Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1(C(OCC)=O)[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[C:7](C)=[C:6]([C:15]#[C:16][C:17]3[CH:31]=[CH:30][C:20]([C:21]([O:23]CC[Si](C)(C)C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CC[CH2:53][CH3:54])(CCCC)CCCC)CCC>C1COCC1>[OH:1][C:2]1([CH2:20][C:21]([O:23][CH2:53][CH3:54])=[O:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:15]#[C:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C1(O)CCC(C)(C)c2c1ccc(C#Cc1ccc(C(=O)OCC[Si](C)(C)C)cc1)c2C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 0.25 g (0.49 mmol) of trimethylsilylethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxy-methylnaphth-2-yl)ethynyl]benzoate (Compound 117) in 5 ml of dry THF (flushed with argon) was added 1.48 ml (1.5 mmol) of tetrabutyl ammonium fluoride (1M solution in THF). The reaction mixture was stirred at room temperature for 12 hours, concentrated in vacuo to an oil and slowly diluted with water. The solution was acidified to pH 4 with 10% HCl and extracted with Et2O . The organic layer was dried over Na2SO4, concentrated in vacuo to an oil and purified by flash chromatography (silica, 90% EtOAc-hexane) to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:10][C:11]1[C:12]([N:22]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH2:23][CH:24]2[CH2:26][CH2:25]2)=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[C:8]#[N:9].[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+]>CN(C=O)C>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:10][C:11]1[C:12]([N:22]([CH2:23][CH:24]2[CH2:25][CH2:26]2)[CH2:27][CH:28]2[CH2:30][CH2:29]2)=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[C:8]1[N:40]=[N:41][NH:42][N:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc2cc(CN(C#N)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(N(CC3CC3)CC3CC3)nc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)nc12
Temperature: 25 °C
Yield: 98.2 %

Procedure:
N-(3,5-Bis(trifluoromethyl)benzyl)-N-((2-(bis(cyclopropylmethyl)amino)-8-methylquinolin-3-yl)methyl)cyanamide (0.118 g, 0.216 mmol), sodium azide (0.70 g 1.08 mmol) and ammonium chloride (0.058 g, 1.08 mmol) were put in a RB flask under N2 atmosphere. To this reaction mixture, DMF (2 mL) was added and was refluxed for 1 h. The reaction mixture was cooled to RT and ice was added to this and extracted with ethylacetate (3×10 mL). The combined organic layer was washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford of (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine as a yellow solid (0.125 g, 99%).
Reaction SMILES: [C:1]1([C:7](SCC(OC)=O)=[S:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[C:17]([C:23]([NH:25][NH2:26])=O)=[N:18][C:19]([Br:22])=[CH:20][N:21]=1.Cl>C(O)C>[Br:22][C:19]1[N:18]=[C:17]([C:23]2[S:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:26][N:25]=2)[C:16]([NH2:15])=[N:21][CH:20]=1
Reactant: COC(=O)CSC(=S)c1ccccc1
Reactant: NNC(=O)c1nc(Br)cnc1N
Agent: Cl
Solvent: CCO
Product: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)s1
Yield: 35.9 %

Procedure:
Methyl 2-((phenylcarbonothioyl)thio)acetate (3.6 g, 15.9 mmol) and 3-amino-6-bromopyrazine-2-carbohydrazide (2.9 g, 12.5 mmol) were suspended in 200 mL of ethanol and refluxed for 2 days. To the mixture, 50 mL of sat. ethanolic HCl was added and the mixture was refluxed overnight. A precipitate formed. The formed solid was filtered and dried to afford 5-Bromo-3-(5-phenyl-1,3,4-thiadiazol-2-yl)pyrazin-2-amine 5 (1.5 g, 36%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[H][H]>[Pd].CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(C(CCCCBr)c2ccc(F)cc2)cc1

Procedure:
A mixture of 92 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis [4-fluorobenzene] and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 84 parts of 1,1'-(5-bromo-1-pentylidene)bis[4-fluorobenzene] as a residue (int. 51).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH:23](Br)([CH3:25])[CH3:24].Cl>C(O)C>[ClH:1].[CH:23]([N:9]1[CH2:8][CH2:7][N:6]([C:4](=[O:5])[N:3]([CH3:2])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:11][CH2:10]1)([CH3:25])[CH3:24]
Reactant: CC(C)Br
Reactant: CN(C)C(=O)N(C)C(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N1CCN(C(=O)N(C)C(=O)N(C)C)CC1
Yield: 65.1 %

