Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]C(N3C4C=CC=CC=4N=N3)(C3C=CC=CC=3)CC3C=CC(CP(OF)(OF)=O)=CC=3)=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:6])[O:4][CH3:5].[Br:52][Si](C)(C)C>C(Cl)Cl>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][Br:52])=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:6])[O:4][CH3:5]
Reactant: C[Si](C)(C)Br
Reactant: COc1ccc(-c2ccc(CC(Cc3ccc(CP(=O)(OF)OF)cc3)(c3ccccc3)n3nnc4ccccc43)cc2)cc1P(=O)(OC)OC
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CBr)cc2)cc1P(=O)(OC)OC

Procedure:
A solution of 4′-{2-benzotriazol-1-yl-3-[4-(difluorophosphonomethy)phenyl]-2-phenylpropyl}-4-methoxybiphenyl-3-yl-phosphonic acid dimethyl ester (330 mg, 0.39 mmol) and bromotrimethylsilane (1 mL) in CH2Cl2 (5 mL) was stirred at r.t. overnight. Volatile mateials were removed in vacuo. The residue was co-evaporated with ˜90% aqueous EtOH (3×) to give the title compound as a light brown foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[N:25])[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[N:25])[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:18][C:13]=2[NH:12][C:11](=[S:36])[CH2:10][N:9]=1
Reactant: COCCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COCCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2

Procedure:
5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxyethoxy-2H-1,4-benzodiazepin-2-thione (IIm) was prepared by reacting 0.00081 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxyethoxy-2H-1,4-benzodiazepin-2-one (Im) with Lawesson's reagent in a manner analogous to Example 38. MH+/Z=386.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](O)=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:10]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=1
Reactant: COc1ccc2c(O)cc(-c3ccccn3)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)cc(-c3ccccn3)nc2c1

Procedure:
A mixture of 7-Methoxy-2-pyridin-2-yl-quinolin-4-ol (2.2 g, 8.71 mmol) in POCl3 (92 mL) was refluxed for 3 h and then removed the solvent in vacuo. Ice water was added to the residue, adjusted the pH>10 with 1.0 N NaOH, and extrated with EtOAc (2×). The combined extract was washed with water, brine, dried (MgSO4), removed solvent to supply the product as a yellow solid (89%, 2.1 g): DMSO-D6) δ ppm 3.97 (s, 3H), 7.40 (dd, J=9.16, 2.44 Hz, 1H), 7.53 (m, 1H), 8.01 (m, 1H), 8.09 (d, J=9.16 Hz, 1H), 8.46 (s, 1H), 8.56 (d, J=7.93 Hz, 1H), 8.74 (d, J=3.97 Hz, 1H). LC-MS (retention time: 1.50, Method D), MS m/z 271 (M++1).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([N:19]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:20][C:21]([O:23]CC)=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].[K+]>>[C:1]([NH:11][C@H:12]([C:17]([N:19]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:20][C:21]([OH:23])=[O:22])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)CC)c1cccnc1
Agent: [K+]
Agent: [OH-]
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)c1cccnc1

Procedure:
An ethanolic solution of ethyl N-carbobenzyloxy-L-isoleucyl-N-(3-pyridyl)glycinate was treated with potassium hydroxide to yield N-carbobenzyloxy-L-isoleucyl-N-(3-pyridyl)glycine.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][N:4]=1.[SH:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:9][C:8]1[C:3]([CH2:2][S:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:10][CH2:11][C:12]([F:15])([F:14])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A mixture of 6.63 g of 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine(30 mmol), 4.5 g of 2-mercaptobenzimidazol(30 mmol) and 8.67 g of triphenyl phosphine(33 mmol) was dissolved in 100 ml of tetrahydrofuran, 5.75 g of diethyl azodicarboxylate(DEAD)(33 mmol) dissolved in 30 ml of tetrahydrofuran was added dropwise thereto at room temperature, and stirred for 1 hour. The reaction mixture was concentrated under a reduced pressure, the resulting residue was combined with looml of ethylacetate, and extracted twice with 50 ml portions of 1N—HCl. The aqueous layer was then washed with 50 ml of diethylether; neutralized with 1N—NaOH to adjust the pH to 7. The resulting precipitates were filtrated, washed with water, and dried, to obtain 10.06 g of the title compound as a white solid(yield: 95%).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[C:11](=[O:12])[CH:10]=[C:9]([O:13]CC(C)C)[CH2:8]2)=[CH:4][CH:3]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:11](=[O:12])[CH:10]=[C:9]([OH:13])[CH2:8]2)=[CH:18][CH:19]=1
Reactant: CC(C)COC1=CC(=O)C(Cc2ccc(Br)cc2)C1
Solvent: CC(C)=O
Product: O=C1C=C(O)CC1Cc1ccc(Br)cc1
Reaction time: 16 h
Yield: 46 %

