Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([N:14]([CH:24]2[CH2:29][CH2:28][P:27]([O:31][CH3:32])(=[O:30])[CH2:26][CH2:25]2)[C:15]([CH:17]2[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C[C@H]1CC[C@H](C(Cl)=O)CC1>C1COCC1>[CH3:33][C:2]([CH3:1])([CH3:34])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([N:14]([CH:24]2[CH2:29][CH2:28][P:27]([O:31][CH3:32])(=[O:30])[CH2:26][CH2:25]2)[C:15]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH:6]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCP(=O)(OC)CC1
Agent: C[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCP(=O)(OC)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Methyl 5-(3,3-Dimethyl-but-1-ynyl)-3-[(1-methoxy-1-oxo-1λ5phosphinan-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylate (420 mg, 1.1 mmol) was dissolved in 2 mL of THF and cooled to −78° C. with a dry ice-acetone bath. A solution of KHMDS (2.6 mL, 0.5 M in toluene) was added slowly, and the mixture was stirred for 5 min. Trans-4-methylcyclohexanecarbonyl chloride (210 mg, 1.3 mmol) was added dropwise and stirring was continued at −78° C. for a further 5 min. The mixture was then allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl, and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 10% MeOH in EtOAc: Hexanes as eluent and then further purified by HPLC (Gemini column; 5% acetonitrile:water, 5 min; 5-100% acetonitrile:water, 18 min; 100% acetonitrile, 6 min; both solvents containing 0.1% trifluoroacetic acid), resulting in the title compound (37 mg) and recovered starting material (210 mg). MS (m/z): 508.2 [M+H]+; HPLC retention time: 4.949 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C[Si](Cl)(C)C>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of 1,4-diiodobenzene (16.5 g, 50 mmol) in THF (350 mL) at −78° C. was added n-BuLi (2.5 M, 24 mL) over 1 hour. After being stirred for an additional 30 minutes, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (7.8 g, 50 mmol) in THF (30 mL) was added in and the resulting mixture was stirred for 3 hours. To the mixture was added TMSCl (5.4 g, 50 mmol) and the resulting mixture was allowed to warm to rt and stirred at rt for 18 hours. The reaction mixture was neutralized to pH 6.0, and extracted with ethyl acetate (3×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (95/5 to 100/0). The appropriate fractions were combined to give 8-(4-Iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (12 g, 66.6%) with LCMS: 361.2 (M+H+, 100%) and {[8-(4-iodophenyl)-1,4-dioxaspiro[4.5]dec-8-yl]oxy}(trimethyl)silane (6 g, 27%) with LCMS: 433.1 (M+H+, 100%).
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:39]([O:43]C=C)[CH:40](C)C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([C:39](=[O:43])[CH3:40])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Reactant: C=COCC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OCc2ccccc2)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (Example 12) (10.2 g, 21.23 mmol) in DMF (100 mL) under nitrogen atmosphere at room temperature were sequentially added triethylamine (2.58 g, 25.47 mmol), TlOAc (6.15 g, 23.35 mmol), isobutylvinylether (14 mL, 106.14 mmol), DPPP (0.87 g, 2.12 mmol) and Pd(OAc)2 (0.24 g, 1.06 mmol). The reaction temperature was raised to 100° C. and stirred for 3 hours, cooled to room temperature, filtered and treated with HCl (5%, 250 mL) and stirred for another 2 hours. The reaction mixture was repeatedly extracted with dichloromethane and the combined organic layers were dried (MgSO4), filtered and the solvent evaporated. Triethylamine and DMF were destined off under reduced pressure to yield 9 g (98%); 1H NMR (CDCl3) δ1.22 (m, 12H), 2.52-2.70 (m, 7H), 3.40 (br, 2H), 4.34 (t, 1H), 5.10 (s, 1H), 6.90 (d, 1H), 7.17-7.40 (m, 10H), 7.82 (m, 1H) and 7.92 (s, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I>C1COCC1>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:19]([OH:21])=[O:20]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
Step AE (1): NaHMDS (1.0 M in THF, 200 mL, 200 mmol) was added to a stirred solution of 2-(4-fluorophenyl)acetic acid (15.41 g, 100 mmol) in THF (200 mL) at 0° C. The resulting mixture was aged for 20 min at 0° C. and neat 1-chloro-4-iodobutane (21.85 g, 100 mmol) was added. The mixture was allowed to warm to rt. After 16 hr, the reaction was quenched with water (3 mL). The crude mixture was concentrated in vacuo. Aqueous NaOH (1 M, 150 mL) was added to the residue and the resulting mixture was extracted with Et2O (2×250 mL). The basic layer was acidified with aqueous HCl (1 M, 200 mL) and the resulting solution was extracted with Et2O (2×250 mL). The combined organic layers from the acidic extraction were washed with mixture of brine/1N HCl/sodium sulfite, dried (MgSO4), filtered, and concentrated in vacuo to afford 6-chloro-2-(4-fluorophenyl)hexanoic acid (22.8 g, 84 mmol, 84% yield) as a viscous oil that slowly solidified upon standing to provide a light brown solid. LC-MS (M−H)− 243.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.29 (dd, J=8.70, 5.34 Hz, 2 H) 7.03 (t, J=8.70 Hz, 2 H) 3.56 (t, J=7.63 Hz, 1 H) 3.51 (t, J=6.56 Hz, 2 H) 2.06-2.14 (m, 1 H) 1.74-1.85 (m, 3 H) 1.33-1.51 (m, 2 H).
