Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[C:7]([C:12](O)([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[C:6](=[C:7](/[C:12](/[CH2:16][CH2:17][CH3:18])=[CH:13]/[CH2:14][CH3:15])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(O)(CCC)c1c2cccc(Br)c2nn1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC/C=C(\CCC)c1c2cccc(Br)c2nn1C
Yield: 88.9 %

Procedure:
A solution of 4-(7-bromo-2-methyl-2H-indazol-3-yl)-heptan-4-ol (1.75 g, 5.38 mmol), 50 mL of toluene, and 4-toluenesulfonic acid (1.23 g, 6.46 mmol) was stirred at 110° C. for 20 h, then allowed to cool. A saturated aqueous NaHCO3 solution (50 mL) was added, and the mixture was extracted with three 30 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated to a brown oil. Column chromatography (0→8% EtOAc/hexanes) afforded of 7-bromo-2-methyl-3-((E)-1-propyl-but-1-enyl)-2H-indazole (43; 1.47 g; 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:12]([Si](C)(C)C)#[CH:13].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([C:12]#[CH:13])[CH:3]=[N:4][CH:5]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Product: C#Cc1cncc(C(=O)OC)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To methyl 5-bromonicotinate (3.0 g, 13.89 mmol) in TEA (50 mL) under N2 was added ethynyltrimethylsilane (5.83 mL, 41.7 mmol), copper(I) iodide (0.132 g, 0.694 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.487 g, 0.694 mmol). The reaction was stirred at 50° C. for 1 h. The reaction was cooled to room temperature and filtered to remove the solids. The precipitate was washed thoroughly with ethyl acetate. The filtrate was then washed with water twice and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford a black color solid. Assuming 100% conversion this was taken on to next step for TMS removal. The crude was dissolved in MeOH (50 mL) and potassium carbonate (0.480 g, 3.47 mmol) was added to it. The reaction mixture was stirred for 30 min. The solids were filtered off, the filtrate was concentrated in vacuo. The crude was purified by silica gel flash chromatography using DCM-MeOH:90-10 to give pure product 5-Ethynyl-nicotinic acid methyl ester as a light yellow solid. ESI-MS: m/z 162.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[C:9]#[N:10])=[CH:4][CH:3]=1.[CH2:15](Br)[Br:16].[OH-].[Na+]>CS(C)=O>[Br:16][CH2:15][C:8]([C:9]#[N:10])([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(C#N)c1ccc(Cl)cc1
Reactant: BrCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCC(C#N)(CBr)c1ccc(Cl)cc1
Reaction time: 0.58 h
Yield: 75.2 %

Procedure:
In a 300 ml three neck flask fitted with a mechanical stirrer, thermometer and addition funnel was added 20.8 gm (0.1 mol) of (p-chlorophenyl)hexanenitrile, 34.8 gm (0.2 mol) of methylene bromide and 50 ml of DMSO. To the reaction flask was added 24 ml of 50% (w/w) sodium hydroxide, dropwise over a 35 minute period. Upon completion of the reaction, it was quenched by adding 500 ml of water. The aqueous mixture was extracted three times with ether, then the combined ether extracts were washed three times with water and once with brine. The organic phase was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation yielding 22.6 gm of a yellow oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>IC1C=CC(C)=CC=1.[Cu]>[CH3:18][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)c1cccc(I)c1
Agent: [Cu]
Agent: Cc1ccc(I)cc1
Product: COC(=O)c1cccc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 29 %

