Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([CH2:21]O)=[CH:19][N:18]=[C:17]3[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[CH:25][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(=O)[NH:38]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O.NN>O1CCCC1>[NH2:38][CH2:21][C:20]1[CH:19]=[N:18][C:17]2[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[CH:24]=[CH:25][C:16]=2[C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CO)cnc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(CN)cnc21
Yield: 24.2 %

Procedure:
{4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl}methanol (212 mg, 0.454 mmol), phthalimide (134 mg, 0.909 mmol) and triphenylphosphine (238 mg, 0.909 mmol) in tetrahydrofuran was stirred at room temperature for 30 minutes and with diisopropyl azodicarboxylate (184 mg, 0.909 mmol) for one day. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with ethyl acetate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1/(v/v)) to remove triphenylphosphine oxide. The residue was dissolved in ethanol (10 mL) and stirred with hydrazine monohydrate (1.00 mL, 11.6 mmol) at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and, after addition of water, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound (51.1 mg, yield 24%).
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[N:26](CC4C=CC(OC)=CC=4)[N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])[C:5]=1[OH:46])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:40][CH2:41][C:42]([F:43])([F:45])[F:44])[C:5]=1[OH:46])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cccc(OCCCOc3ccc(C(C)=O)c(O)c3CCC(F)(F)F)c2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)c1ccc(OCCCOc2cccc(NC(=O)c3nnn[nH]3)c2C#N)c(CCC(F)(F)F)c1O

Procedure:
A solution of 7.05 g of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-2-cyano-phenyl}}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 150 ml of trifluoroacetic acid and 15 ml of anisole is refluxed for 30 minutes. The reaction mixture is concentrated under reduced pressure, about 200 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-2-cyano-phenyl}}-1H-tetrazole-5-carboxamide thus obtained of melting point 206°-208°, is dissolved hot in 50 ml of acetone, and the calculated amount of triethanolamine in 30 ml of acetone is added. After addition of ether, crystallisation starts. The triethanolammonium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)phenoxy]-propoxy}-2-cyano-phenyl}}-1H-tetrazole-5-carboxamide is thus obtained.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]2([C:27]([O:29][CH3:30])=[O:28])[O:26][C:24](=[O:25])[CH2:23][CH2:22]2)=[CH:12]1.C(C1C=CC(S([N:43]=[N+:44]=[N-:45])(=O)=O)=C(C(C)C)C=1C(C)C)(C)C.C(O)(=O)C>C1COCC1>[N:43]([CH:23]1[CH2:22][C:21]([CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][CH:12]=2)([C:27]([O:29][CH3:30])=[O:28])[O:26][C:24]1=[O:25])=[N+:44]=[N-:45]
Reactant: CC(C)c1ccc(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1C(C)C
Reactant: COC(=O)C1(Cc2c[nH]c3ccccc23)CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2c[nH]c3ccccc23)CC(N=[N+]=[N-])C(=O)O1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63.9 %

