concentrated. The residue was dissolved in ethyl acetate, and the resulting solution was washed with ice cold dilute HCl. The organic layer was removed and the aqueous layer re-extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (20% up to 80% ethyl acetate in hexane) to afford the title compound as a yellow oil (480 mg, 46%): [α]27D=−56.4° (c=0.275, CH2Cl2); 1H NMR (400 MHz CDCl3) δ 1.3 (3H, t), 1.65 (3H, d), 4.2 (2H, q), 5.6 (1H, q), 6.2 (1H, t), 6.4 (1H, d), 7.2-7.3 (2H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:6][C@@H:5]2[C:7]([CH2:11][O:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1.N1C=CC=CC=1.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:40](=[O:41])([O:42][CH3:43])[O:10][C@@H:9]1[C@H:4]2[C@H:5]([O:6][C:2]([CH3:32])([CH3:1])[O:3]2)[C:7]([CH2:11][O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C[C@@H]2O
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)O[C@H]1C=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 0 °C

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1-1) (1.44 g, 3.36 mmol, 1.0 equiv) as dissolved in DCM (11.2 mL). Pyridine (0.489 mL, 6.05 mmol, 1.8 equiv) was added and the mixture stirred at 0° C. After 1 hour DMAP (164 mg, 1.34 mmol, 0.4 equiv) was added followed by methyl chloroformate (1.04 mL, 13.44 mmol, 4 equiv). The resulting mixture was stirred 12 h, and the temperature was allowed to slowly increase to 23° C. The reaction was partitioned between DCM and water, and the organic layer was separated and washed with water, dried (MgSO4), and concentrated to yield (3aS,4S,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methyl carbonate (1-2) as a white foam. 1H NMR (00 MHz, CDCl3) δ 7.21-7.47 (m, 15H), 6.03 (d, 1H, J=3.0 Hz), 5.32 (brm, 1H), 4.93 (t, 1H, J=9 Hz), 4.85 (d, 1H, J=10 Hz), 3.96 (d, 1H, J=24.5 Hz), 3.83 (s, 3H), 3.67 (d, 1H, J=24.5 Hz), 1.36 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[C:16](Cl)(=[O:18])[CH3:17].Cl>ClCCl>[C:16]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([Cl:5])=[CH:7][CH:8]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Clc1cccc2ccccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
To aluminum chloride (54.5 g) and dichloromethane (250 ml) was dropwise added 1-chloronaphthalene (47 ml) under ice-cooling over 10 minutes. The obtained reaction mixture was stirred for 20 minutes and acetyl chloride (25 ml) was dropwise added over 40 minutes. The reaction mixture was stirred at room temperature for 4 hours and with refluxing for 20 minutes. The reaction mixture was cooled to room temperature, poured into 1N hydrochloric acid (300 ml), extracted with dichloromethane, washed with saturated brine and dried over magnesium sulfate. The solvent was distilled away and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to give 37.3 g of a red-brown liquid (yield 55%).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([C:9]([OH:11])=O)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([N:19]2[N:20]=[CH:2][C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:9]2=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1C(Br)Br
Reactant: NNc1ccccc1
Product: O=c1c2ccccc2cnn1-c1ccccc1
Yield: 30.1 %

Procedure:
α,α-dibromo-o-toluic acid (29.4 g) and phenylhydrazine (34.6 g) were allowed to react as in Example 4. There was obtaoined 6.7 g (yield: 30%) of 2-phenyl-1-phthalazinone having a melting poin of 104°-105° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>>[CH2:19]([O:18][C:16]([NH:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
A 15.0 g sample of D-phenylalanine was dissolved in 45 ml of aqueous solution containing 7.26 g of 50% sodium hydroxide. This solution was stirred at 0°-10° C. as 16.3 g of benzyl chloroformate was added rapidly in portions. The resulting reaction was mildly exothermic, and shortly after addition, solids precipitated. An additional 45 ml of water and 3.63 g of 50% sodium hydroxide were added, causing most of the solids to redissolve. The reaction mixture was stirred for 20 minutes and then acidified with 6 N hydrochloric acid. The resulting solids were filtered, washed with water and then with hexane, and dried by suction and then under vacuum to give 47 g of white solids. These solids dissolved in ether were washed twice with 1 N hydrochloric acid and then with water, dried over MgSO4 and stripped to 35° C. at 2.5 mm Hg to give 27.7 g of the desired product as a colorless oil.