Reaction SMILES: O[CH2:2][CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][N:4]1[CH2:17][C:18]([NH:20][CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1)=[O:19].[CH3:30][C:31]1[C:39]([CH3:40])=[CH:38][C:34]2[N:35]=[CH:36][NH:37][C:33]=2[CH:32]=1>>[CH3:30][C:31]1[C:39]([CH3:40])=[CH:38][C:34]2[N:35]([CH2:2][CH:3]3[C:12]4[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)[CH2:6][CH2:5][N:4]3[CH2:17][C:18]([NH:20][CH:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)=[O:19])[CH:36]=[N:37][C:33]=2[CH:32]=1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: COc1cc2c(cc1OC)C(CO)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1cc2c(cc1OC)C(Cn1cnc3cc(C)c(C)cc31)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 2-(1-Hydroxymethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-N-(indan-1-yl)-acetamide with 5,6-dimethylbenzimidazole
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([N:11]([CH:20]([CH3:22])[CH3:21])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:10])[C:6]2[CH:23]=[CH:24][CH2:25][CH2:26][C:5]=2[C:4](=O)[O:3]1.[NH2:28][C@@H:29](C(O)=O)[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.C(N(CC)CC)C>O>[NH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH2:30][C@@H:29]2[C:2](=[O:1])[N:7]([CH2:8][C:9]([N:11]([CH:20]([CH3:22])[CH3:21])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[O:10])[C:6]3[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=3[C:4](=[O:3])[NH:28]2)=[CH:32]1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: COc1ccc(N(C(=O)Cn2c3c(c(=O)oc2=O)CCC=C3)C(C)C)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(N(C(=O)CN2C(=O)[C@@H](Cc3c[nH]c4ccccc34)NC(=O)c3ccccc32)C(C)C)cc1
Reaction time: 5 h
Yield: 33.9 %

Procedure:
A mixture of 2-(2,4-Dioxo-6H-benzo[d][1,3]oxazin-1-yl)-N-isopropyl-N-(4-methyoxy-phenyl)-acetamide (1.00 g, 2.71 mmol), D-tryptophan (554 mg, 2.71 mmol) and triethylamine (0.378 mL, 2.71 mmol) are combined in water (20 mL) and stirred for 5 hrs. at 50° C. After concentration in vacuo, the reaction mixture is combined with glacial acetic acid (20 mL) and refluxed for 5 hrs. The reaction mixture is filtered and then concentrated in vacuo to an oil. The oil is dissolved in ethyl acetate and washed consecutively with water (2×), saturated aqueous sodium bicarbonate, and brine. The solution is dried over anyhydrous magnesium sulfate, filtered, treated with activated charcoal, filtered and concentrated in vacuo to a yellow foam. The product is crystallized from methanol (15 mL). The resulting slurry is cooled with an ice/water bath, filtered and washed with cold methanol (3×4 mL), and dried under high vacuum to provide the title compound as white solid (469 mg, 0.918 mmol). 1H NMR (300 MHz, CDCl3): 1.11 (m, 6H); 3.22 (m, 1H); 3.46 (m, 1H); 3.69 (d, 1H, J=16.6 Hz); 3.83 (s, 3H); 4.20 (m, 1H); 4.45 (d, 1H, J=16.6 Hz); 5.06 (m, 1H); 6.06 (d, 1H, J=5.4 Hz); 6.88-7.37 (m, 10H); 7.50 (m, 2H); 7.73 (m, 1H); 8.14 (s, 1H). MS(FAB): [M+H]+ =511.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([NH:17][NH2:18])=[O:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:19](OCC)(OCC)OCC.CS(O)(=O)=O>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]3[O:16][CH:19]=[N:18][N:17]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)/C=C\n1cnc(-c2cccc(Cl)c2)n1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1cccc(-c2ncn(/C=C\c3nnco3)n2)c1
Temperature: 80 °C
Yield: 24.1 %

Procedure:
In a 3-neck 25 mL round-bottomed flask, (Z)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.180 g, 1.0 eq.), triethyl orthoformate (0.2006 g, 1.9 eq.) and Methane sulphonic acid (0.009 g, 0.1 eq.) was mixed. Reaction was carried out under N2 atmosphere. Reaction mixture was refluxed at 80° C. for 1 h. Completion of the reaction was monitored on TLC using ethyl acetate:n-hexane (1:1) as mobile phase. The resulting reaction mass was poured in ice-water slurry (50 mL) and extracted with ethylacetate (3×20 mL). Organic layer was washed with brine solution followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 0.150 g of crude compound which was further purified using column chromatography to afford 0.045 g pure compound (Yield 24.2%): 1H NMR (400 MHz, CDCl3) δ 10.21 (S, 1H), 8.5 (S, 1H), 8.18 (S, 1H), 8.05-8.06 (t, 1H), 7.50-7.53 (d, J=10.8 Hz, 1H), 7.40-7.43 (t, 1H), 6.25-6.27 (d, J=11.2 Hz, 1H): LCMS for C12H8ClN5O [M+1]+ 273.68 found 273.80 at 3.336 min.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[NH:5][CH:6]=1.C([Mg]Br)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[CH3:29])[O:25][CH2:24][CH2:23][C:22]2=[O:30].[Cl-].[NH4+]>C(Cl)Cl>[OH:30][C:22]1([C:2]2[N:3]=[C:4]([S:7]([N:10]([CH3:12])[CH3:11])(=[O:9])=[O:8])[NH:5][CH:6]=2)[C:21]2[C:26](=[CH:27][C:28]([CH3:29])=[C:19]([O:18][CH3:17])[CH:20]=2)[O:25][CH2:24][CH2:23]1