Procedure:
To a solution of LHMDS (1.0 M, 24.2 mL, 24.2 mmol) in THF was added indole lactone 11 (3.00 g, 11 mmol) in freshly distilled THF (33 mL) at -78° C. The light yellow solution was stirred for 40 min, and triisopropylbenzenesulfonyl azide (3.40 g, 11 mmol) in 33 mL dry THF was added at -78° C. via syringe. The reaction mixture was stirred for 20 min before quenching with acetic acid (49.5 mmol, 2.83 mL). The reaction mixture was allowed to warm to room temperature over 30 min before being diluted with saturated NH4C1 solution. This solution was stirred for 5 min and extracted with EtOAc (2×75 mL). The combined organic layers were dried (MgSO4), and the solvent was removed under reduced pressure. The crude oil was flash chromatographed on silica gel (1:2, EtOAc-hexanes eluant) to afford 2.21 g (64%) of pure azido lactone 12 as a mixture of diastereomers (3:2; SS/RR:SR/RS). A sample was crystallized from ethyl acetate/hexanes: mp. 110-112° C., SS/RR recemate; 1H NMR (300 MHz, CDC13) δ 2.19 (dd, 1H, J=14.0, 7.3 Hz), 2.63 (dd, 1H, J=14.0, 9.3 Hz), 3.34 (dd, 1H, J=9.0, 2.6 Hz), 3.39 (ABq, 2H, J=15.3 Hz), 3.84 (s, 3H), 7.10 (d, J=2.4 Hz), 7.14-7.24 ((m, 2H), 7.37 (d, 1H, J=8.3 Hz), 7.63 (d, 1H, J=7.6 Hz), 8.32 (brs 1H, D2O Exchangeable).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.C(N1CC(OC2C=CC=C(C(F)(F)F)C=2)C1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:44][N:45]=[C:46]=[S:47]>C(Cl)Cl>[CH3:44][NH:45][C:46]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[S:47]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: CN=C=S
Agent: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Solvent: ClCCl
Product: CNC(=S)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Crude 3-[3-(trifluoromethyl)phenoxy]azetidine from catalytic debenzylation of 26.0 g (0.078 mole) of 1-benzhydryl-3-[3-(trifluoromethyl)phenoxy]azetidine was dissolved in 100 ml of methylene chloride and treated dropwise under a nitrogen atmosphere with a solution of 5.0 g (0.0678 mole) of of methylisothiocyanate in 15 ml of methylene chloride. The reaction mixture was stirred for 16 hr at ambient temperature and let stand over the weekend. The solution was filtered through a celite filter pad to remove a fine crystalline precipitate and the filtrate was evaporated under reduced pressure. The residual oil was crystallized from isopropyl ether to give 12.6 g of product, m.p. 79°-86° C. A 5.0 g sample was recrystallized from isopropyl ether (charcoal) to give 3.2 g, m.p. 89°-93° C., which was shown by TLC on silica gel (10% methanol-toluene) to be contaminated by a lower Rf material. The filtrate was evaporated under reduced pressure, combined with the 3.2 g of solid and dissolved in 100 ml of methylene chloride. The solution was stirred with 25 g of silica gel for 0.5 hr and filtered through a sintered glass filter. The silica gel was washed with a small volume of methylene chloride and the filtrate evaporated under reduced pressure. The residual solid was recrystallized from isopropyl ether to give 1.3 g of pure product, m.p. 96°-98° C.
Reaction SMILES: [NH2:1][C:2](=[C:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[NH:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:21](OCC)(OCC)OCC>C1(C)C=CC=CC=1>[CH3:15][N:13]1[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[N:9]2[CH:21]=[N:1][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]2[CH2:14]1
Reactant: CCOC(=O)C(N)=C1CN(C)C(=O)c2ccccc2N1
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2

Procedure:
1.10 g of ethyl α-amino-1,3,4,5-tetrahydro-4-methyl-5-oxo-2H-1,4-benzodiazepin-2-ylidene-acetate are dissolved in 15 ml of toluene and treated with 1.0 ml of triethyl orthoformate. The mixture is heated to reflux for 50 minutes, subsequently cooled and evaporated in vacuo. The crystalline residue is suspended in 25 ml of ethyl acetate, filtered off and dried. There is obtained ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate of melting point 165° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:13][NH2:14].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:20]=O.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:11])([F:12])[F:10])=[CH:4][C:3]=1[CH2:13][NH:14][CH2:20][C:19]1[CH:22]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:24]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc(Br)c(CN)cc1C(F)(F)F
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
A mixture of (2-bromo-4-methyl-5-(trifluoromethyl) phenyl) methanamine (189 mg, 0.705 mmol) and 3,5 bistrifluoromethyl benzaldehyde (170 mg, 0.705 mmol) in anhydrous toluene (10 mL) was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (25 mL). Sodium triacetoxyborohyride (373.5 mg, 1.76 mmol) was added and the mixture was stirred for 18 hours at room temperature. The mixture was poured into a mixture of saturated NaHCO3 (50 mL) and ethyl acetate (50 mL) and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried with anhydrous sodium sulfate, filtered and concentrated to give the title compound (98.4%). 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 2H) 7.76(s, 1H) 7.58(s, 1H) 7.41 (s, 1H) 3.92(s, 2H) 3.89(s, 2H) 2.44(s, 3H)
Reaction SMILES: CN(C)C=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[C:26](I)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Sn](CCCC)(CCCC)[C:40]1[S:41][CH:42]=[CH:43][N:44]=1)CCC>[Cu]=O.O>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[C:26]([C:40]4[S:41][CH:42]=[CH:43][N:44]=4)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc2c(Oc3ccc(C)nc3I)ccnc2cc1OCc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: O=[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)nc3-c3nccs3)ccnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
N,N-Dimethylformamide (2 ml) was added to 7-benzyloxy-4-(2-iodo-6-methyl-pyridin-3-yloxy)-6-methoxyquinoline (100 mg), tetrakistriphenylphosphine palladium (23 mg), tri-n-butyl-(thiazol-2-yl)-tin (113 mg), and copper(II) oxide (32 mg) under an argon atmosphere, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (43 mg, yield 46%).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[O:33][C:34](=[O:38])[O:35][C:36]=1[CH3:37].CCOC(C)=O>CN(C=O)C>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:31][C:32]2[O:33][C:34](=[O:38])[O:35][C:36]=2[CH3:37])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: Cc1oc(=O)oc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCc2oc(=O)oc2C)o1
Reaction time: 14 h