Procedure:
To 20 ml of ethanol, were added 5.0 g of 1-(2,4,4-trimethylallophanoyl)piperazine hydrochloride and 3.7 g of sodium carbonate. To the resulting mixture, was added dropwise with stirring 2.5 g of isopropyl bromide. The mixture was allowed to react under reflux for 8 hours and the precipitate was removed by filtration. The filtrate was concentrated and the residue was purified with a silica gel column to obtain an oil. This oil was converted to hydrochloride in the customary way and recrystallized from ethanol to obtain 3.8 g (65% yield) of 1-(isopropyl)-4-(2,4,4-trimethylallophanoyl)piperazine hydrochloride having a melting point of 213°-215° C.
Reaction SMILES: [C:1]([Br:4])(=O)[CH3:2].[N+](C1C=[C:12]([CH2:14][C:15]([F:18])([F:17])[F:16])[N+:11]([O-:19])=[C:10]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH:9]=1)([O-])=O.[OH-].[Na+]>CC(O)=O>[Br:4][C:1]1[CH:9]=[C:10]([CH2:20][C:21]([F:22])([F:23])[F:24])[N+:11]([O-:19])=[C:12]([CH2:14][C:15]([F:16])([F:17])[F:18])[CH:2]=1
Reactant: CC(=O)Br
Reactant: O=[N+]([O-])c1cc(CC(F)(F)F)[n+]([O-])c(CC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: [O-][n+]1c(CC(F)(F)F)cc(Br)cc1CC(F)(F)F
Temperature: 90 °C
Yield: 72 %

Procedure:
Acetyl bromide (14 mL) was added to a solution of 4-nitro-2,6-bis-(2,2,2-trifluoro-ethyl)-pyridine 1-oxide (2.7 g, 8.9 mmol) dissolved in AcOH (25 mL). The reaction mixture was heated to 90° C. for 5 hours. The reaction was cooled to room temperature, poured into ice, made basic with NaOH pellets and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 30% EtOAc in hexanes) gave the product as a yellow oil (2.18 g, 72%). 1H NMR (400 MHz, CDCl3): δ 3.92 (t, J=10.1 Hz, 4H), 7.59 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([Cl:12])[C:5]=1[NH2:13].[CH3:15][C:16](=O)[C:17](=O)[CH3:18].CCOC(C)=O>CCO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([Cl:12])[C:5]=1[NH2:13])[N:11]=[C:17]([CH3:18])[C:16]([CH3:15])=[N:10]2)=[O:14]
Reactant: CC(=O)C(C)=O
Reactant: COC(=O)c1cc(N)c(N)c(Cl)c1N
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nc(C)c(C)nc2c(Cl)c1N
Yield: 60.6 %

Procedure:
To a solution of 1.5 g (6.96 mmol) of 2,4,5-triamino-3-chloro-benzoic acid methyl ester in 27 ml of EtOH, is added 0.81 ml (9.18 mmol) of 2,3-butanedione. The mixture is stirred under reflux during 1 hour. After cooling the mixture to ambient temperature EtOAc is added and the organic phase is washed with H2O (2 times). The organic phase is dried on Na2SO4, filtrated and evaporated. After purification by flash chromatography on silica gel, 1.18 g (4.22 mmol, 62%) of an orange-coloured solid were obtained. 1H-NMR (CDCl3, 300 MHz): ? ppm=2.67 (s, 3H), 2.75 (s, 3H), 3.97 (s, 3H), 6.47 (s br, 2H), 8.58 (s, 1H).
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:38])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:37])[CH:17]=1.CO>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:38])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:2])=[O:35])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:37])[CH:17]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12
Reaction time: 0.17 h

Procedure:
A solution of TMSCHN2 (0.75 mL, 2M Et2O, 1.5 mmol) was added to a solution of 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (115 mg, 0.25 mmol, Example 44), methanol (1 mL), and toluene (8 mL). After 10 min, the reaction was concentrated and purified by silica gel chromatography (4:1→1:4; hexanes:ethyl acetate) to give methyl 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoate: 1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 3.56 (s, 3H), 2.31 (t, 2H), 1.67 (m, 2H), 1.57 (m, 2H), 1.46 (m, 2H); MS (ESI): 480.9.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH3:6])[CH:12]1[C:8]1[S:7][CH:11]=[CH:10][CH:9]=1
Reactant: CNCCNC
Reactant: O=Cc1cccs1
Solvent: Cc1ccccc1
Product: CN1CCN(C)C1c1cccs1