Reactant: CN(C)S(=O)(=O)c1nc(I)c[nH]1
Reactant: COc1cc2c(cc1C)OCCC2=O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1cc2c(cc1C)OCCC2(O)c1c[nH]c(S(=O)(=O)N(C)C)n1
Reaction time: 2.5 h
Yield: 56.1 %

Procedure:
A solution of 4.6 grams (0.016 mole) of [(4-iodoimidazolyl)sulfonyl]dimethylamine (commercially available) in 10 mL of dry methylene chloride was stirred and 5.7 mL (0.018 mole) of ethylmagnesium bromide (3M in diethyl ether) was added. Upon completion of addition, the reaction mixture was stirred during a 2.5 hour period. After this time, 3.0 grams (0.016 mole) of 6-methoxy-7-methylchroman-4-one (ii) (prepared in Step C of Example 5) was added, and the reaction mixture was stirred for an additional 18 hours. After this time, the reaction mixture was poured into 100 mL of an aqueous solution of ammonium chloride and extracted with three 100 mL portions of methylene chloride. The combined extracts were washed with one 50 mL portion of water, and dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on Grade II basic alumina (3% water) using a 99:1 mixture of methylene chloride and methanol, respectively, as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 3.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH:5]1([CH:11]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[BH3-]C#N.[Na+].Cl>O.CO>[CH2:1]([NH:4][CH2:11][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: O=CC1CCCCC1
Reactant: C=CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCNCC1CCCCC1

Procedure:
To 100 mL of MeOH is added 2-propenylamine (5.7 g, 0.1 mol), 11.2 g (0.1 mol) of cyclohexane carboxaldehyde and 12 g (0.2 mol) of NaBH3CN. The pH is adjusted to 6 with concentrated HCl. Monitor the reaction by thin layer chromatography. Upon completion add concentrated HCl until gas evolution ceases. Add 300 mL of H2O and extract once with 200 mL of Et2O. Add 1N NaOH to the aqueous solution until it is basic (pH=11) and extract 2 times with 200 mL of Et2O. Dry the organic phase over Na2SO4. Filter the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[CH:7][CH:6]=[CH:5]2
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C1CCCc2cc(Br)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1cccc2cc(Br)ccc12)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 6-bromo-1-tetralone (10.6 g, 47.1 mmol) in dichloromethane (145 mL) cooled to 0° C. were sequentially added triethylamine (12 mL, 86.1 mmol) and triisopropylsilyl trifluoromethanesulfonate (15.3 mL, 56.7 mmol). After stirring for ten minutes, the ice bath was removed and the reaction was allowed to warm to room temperature for 30 minutes. The reaction was diluted with 1:1 ethyl acetate:hexanes and the organic layer was washed with water and brine. The organics were dried (MgSO4), concentrated, and the resulting material was used without further purification. The crude enolsilane was dissolved in tetrahydrofuran (470 mL) and cooled to 0° C. To the solution was added solid 2,3-dichloro-5,6-dicyanobenzoquinone (16 g, 70.5 mmol) and the reaction was warmed to room temperature. After 30 minutes the reaction was concentrated and the crude material was purified by flash column chromatography (hexanes) to afford (6-bromonaphthalen-1-yloxy)triisopropylsilane (17.1 g, 96% over 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Br[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>O1CCCC1.CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=[C:10]2[CH:9]1[CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1