Procedure:
To a mixture of methyl 3-iodobenzoate (26.1 g) in 4-iodotoluene (21.9 g) was added copper powder (31.8 g) gradually at 180°-190° C. The mixture was then stirred for 6 hours at 200°-210° C. The reaction mixture was cooled to room temperature, to which was added toluene. Insoluble materials were filtered off, and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to afford the title compound as a colorless oil (6.61 g, 29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>>[F:11][C:8]1[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=[C:2]([F:1])[C:9]=1[O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: N#Cc1cccc(O)c1
Product: N#Cc1cccc(Oc2c(F)cc(C=O)cc2F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 3-hydroxybenzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Br)cc1Oc1ccccc1
Temperature: 150 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A 250 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with 4-bromo-2-fluorobenzaldehyde (2.00 g, 9.85 mmol, 1.00 equiv), phenol (0.926 g, 9.84 mmol, 1.00 equiv), potassium carbonate (1.35 g, 9.77 mmol, 0.99 equiv), and N,N-dimethylacetamide (30 mL). The resulting solution stirred for 4 h at 150° C. and then diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/99) to provide 2.40 g (88% yield) of 4-bromo-2-phenoxybenzaldehyde as a light yellow solid. 1H NMR 400 MHz (CDCl3) δ 10.51 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.41-7.48 (m, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.25-7.29 (m, 1H), 7.12 (d, J=7.6 Hz, 2H), 7.04 (s, 1H). LCMS (ESI, m/z): 277 [M+H]+.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]([O:7][C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[O:9])[CH3:6]>O1CCOCC1>[CH3:1][NH:2][C:3]([NH:13][C:11]([NH:10][C:8]([O:7][CH2:5][CH3:6])=[O:9])=[NH:12])=[O:4]
Reactant: CCOC(=O)NC(=N)N
Reactant: CN=C=O
Solvent: C1COCCO1
Product: CCOC(=O)NC(=N)NC(=O)NC

Procedure:
5.1 parts by weight of methylisocyanate were added to a suspension of 10 parts by weight of ethoxycarbonylguanidine (manufactured according to Isr. J. Chem. 8, 651 [1970] ) in 60 parts by volume of anhydrous dioxane, in the course of which the temperature rose to 45°C and the precipitate dissolved. After a short time, a crystalline precipitate separated out again, which was filtered off after cooling and washed with ether. It was dried in vacuo over P2O5 and paraffin chips.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[Cl:24][C:25]1[CH:26]=[C:27](O)[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([CH:28]=[CH:27][CH:26]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])[CH2:7]1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1cccc(Cl)c1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(Cl)c2)C1
Yield: 88.4 %

Procedure:
The title compound (D124) (85 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 3-Chlorophenol (0.035 ml, 0.338 mmol).
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[NH:13][C:12]2([CH2:20][CH3:21])O.ClC1C=C2C(C(CC)(O)NC2=O)=CC=1>C(O)(C(F)(F)F)=O>[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[NH:13][CH:12]2[CH2:20][CH3:21]
Reactant: CCC1(O)NC(=O)c2ccc(Cl)cc21
Agent: CCC1(O)NC(=O)c2cc(Cl)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCC1NC(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under N2 protection, triethylsilane (19.3 g, 166 mmol) and TFA (20 mL) were added successively to a mixture of 5-chloro-3-ethyl-3-hydroxy-2,3-dihydro-isoindol-1-one and 6-chloro-3-ethyl-3-hydroxy-2,3-dihydro-isoindol-1-one (3.52 g, 16.6 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was treated with a satd. aq. solution of NaHCO3 (30 mL) and extracted with DCM (2×30 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude mixture of products. The desired regioisomer, 5-chloro-3-ethyl-2,3-dihydro-isoindol-1-one was obtained by prep-HPLC separation as a white solid (0.65 g, 20%). MS: 196.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11](C(OC)=O)[C:12]([O:14]C)=[O:13].S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Yield: 80 %