Procedure:
23.5 g (267 mmol) of N,N′-dimethylethylenediamine were dissolved in 300 ml of toluene and treated with 29.8 g (266 mmol) of thiophene-2-carbaldehyde. The clear mixture was refluxed for 4 hours using a Dean-Stark trap. After that time 4.9 ml of water had separated in the trap. After cooling, the solution was filtered and evaporated. The oily residue was destilled in vacuo. Yield: 45 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>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.O.O1CCOCC1>[O:19]=[S:16]1(=[O:20])[CH2:17][CH2:18][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 16.3 %

Procedure:
5-Bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxamide (100 mg, 0.28 mmol), and dioxane water (3:1, 2 mL) were dissolved together. 4-fluorophenyl boronic acid (59 mg, 0.42 mmol), potassium carbonate (116 mg, 0.84 mmol) were added and a stream of Ar was passed through the solution for 5 min and then Pd(PPh3)4 was added (32 mg, 0.028 mmol). Argon was passed through the solution for 5 min and then the mixture was heated on the microwave at 150° C. for 20 min. The reaction mixture was concentrated and purified by HPLC to afforded 17 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][Si](C)(C)C)[C:3]=1[CH:4]=O.CO.[NH3:18]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:18][CH:11]=[CH:10]2
Reactant: N
Reactant: C[Si](C)(C)C#Cc1cccc(F)c1C=O
Solvent: CO
Product: Fc1cccc2ccncc12
Temperature: 80 °C
Yield: 58 %

Procedure:
2-Fluoro-6-[(trimethylsilyl)ethynyl]benzaldehyde Description 40; 10.38 g, 47.1 mmol) was dissolved in 2M ammonia in methanol (235 ml, 471 mmol) in a Parr flask and the resulting mixture heated at 80° C. with shaking on a Parr apparatus (ca. 35 psi achieved). The reaction was cooled and the solvents evaporated. The residue was purified by column chromatography on silica eluting with a gradient from neat dichloromethane to 2% methanol in dichloromethane to give the title compound (4.0 g, 58%).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[N-:27]=[N+:28]=[N-:29].[Na+]>>[N:27]([CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:13][CH:14]=1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC(Cc1ccc(OCCCOS(C)(=O)=O)cc1)C(=O)OCC
Agent: [Na+]
Product: CCCCC(Cc1ccc(OCCCN=[N+]=[N-])cc1)C(=O)OCC
Yield: 95.3 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 2-butyl-3-[4-(3-methanesulfonyloxypropoxy)phenyl]propionate (2.98 g) and sodium azide (1.50 g) and the reaction mixture was treated to afford the desired compound (2.45 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][NH:31][C:32](=[O:34])[CH3:33].[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:4]=1)[C:32](=[O:34])[CH3:33]
Reactant: CCCCCCCCCCCCCCOc1cccc(CBr)c1
Reactant: CC(=O)NCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CN(Cc2ccccn2)C(C)=O)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The title compound is prepared by the procedure of Example 27 using 2.25 g of product from Example 25, 0.881 g of product from Example 12, 0.282 g of 50% sodium hydride and 30 ml of tetrahydrofuran. The reaction is stirred at 0° C. for I hour, room temperature for 18 hours and at reflux temperature for 6 hours. The residue is purified by column chromatography (silica gel: 90% ethyl acetate/hexane) to give 1.57 g of product as pale yellow crystals. Spectral data shows the product as 2 rotomers.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH2:28][CH3:29])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=[O:12]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH2:28][CH3:29])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCC(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Product: CCC(Nc1ccc(Cl)cc1)C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
4-Chloroaniline is reacted with m-phenoxybenzyl 2-bromobutanoate using the process of Example 4 to yield m-phenoxybenzyl 2-(4-chlorophenylamino)butanoate, MS m/e 395 (M+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:15](=[O:27])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17](=[O:18])[C:13]=2[C:12]([O:28]COC)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[CH:2]=[CH2:3].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:4][C:5]1[C:14]2[C:15](=[O:27])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:17](=[O:18])[C:13]=2[C:12]([OH:28])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[CH:2]=[CH2:3]
Reactant: C=CCOc1c2c(c(OCOC)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Yield: 44 %