Procedure:
To a stirred, room temperature solution of 5-(tetradecyloxy)furan-2-carboxylic acid (0.228 g, 0.70 mmol) in DMF (4 mL) was added potassium carbonate (0.146 g, 1.05 mmol) and 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (0.160 g, 0.84 mmol). The reaction vessel was capped and stirring was continued for 14 hrs at which time TLC ((20% EtOAc in Hexanes Rf=0.10 (SM) and 0.40 (Prod)) indicated complete consumption of the starting material. The reaction was quenched by the addition of water (5 mL), brine (5 mL) and EtOAc (30 mL). The biphasic mixture was transferred to a separatory funnel and the organic phase was extracted 3 times with brine (3×10 mL). The organic phase was dried and concentrated to give a colourless oil. The resulting crude material was purified by flash chromatography eluting with 5-20% EtOAc in hexanes to yield a colourless syrup that solidified on standing. 1H NMR (400 MHz, DMSO-d6) δ: 7.2 (d, 1H), 5.6 (d, 1H), 5.1 (s, 2H), 4.1 (t, 2H), 2.18 (s, 3H), 1.6-1.8 (m, 2H), 1.3-1.4 (m, 2H), 1.23 (d, 6H), 1.2 (s, 20H), 0.85 (t, 3H).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]4[C:35](=[O:47])[N:36]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:37]([CH3:40])[C:38]=4[CH3:39])=[O:33])=[N:29][CH:30]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]6[C:35](=[O:47])[N:36]([C:41]7[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=7)[N:37]([CH3:40])[C:38]=6[CH3:39])=[O:33])=[N:29][CH:30]=5)=[CH:19][CH:20]=[N:21]4)=[CH:16][CH:15]=3)[CH2:5][O:4]2)[CH2:1]1
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC5COC6(CC6)C5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C

Procedure:
The title compound was prepared according to the procedure described in Example 6 by using (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (220 mg, 1.14 mmol), N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (300 mg, 0.64 mmol), and cesium carbonate (450 mg, 2.4 mmol, Aladdin) in DMA (6 mL). The title compound was purified with a silica gel column chromatography (EtOAc) to give a white solid (140 mg, 39%).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].I[CH:28]([CH3:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:28]([N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:3]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]1=[O:1])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (125 mg, 0.352 mmol) in dry DMF (3 mL) under nitrogen was added 2-iodopropane (90 mg, 0.529 mmol) and powdered cesium carbonate (172 mg, 0.529 mmol). The mixture was stirred overnight at ambient temperature then diluted with water and extracted with ethyl acetate three times. The residue from the organic extract was purified by flash chromatography on silica gel eluting with 5:1 (v/v) hexane:ethyl acetate to afford the title compound (82 mg, 58%) as a white solid. TLC Rf=0.35 (5:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.28 (d, 6H, J=7.0 Hz), 1.37 (s, 9H), 4.81 (m, 2H), 4.99 (m, 1H), 5.58 (d, 1H, J=7.0 Hz), 7.19-7.48 (m, 9H). MS APCI, m/z=397 (M+1). LC/MS: 2.75 min.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH:26][C:27]([NH2:29])=[S:28])([CH3:25])([CH3:24])[CH3:23]>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:29]=[C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])[S:28][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(N)=S
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Product: CC(C)(C)Nc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.406 g, 1.09 mmol) in ethanol (11 mL) in a 25 mL round bottom flask was added N-(t-butyl)thiourea (0.144 g, 1.09 mmol) and the solution heated to reflux (14 hours). The reaction was cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), sodium carbonate solution (10%, 3×20 mL), dried over sodium sulfate, filtered and concentrated. The crude product was recrystallized from methylene chloride and isooctane yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-tert-butylaminothiazole (0.226 g, 51%) as a yellow crystalline plates: mp 250°-253° C.; 1HNMR (DMSO d6) 400 mHz 7.78 (d, J=8.32 Hz, 2 H), 7.70 (s, 1 H), 7.46-7.35 (m, 4 H), 7.15 (t, J=9.05 Hz, 2 H), 3.19 (s, 3 H), 1.40 (s, 9 H); MS m/z 405 (M+H). HRMS Δ=4.78 mmu.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:16]([F:20])=[C:17]([F:19])[F:18]>C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Zn]>[F:20][C:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:16]([F:20])=[C:17]([F:19])[F:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[C:17]([F:19])[F:18]
Reactant: FC(F)=C(F)I
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)=C(F)c1ccc(-c2ccc(C(F)=C(F)F)cc2)cc1
Reaction time: 24 h