Procedure:
Dimethyl 2-(2-chloro-4-nitrophenyl)malonate (96 mmol) was suspended in acetic acid (175 mL). Conc. sulfuric acid (3.5 mL) was added and the mixture was stirred at 80° C. over night. Water (30 mL) was added and the mixture was stirred at 100° C. for 2 h. after which conc. sulfuric acid (1 mL) was added. The mixture was stirred at room temperature over night. The formed precipitate was filtered off and washed with water. The remaining solid was dried under reduced pressure to give 2-(2-chloro-4-nitrophenyl)acetic acid as a solid (80%).
Reaction SMILES: CC1C=CC([C@@H](N[C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])C)=NC=1.Cl.[F:23][C:24]([F:35])([F:34])[C:25]1[N:30]=[CH:29][C:28]([C@@H:31]([NH2:33])[CH3:32])=[CH:27][CH:26]=1>>[F:35][C:24]([F:34])([F:23])[C:25]1[N:30]=[CH:29][C:28]([C@@H:31]([NH:33][C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[CH3:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1
Reactant: C[C@H](N)c1ccc(C(F)(F)F)nc1
Agent: Cl
Product: C[C@H](NC(=O)[C@H]1C[C@@H]1c1ccccc1)c1ccc(C(F)(F)F)nc1

Procedure:
Prepared analogously to Compound 2 using IM46 and commercially available (S)-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine hydrochloride. (Supplier Netchem Inc., Catalog No 517662). Yield=0.33 g (55%). %). 1H NMR (500 MHz, DMSO) δ 8.77 (d, 1H), 8.72 (s, 1H), 7.99 (d, 1H), 7.88 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.13 (d, 2H), 5.05 (m, 1H), 2.20 (m, 1H), 1.93 (m, 1H), 1.41 (d, 3H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z) 335.2 (MH+), tR=1.59 min (method A).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1.O=S(Cl)[Cl:23]>C(Cl)Cl>[Cl:23][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[CH:5][CH:6]=1
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CCl

Procedure:
0.300 g (1.059 mmol) of the above prepared [2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-yl]-methanol was dissolved in 5.3 ml of CH2Cl2 and treated dropwise at 0° C. with 0.15 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate and evaporation of the solvents generated 0.315 g of pure title compound as light yellow oil.
Reaction SMILES: CO[S:3][CH2:4][O:5][N:6]=[C:7]([C:30]1[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=1)[C:8]([NH:10][CH:11]1[C:28](=[O:29])[N:13]2[C:14]([C:25]([OH:27])=[O:26])=[C:15]([CH2:18][S:19][C:20]3[S:21][CH:22]=[N:23][N:24]=3)[CH2:16][S:17][C@H:12]12)=[O:9].Cl.[CH3:39]O>O1CCCC1>[CH3:39][S:3][CH2:4][O:5][N:6]=[C:7]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:8]([NH:10][CH:11]1[C:28](=[O:29])[N:13]2[C:14]([C:25]([OH:27])=[O:26])=[C:15]([CH2:18][S:19][C:20]3[S:21][CH:22]=[N:23][N:24]=3)[CH2:16][S:17][C@H:12]12)=[O:9]
Reactant: CO
Reactant: COSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Product: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 7-[2-methoxythiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.58 g.), conc. hydrochloric acid (0.405 g.), methanol (8.7 ml.) and tetrahydrofuran (5 ml.) was stirred for 2 hours and 10 minutes at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous solution of sodium hydroxide (pH 7~8.5). An insoluble material was filtered off and the filtrate was adjusted to pH 3.4 with 10% hydrochloric acid under ice-cooling and stirred for 30 minutes. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.4 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([O:37][C:38]2[CH:39]=[N:40][CH:41]=[N:42][CH:43]=2)[CH:36]=1)[C:30](OC)=[O:31].Cl>C1COCC1.CCOC(C)=O>[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]=[C:35]([O:37][C:38]2[CH:43]=[N:42][CH:41]=[N:40][CH:39]=2)[CH:36]=1)[C:30]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1)=[O:31]
Reactant: Nc1cc(F)ccn1
Reactant: COC(=O)c1cc(Cl)cc(Oc2cncnc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(F)ccn1)c1cc(Cl)cc(Oc2cncnc2)c1
Reaction time: 0.08 h
Yield: 38.5 %