Procedure:
To a mixture of 5 (0.110 g, 0.34 mmol) in acetone (4.2 mL) 2 N hydrochloric acid (1.7 mL) was added at rt and the mixture was stirred for 16 h. The reaction mixture was then concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC providing 7 as a white solid (46% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:70])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:67]=[CH:66][C:34]([C:35]([O:37][CH2:38][O:39][C:40]([NH:42][C@@H:43]([CH2:54][CH2:55][C:56]([O:58]CC3C=CC=CC=3)=[O:57])[C:44]([O:46]CC3C=CC=CC=3)=[O:45])=[O:41])=[O:36])=[CH:33][C:32]=2[O:68][CH3:69])=[O:29])[CH:5]=[CH:6][CH:7]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[C:3]([F:70])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:67]=[CH:66][C:34]([C:35]([O:37][CH2:38][O:39][C:40]([NH:42][C@@H:43]([CH2:54][CH2:55][C:56]([OH:58])=[O:57])[C:44]([OH:46])=[O:45])=[O:41])=[O:36])=[CH:33][C:32]=2[O:68][CH3:69])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)OCOC(=O)N[C@@H](CCC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OCOC(=O)N[C@@H](CCC(=O)O)C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 24, a solution of chiral (S)-dibenzyl 2-(((4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)methoxy)carbonylamino)pentanedioate (Example 31) in ethyl acetate was treated with 10% palladium on carbon under 1 atm of hydrogen to give chiral (S)-2-(((4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)methoxy)carbonylamino)-pentanedioic acid as a white solid. MS (ES+) m/z calcd. for C38H39Cl2F2N4O10 [(M+H)+]: 819, found: 819.
Reaction SMILES: C([NH:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([CH3:22])[C:10]=1[CH3:23])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[NH2:8][C:9]1[C:17]2[O:16][C:15]([CH3:18])([CH3:19])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([CH3:22])[C:10]=1[CH3:23]
Reactant: Cc1c(C)c(NCc2ccccc2)c2c(c1C)C(=O)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c(N)c2c(c1C)C(=O)C(C)(C)O2

Procedure:
Using 7-(benzylamino)-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one obtained in Reference Example 53, the title compound was synthesized in the same manner as in Reference Example 30. Yield: quantitative. Melting point: 141-142° C. (ethyl acetate-hexane).
Reaction SMILES: C([NH:4][C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH3:17])[C:10](=[O:18])[N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[NH:7][N:6]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH3:17])[C:10](=[O:18])[N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=2[NH:7][N:6]=1
Reactant: CCCn1c(=O)c2c(NC(C)=O)n[nH]c2n(Cc2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(=O)c2c(N)n[nH]c2n(Cc2ccccc2)c1=O
Yield: 69.7 %

Procedure:
3-Acetylamino-7-benzyl-5-propylpyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (18 g) was refluxed for 5 hours in 80% ethanol (200 ml) dissolving sodium hydroxide (6 g). The reaction mixture was concentrated, and the resulting crystals were suspended in water. To the suspension was added 6N-HCl to obtain colorless crystals (11 g, 70%), m.p. 214°-215° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)C.C(O)CO.[OH-].[K+]>O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1ccc(-c2nc3cccnc3n2CC(=O)O)cc1
Yield: 1.7 %