Reactant: CN(C)C(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: CN(C)C(=O)CC1c2nc(C(F)(F)F)nn2CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.13 g (7.30 mmol) of 7-N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine (Example 2, Step A) in 10 mL of tetrahydrofuran at −78° C. was added lithium diisopropylamide (4.02 mL of a 2.0M solution in heptane/tetrahydrofuran/ethylbenzene, 8.03 mmol). The mixture was allowed to stir at −78° C. for 15 min, and then 2-bromo-N,N-dimethylacetamide from Step A in 5 mL of tetrahydrofuran was added, and the mixture slowly warmed to ambient temperature over 18 h. The reaction was quenched with aqueous ammonium chloride and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, gradient of 50% to 75% ethyl acetate/hexane) yielded the title compound. LC/MS 322 ((M+1)-t-butyl).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Br[CH2:22][CH2:23]Br>C1COCC1>[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:23][CH2:22]1
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)Cc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(c2nccs2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Sodium hydride (702 mg, 17.56 mmol) was suspended in THF (7 mL)/DMF (7 mL) under nitrogen and cooled to 0° C. The product from Step 1 (875 mg, 4.39 mmol) in THF (3 mL)/DMF (3 mL) was added dropwise. The ice bath was removed, and the yellow-orange suspension was stirred at room temperature for 30 min. The mixture was then cooled back down to 0° C., and 1,2-dibromoethane (2.475 g, 13.17 mmol) was added in one portion. The reaction was allowed to warm to room temperature and stirred for 2 h. It was then quenched with saturated NH4Cl and water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (Na2SO4), and evaporated. Flash chromatography (0-20% ethyl acetate in hexanes) afforded tert-butyl 1-(1,3-thiazol-2-yl)cyclopropanecarboxylate (866 mg, 88%) as a colorless oil. MS ESI: [M+H]+ m/z 226.1.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][C:31](=[O:37])[NH:32]2>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1/[C:30](=[CH:16]/[C:13]1[NH:12][C:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[C:6](=[O:18])[C:7]=3[C:14]=1[CH3:15])/[C:31](=[O:37])[NH:32]2
Reactant: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4c(F)cccc4F)c32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 36.4 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-[4-(2,6-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 40 (36 mg, yield 36.4%) as an orange solid.
Reaction SMILES: [F:1][C:2]([C:8]([CH3:10])=[O:9])([F:7])[C:3]([F:6])([F:5])[F:4].[Br:11]Br>S(=O)(=O)(O)O>[Br:11][CH2:10][C:8](=[O:9])[C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4]
Reactant: BrBr
Reactant: CC(=O)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=C(CBr)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl pentafluoroethyl ketone (3.9 g, 0.02407 mole) (JACS, 78, 2268-70 [1956]) was stirred in concentrated sulphuric acid (10 ml) at room temperature under a dry-ice condenser. Bromine (1.92 g; 0.012035 mole) was added slowly over two hours with vigorous stirring. The mixture was then stirred for one hour at room temperature and then at 50° C. for one hour. The resulting amber solution was distilled at atmospheric pressure, yielding one main fraction of 4.41 g (76%), boiling at 94-97° C. The mass spectrum confirmed the structure, showing parent ions at 240 and 242 m/e corresponding to C4H2BrF5O (2 isotopes of Br).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:11][N:12]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:13][CH2:14][N:15]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:16][CH2:17][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19][C:20]([N:23]=2)=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:10]2[CH2:11][N:12]([CH2:33][C:34]([OH:36])=[O:35])[CH2:13][CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19][C:20]([N:23]=2)=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN1CCN(CC(=O)O)Cc2ccc(OCc3ccccc3)c(n2)CN(CC(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CCN(CC(=O)O)Cc2ccc(OCc3ccccc3)c(n2)CN(CC(=O)O)CC1

Procedure:
9 g (0.0170 mol) of the methyl ester of (12-benzyloxy-6,9-bis(methoxy-carbonylmethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(14),11(15),12-trien-3-yl)acetic acid are added to a solution of 50 ml of methanol and 50 ml of 5N NaOH. The combined mixture is brought to reflux for 6 h. After concentrating and neutralizing by passing through IRC50 resin, the product is hardened in isopropanol. White crystals are obtained. w=8 g.