Procedure:
2-Amino-4-fluoropyridine (254 mg, 2.27 mmol, 2.00 eq) was dissolved in THF (2.5 mL) in a flame-dried round bottom flask. A 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (4.76 mL, 2.27 mmol, 2.00 eq) was added dropwise and the reaction was stirred for 5 min. Compound 7 (300 mg, 1.13 mmol, 1.00 eq) was added as a solution in THF (2.5 mL) and the reaction was stirred for 30 min. The reaction was diluted with EtOAc, neutralized with 1N HCl and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 150 mg (38%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 11.12 (s, 1H), 9.07 (s, 1H), 8.75 (s, 2H), 8.39 (d, J=3.0 Hz, 1H), 8.16 (dd, J=5.0, 4.2 Hz, 1H), 7.88 (t, J=1.6 Hz, 1H), 7.80 (td, J=8.7, 31. Hz, 1H), 7.68 (t, J=2.0 Hz, 1H), 7.58 (t, J=2.1 Hz, 1H); [M+1]+: 345.2
Reaction SMILES: [CH2:1]([C:3]1([CH3:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([CH2:16][CH3:17])([CH3:15])[NH:5][NH:4]1)[CH3:2]>C1CCCCC1.[O-2].[Al+3].[Rh+3].[O-2].[O-2]>[CH2:1]([C:3]([CH3:18])([NH2:4])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([CH2:16][CH3:17])([CH3:15])[NH2:5])[CH3:2]
Reactant: CCC1(C)CCCCCCCCC(C)(CC)NN1
Agent: [Rh+3]
Agent: [Al+3]
Agent: [O-2]
Solvent: C1CCCCC1
Product: CCC(C)(N)CCCCCCCCC(C)(N)CC

Procedure:
23 g (90 mmols) of the above 3,12-diethyl-3,12-dimethyl-1,2-diazacyclododecane are hydrogenated, in 200 ml of cyclohexane in a stirred autoclave and with the addition of 3 g of rhodium-aluminum oxide catalyst (5% by weight of Rh), for 17 hours at 200° C. After filtering off the catalyst and stripping off the solvent on a rotary evaporator, the residue is fractionated at 0.2 mm Hg. This gives 7.7 g (30%) of 1,10-diethyl-1,10-dimethyl-1,10-diaminodecane as a colorless oil, boiling point 118°-22° C/0.2 mm Hg, nD20 = 1.4597.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([OH:20])=[O:19])[C:9]2=[O:21])[CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=[O:26])[C:23](Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([O:20][C:2]3[CH2:3][CH2:4][CH2:23][C:22](=[O:26])[CH:1]=3)=[O:19])[C:9]2=[O:21])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(-n2c(=O)c(C(=O)O)nc3ccccc32)n1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-n2c(=O)c(C(=O)OC3=CC(=O)CCC3)nc3ccccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 185.2 %

Procedure:
23.3 g of 1-(6-methyl-2-pyridyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid was dissolved in chloroform (100 mL), and 21.0 g of oxalyl chloride was added thereto. The mixture was stirred for one hour at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 mL of chloroform. 10.2 g of 1,3-cyclohexadione and 10.1 g of triethylamine were added, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, to obtain 28.8 g of 3-oxo-1-cyclohexenyl 1-(6-methyl-2-pyridyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][C:32]=1O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:38]1[CH:37]=[C:34]([C:35]#[N:36])[CH:33]=[CH:32][C:31]=1[O:30][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CC(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1cc(C#N)ccc1OCc1ccccc1)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.8 g (15.5 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-hydroxybutanoate was dissolved in 100 ml of tetrahydrofuran. 2.9 g (12.9 mmol) of 4-benzyloxy-3-hydroxybenzonitrile, 4.1 g (15.5 mmol) of triphenylphosphine and 6.7 g (15.5 mmol) of diethyl azodicarboxylate were added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH:1]S(O)(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[CH:15]=NO)=[CH:9][CH:8]=1>>[Br:6][C:7]1[CH:12]=[C:11]2[C:10](=[CH:9][CH:8]=1)[NH:13][C:14](=[O:18])[C:15]2=[O:1]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc(Br)cc1
Product: O=C1Nc2ccc(Br)cc2C1=O
Temperature: 80 °C