Procedure:
A mixture of N-[3-[(4-methoxybenzoyl)amino]-2-pyridinyl]glycine ethyl ester (32 g, 0.1 mole) and 167 ml of ethylene glycol was heated at reflux for 11/2 hr. After cooling, potassium hydroxide (8.4 g) in 40 ml of water was added, and the reaction mixture was heated at reflux for 1 hr. The solution was filtered to remove yellow precipitate, the filtrate was diluted with 650 ml of water, and acidified with 3N hydrochloric acid. The solid which formed, was collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 25.5 g (90.1% yield). A 0.5-g sample was recrystallized from ethanol, collected by filtration, washed with cold ethanol and water, and dried under high vacuum at 70° C. over 2 days to give 0.47 g of crystals, mp 260°-63° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:12]=1)[CH2:7][NH:8][C:9](=[O:11])[CH3:10].C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>O1CCCC1.[Br-].[Zn+2].[Br-].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>[F:13][C:5]1[CH:4]=[CH:3][C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:12][C:6]=1[CH2:7][NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)NCc1cc(Br)ccc1F
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1cc(C#C[Si](C)(C)C)ccc1F
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Combine N-(5-bromo-2-fluorobenzyl)acetamide, (prepared as described in PREPARATION 30), (370 mg, 1.50 mmol, zinc(II) bromide (588 mg, 2.25 mmol), and triethylamine (1.00 mL, 7.20 mmol) in tetrahydrofuran (3.7 mL). After stirring for 5 min, add trimethylsilylacetylene (0.53 mL, 3.76 mmol) and tetrakis(triphenylphosphine)palladium (0) (87 mg, 0.075 mmol). Heat the mixture in a sealed tube at 60° C. overnight. Cool the reaction to room temperature and filter through diatomaceous earth. Concentrate the filtrate and purify the residue by silica gel chromatography, eluting with a gradient from 75:25 to 65:35 with a solution of (1:1 hexanes and dichloromethane):ethyl acetate to give the title compound as a yellow oil which crystallizes upon standing (309 mg, 78%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:32][N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:31][CH2:30]1
Reactant: CN1CCN(Cc2nnc3ccc(F)cn23)CC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Intermediate A (200 mg, 1.22 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 146 mg, 3.66 mmol) in DMF (6.0 mL) and stirred for 20 min. Intermediate 14b (305 mg, 1.22 mmol) was added and the reaction heated to 60° C. for 90 min. The mixture was cooled and quenched by dropwise addition of MeOH. The solution was diluted with MeOH and loaded onto an SCX-2 cartridge, washing with MeOH and eluting with 2M NH3 in MeOH. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (240 mg, 0.61 mmol, 50%). LCMS (Method 4): Rt 0.29 min, m/z 393 [MH+].
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22].C1COCC1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)(=O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:20]([C:21]([OH:23])=[O:22])[CH:19]=2)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Yield: 65.5 %

Procedure:
A mixture of 6.6 g of 2,6-di-tert-butyl-1,4-benzoquinone, 4.2 g of m-aminobenzoic acid and 6 drops of acetic acid was stirred with heating at a temperature of 150°-160° C. for 2 hours and then allowed to cool. To the reaction mixture were added about 50 ml of water and then 200 ml of THF. Further a solution of 50 g of Na2S2O4 in 300 ml of water was also added to the red mixture at room temperature, and the mixture was stirred for about 15 minutes until a decoloration took place. Then the mixture was poured into water and extracted with ethyl acetate. The organic layer was treated in the same manner as in Example 1 and the resulting crude product was purified by silica gel column chromatography (eluent: CH2Cl2 -THF=5:1), giving 6.7 g of the title compound. The title compound will be referred to as "Compound 24."
Reaction SMILES: [F:1][C:2]1[C:14]2[C:13](O)([C:15]3[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=3[F:25])[C:12]3[C:7](=[C:8]([F:30])[C:9]([F:29])=[C:10]([F:28])[C:11]=3[F:27])[C:6]=2[C:5]([F:31])=[C:4]([F:32])[C:3]=1[F:33].P(Br)(Br)Br>>[F:1][C:2]1[C:14]2[CH:13]([C:15]3[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=3[F:21])[C:12]3[C:7](=[C:8]([F:30])[C:9]([F:29])=[C:10]([F:28])[C:11]=3[F:27])[C:6]=2[C:5]([F:31])=[C:4]([F:32])[C:3]=1[F:33]
Reactant: OC1(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2-c2c(F)c(F)c(F)c(F)c21
Agent: BrP(Br)Br
Product: Fc1c(F)c(F)c(C2c3c(F)c(F)c(F)c(F)c3-c3c(F)c(F)c(F)c(F)c32)c(F)c1F
Yield: 84 %