Procedure:
5-Allyloxy-7-(4-fluoro-benzyl)-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione 10 was dissolved in 1 mL dichloromethane. Ten equivalents of trifluoroacetic acid was added and the mixture was stirred at room temperature. After one hour another 10 equivalents of trifluoroacetic acid was added. The mixture was then stirred overnight, concentrated in vacuo, and azeotroped with toluene (2×), to give crude 11 which was triturated with 2 mL of 1:1 diethylether/hexane two times to give allyl ether 11 (0.0025 g, 0.0066 mmol, 44%). 1H NMR (CDCl3) δ 9.0 (s, 1H), 8.7 (d, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.0 (t, 2H), 6.1 (m, 1H), 5.4 (d, 1H), 5.3 (d, 1H), 5.1 (d, 2H), 4.8 (s, 2H). MS: 379 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][SH:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][S:28][CH2:30][C:31](=[O:32])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CS)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CSCC(=O)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-mercaptomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-1-phenyl-ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH2:31][NH2:32])[CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:32][CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CS(=O)(=O)c1cccc(CN)c1
Product: CS(=O)(=O)c1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and (3-methylsulfonylphenyl)methanamine (22.0 mg, 0.12 mmol). The title compound was obtained as a solid (22.8 mg, 44% yield). MS m/z: 517.95, 519.95 [M+H]+.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl[Si](C)(C)C.[CH:12]([Mg]Br)([CH3:14])[CH3:13]>C1COCC1>[CH:12]([CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)([CH3:14])[CH3:13]
Reactant: CC(C)[Mg]Br
Reactant: O=C1C=CCC1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CC(C)C1CCC(=O)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclopent-2-enone (1.5 mL, 18.27 mmol), CuBr—SMe2 (188 mg, 0.91 mmol), chlorotrimethylsilane (4.59 mL, 36.54 mmol) amd HMPA (6.55 g, 36.54 mmol) in THF (30 mL) was added isopropylmagnesium bromide (36.54 mL, 1 M in THF) at −70° C. After stirring for 1 h at −70° C., the reaction mixture was quenched with HCl (10%). The mixture was extracted with Et2O. The organic layer was washed with aqueous NaHCO3 and brine. After dried over Na2SO4, the organic layer was concentrated to give 3-isopropylcyclopentanone (4 g, 100%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].I[C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>[Cu]>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[S:1][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: Nc1ccc(C(=O)O)cc1S
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]
Product: Nc1ccc(C(=O)O)cc1Sc1ccccc1C(=O)O

Procedure:
Reflux a mixture of 200 ml of the 50% potassium hydroxide solution of Step A, 24.15 gm (97 mmoles) of o-iodobenzoic acid and 7.5 gm of copper metal powder for 11/2 hours. Cool the mixture and filter. Dilute the filtrate to twice its volume with water and acidify. Separate the solids by filtration, wash well with water and air dry.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:10]([CH2:12][CH3:13])=[N:11][C:6]2=[C:5]([CH3:32])[CH:4]=1)#[N:2].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C.C1(C)C=CC=CC=1>CN(C=O)C>[CH2:12]([C:10]1[N:9]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:7]2=[N:8][C:3]([C:1]3[NH:39][N:38]=[N:37][N:2]=3)=[CH:4][C:5]([CH3:32])=[C:6]2[N:11]=1)[CH3:13]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(-c3nnn[nH]3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 110 °C
Yield: 79 %

Procedure:
A mixture of 5-Cyano-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (54 mg), trimethylstannyl azide (79 mg), toluene (5 mL), and DMF (1 mL) was heated to 110° C. for 24 hour. Concentration and purification (SiO2, 70/30/1 CH2Cl2 /MeOH/NH4OH) gave 47 mg solid. 1H NMR (300 MHz, CD3OD) δ7.93 (s, 1H), 7.56-7.38 (m, 4H), 7.14-7.05 (AB quartet, 4H), 5.61 (s, 2H), 2.86 (q, 2H, J=7.5 Hz), 2.71 (s, 3H), 1.27 (t, 3H, J=7.5 Hz)
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[C:24]=1[CH:25]=O>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:25]([C:24]3[C:27]([O:31][CH3:32])=[CH:28][CH:29]=[CH:30][C:23]=3[O:22][CH3:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Br)cnc2[nH]1
Yield: 68.4 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 2,6-Dimethoxy-benzaldehyde (27 mg, 0.163 mmol) were reacted to produce 49 mg (68%) of the title compound. mp: 194-197° C., 1H NMR (300 MHz, DMSO-d6): 12.6 (s, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 7.45 (t, J=8 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J=8 Hz, 2H), 6.23 (br s, 1H), 6.17 (br s, 1H), 5.14 (t, J=8 Hz, 1H), 3.73 (s, 6H), 2.84 (s, 1H), 2.69 (s, 1H), 2.54 (d, J=8 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 2.09 (s, 1H), 1.38 (d, J=8 Hz, 1H). MS: 484, 486 (M+H), HPLC: 2.33 min (G method)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: COCCN
Product: COCCNC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Yield: 68 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 2-methoxyethylamine instead of 2-amino-2-methyl-1-propanol, to the title compound (80 mg, 68%) which was obtained as a colorless gum MS: m/e=389.1 [M+H]+.