Procedure:
To a hot solution of conc. H2SO4 (48 mL) at 60° C. was added portion wise (N-(4-bromo-phenyl)-2-hydroxyimino-acetamide (12 g, 41.1 mmol). After completion of the addition, the temperature was increased to 80° C. and maintained for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice and the resulting precipitate was filtered, washed with water (2-3 times) and dried to obtain the title compound as brick red solid (10 g, 89%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3]I.C([O:7][C:8]1[C:9](/C(/CC)=C(/F)\C=C\C(\C)=C\C(OCC)=O)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)C.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)[CH2:2][CH3:1]
Reactant: CCCI
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCOc1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
N-Propyl iodide (4.9 mL, 50 mmol) was added to a stirring suspension of 6-hydroxy-1,2,3,4-tetrahydronaphthalene (Intermediate 1, 2.07 g, 10 mmol), potassium carbonate (6.9 g, 50 mmol), in acetone (50 mL), and the mixture was stirred at reflux for 14 h. The solution was poured into a separatory funnel, water was added, and the products were extracted three times with hexane. The combined organic layers were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound as a yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([F:17])[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.N(CCO)CCO>C1(C)C=CC=CC=1>[Br:1][CH2:2][C@@H:3]([C:5]1[C:14]2[C:9](=[C:10]([F:17])[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: COc1cc(F)c2nccc(C(=O)CBr)c2c1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: Cc1ccccc1
Solvent: OCCNCCO
Product: COc1cc(F)c2nccc([C@@H](O)CBr)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
8.0 g (26.8 mmol) of 2-Bromo-1-(8-fluoro-6-methoxy-quinolin-4-yl)-ethanone was dissolved in 200 mL of toluene. 17.2 g (53.6 mmol) of (+)-DIP-chloride was added and the contents were allowed to stir at rt overnight (16 hrs). 8 mL (80.4 mmol) of diethanolamine was added and the contents were allowed to stir at rt for 3 hrs. The contents were filtered and the solids washed; first with hot toluene, then with ethyl acetate until the washings no longer had UV activity. The crude material was preadsorbed onto silica gel and purified by flash chromatography using 2:1 hexanes/ethyl acetate and going to 100% ethyl acetate afforded 7.95 g (98%) of the product. 1H NMR (DMSO, 400 MHz) 8.81 (d, 1H), 7.71 (d, 1H), 7.39 (d, 1H), 7.30 (s, 1H), 6.28 (d, 1H), 5.75 (m, H), 4.00 (s, 3H), 3.97 (dd, 1H), 3.91 (dd, 1H). LCMS (M+H)+ 300. Enantiomeric excess was determined by chiral HPLC to be ≧94%.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.Cl.[F:14][C:15]([F:31])([F:30])[C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[C:23]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:21][CH:20]=2>>[Br:1][C:2]1[C:3]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([NH:7][C:27](=[O:28])[CH2:26][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:24]=2[CH:25]=[C:16]([C:15]([F:14])([F:31])[F:30])[CH:17]=[N:18]3)[S:5][CH:6]=1
Reactant: O=C(O)Cc1cccc2ncc(C(F)(F)F)cc12
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Agent: Cl
Product: O=C(Cc1cccc2ncc(C(F)(F)F)cc12)Nc1scc(Br)c1-c1nc[nH]n1

Procedure:
The title compound was prepared from 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (56 mg, 228 umol) and 2-(3-trifluoromethylquinolin-5-yl)acetic acid hydrogen chloride (200 mg, 784 umol) according to the procedures outlined in Example 1.68.6., above. Method [7] retention time 5.93 min by HPLC (M+ 482 and 484) and (M+Na 504 and 506). 1H NMR (300 MHz, CDCl3) δ 12.45 (s, 1H), 9.23 (s, 1H), 8.84 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.03 (m, 1H), 7.85 (d, J=6.9 Hz, 1H), 7.74 (s, 1H), 6.95 (s, 1H), 4.38 (s, 2H).