Procedure:
4.5 g (0.009 moles) of 1,2,3,4,5,6,7,8-octafluoro-9-hydroxy-9-(pentafluorophenyl)fluorene thus prepared, are added to 25 ml (0.26 moles) of PBr3 and heated to 1100C for 30 minutes in an inert atmosphere. The reaction mass is hydrolyzed in ice, extracted with ethyl ether, the extract is washed with an aqueous solution (10%) of NaHCO3, dried on sodium sulfate, filtered and dried. The residue is purified by chromatography on a silica gel column (eluant: petroleum ether/methylene chloride, 98/2), obtaining, after evaporation of the pure fractions, 3.61 g of white crystalline product corresponding to the desired product having formula (VI) (yield 84%) (characterization by means of 1H-NMR and
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH3:20][O:21][C:22](=[O:27])[C@@H:23]([CH3:26])[NH:24][CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:25][N:24]([C@H:23]([CH3:26])[C:22]([O:21][CH3:20])=[O:27])[C:3](=[O:5])[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH3:1]
Reactant: CC(C(=O)O)c1ccc(OCc2ccccc2)cc1
Reactant: CN[C@H](C)C(=O)OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)N(C)C(=O)C(C)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
To a solution of (R/S)-α-methyl-4-benzyloxyphenylacetic acid 45b (300 mg, 1.17 mmol) and N-methyl-D-alanine methyl ester (200 mg, 1.3 mmol) in DMF (5 mL) cooled in an ice bath was added BOP (531 mg, 1.2 mmol) followed by DIEA (0.7 mL, 4 mmol). The mixture was stirred at room temperature for 5 hours. EtOAc was added and the solution washed with NaHCO3, brine, citric acid and brine, dried (MgSO4), and concentrated. Purification on a silica gel column (40% EtOAc/hexane) gave the amide product (398 mg, 99%) as a solid. MS (CI—NH3): (M+H)+=356.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[CH3:10][C:11](O)([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1.CCCCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([O:8][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)O
Reactant: O=C(O)C1CC(F)(F)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
3,3-difluorocyclobutanecarboxylic acid (1.0 g, 7.3 mmol) was dissolved in DCM (10 mL) and cooled in an ice bath. To the solution was added N,N-dimethylpyridin-4-amine (92 mg, 0.735 mmol) portionwise followed by 2-methylpropan-2-ol (1.1 g, 14.7 mmol) in one portion. A 1M solution of N,N′-dicyclohexylcarbodiimide in DCM (8.1 mL, 8.1 mmol) was added dropwise keeping the temperature below 10° C. The resulting slurry was warmed up to room temperature and stirred for 18 hours. The solid was removed by filtration and the filtrate was washed with 2N aqueous HCl solution (2×15 mL), water (2×15 mL), and then saturated aqueous NaHCO3 solution (2×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 1.49 g of a crude product as a mixture of white solid and yellow oil. To the mixture was added pentane (30 mL) and the mixture as then filtered through a silica gel pad eluting with pentane to give the title compound (896 mg, 63%) as colourless oil.
Reaction SMILES: [OH:1][C:2]([C:7]1[O:11][N:10]=[C:9]([CH3:12])[N:8]=1)([CH3:6])[C:3](=[O:5])[CH3:4].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:4][C:3](=[O:5])[C:2]([OH:1])([C:7]1[O:11][N:10]=[C:9]([CH3:12])[N:8]=1)[CH3:6]
Reactant: CC(=O)C(C)(O)c1nc(C)no1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: Cc1noc(C(C)(O)C(=O)C=CN(C)C)n1

Procedure:
3-Hydroxy-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-butan-2-one (see example 58a) (102 mg, 0.6 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (138 mg) as a yellow oil which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][F:9])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:8]([F:9])[C:7]1[C:2]([F:1])=[C:3]([F:13])[C:4]([F:12])=[C:5]([F:11])[C:6]=1[F:10]
Reactant: FCc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1c(F)c(F)c(C(F)Br)c(F)c1F

Procedure:
A mixture of pentafluorobenzyl fluoride (0.37 g), N-bromosuccinimide (0.36 g) and dry carbon tetrachloride (30 ml) was heated under reflux and irradiated with ultra violet light for a period of 4 hr. The reaction mixture was cooled, the insoluble material was removed by filtration and the solvent was removed by distillation under reduced pressure to give α-bromopentafluorobenzyl fluoride. The product was characterised by p.m.r. spectroscopy. Chemical shift δppm (solvent CDCl3): 7.63 (d, J=48 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:12]1([C:18]([NH:31][CH2:32][C:33]([NH2:36])([CH3:35])[CH3:34])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:12]1([C:18]([NH:31][CH2:32][C:33]([NH:36][C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([F:1])[CH:3]=2)([CH3:34])[CH3:35])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(N)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1cc(Br)c2occc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)Nc1cc(F)cc2ccoc12
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 5.0 gm (23.3 mmol) 5-fluoro-7-bromobenzofuran, 10.3 gm (32.6 mmol) 1-(triphenylmethyl)amino-2-amino-2-methylpropane, 0.87 gm (1.4 mMol) racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 0.64 gm (0.7 mMol) tris(dibenzylideneacetone)dipalladium, and 3.13 gm (32.5 mMol) sodium tert-butoxide in 60 ml anhydrous toluene was degassed and purged with nitrogen. The reaction mixture was heated at reflux for 2 hours and was then allowed to cool to room temperature. The reaction mixture was diluted with 50 mL diethyl ether, filtered through celite, and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 15:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 7.6 gm (70%) of the desired product.