Procedure:
After 24 hours, a GC/MS of the mixture allows identification of all the reaction components. After 72 hours, the reaction seems to stop proceeding while excess diiodobiphenyl remains: another batch of iodotrifluoroethylene (25.0 g, 0.12 mole) is reacted with zinc in THF and added to the reaction mixture along with 1.0 g of palladium tetrakis(triphenylphosphine) catalyst. The reaction is allowed to stir an additional 12 hours, then is removed and evaporated to dryness under high vacuum on a rotary evaporator. Residue from evaporation is added to a 3 fold volumetric excess of water. A heavy precipitate is formed which is filtered and air dried on a vacuum funnel. The precipitate is dissolved in THF and filtered. Resulting filtrate is coated on silica gel by adding the silica gel to the THF solution and evaporating to dryness. This silica gel is then eluted on a short silica gel column using hexane as eluent to remove the colored material from the product. A fine white crystalline material remains after evaporation of the hexane. This crystalline material is then chromatographed again carefully on an alumina column using hexane as an eluent. The first band to elute from the column is the desired monomer product CF2 =CF--Ph--Ph--CF=CF2. A total of 44.2 g of product is recovered (58.7% yield).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:11]([C:26](=[O:31])N(OC)C)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li][CH3:33]>C1COCC1.CCOCC>[C:26]([C@@H:11]1[CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:14][CH2:13][C@@H:12]1[NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:31])[CH3:33]
Reactant: [Li]C
Reactant: CON(C)C(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: -22 °C
Reaction time: 0.67 h

Procedure:
Benzyl (1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-(methoxy(methyl)carbamoyl)cyclohexylcarbamate (4.0 g) was dissolved in THF (40 mL) and cooled to −22° C. prior to the addition of 1.6 M MeLi (14.5 mL) in Et2O. After 40 min at −22° C., the reaction was quenched with 0.5 N HCl solution and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to afford benzyl (1S,2R,4R)-2-acetyl-4-(tert-butyldimethylsilyloxy)cyclohexylcarbamate (5.7 g). MS found: (M+H)+=406.3.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>C1C=CC=CC=1>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([Cl:23])=[O:9]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-nitrobenzoic acid (1.5 g) and phosphorus pentachloride (1.1 g) in benzene (10 ml) was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure to give crystals of 3-(2,4-difluorophenoxy)-4-nitrobenzoyl chloride. A solution of the above chloride in dichloromethane (5 ml) was added to a mixture of methoxylamine hydrochloride (0.85 g) and sodium bicarbonate (2.2 g) in water (10 ml) and dichloromethane (5 ml) at to 5° C. After stirring for 1 hour at the same temperature, the mixture was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was crystallized from isopropyl ether to give pale brown crystals of N-methoxy-3-(2,4-difluorophenoxy)-4-nitrobenzamide (1.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].[CH:19](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:20].CN(C)CCN>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([CH:19]=[O:20])[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=COc1c(F)c(F)c(F)c(F)c1F
Agent: CN(C)CCN
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (38.22 g, prepared according to the procedure described in WO 96/31478 Step B page 94) in dry dichloromethane (400 mL) was treated with pentafluorophenyl formate (43.32 g, prepared according to the procedure of Kisfaludy and Otvos, Synthesis, 1987, 510). After stirring at room temperature overnight the reaction mixture was treated with N,N-dimethylethylenediamine (32.5 mL) and stirring continued for a further 1.5 hours. The reaction mixture was then washed with 1 M hydrochloric acid (400 mL), then a saturated solution of sodium hydrogen carbonate (400 mL), then water (400 mL), dried over sodium sulfate and then evaporated. The residue was triturated with a mixture of diethyl ether and pentane to give the title compound (27.21 g) as an off white solid, MS: 309 [MNa]+.