Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12].C(NCCCC)CCC>[Pd].CN1CCCC1=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([OH:14])=[O:13])=[CH:3][CH:4]=1
Reactant: C=CC(=O)O
Reactant: COc1ccc(Br)cc1
Agent: [Pd]
Solvent: CCCCNCCCC
Solvent: CN1CCCC1=O
Product: COc1ccc(C=CC(=O)O)cc1
Reaction time: 4 h
Yield: 56.1 %

Procedure:
18.7 g (0.1 mole) p-bromoanisole, 500 mg Pd on carbon (5%), 40 ml N-methylpyrrolidone, 7.57 g (0.105 mole) acrylic acid and 13.57 g (0.105 mole) dibutylamine are stirred under nitrogen at 80° for 1 hour and then at 180° for 4 hours. The catalyst is removed by filtration at 100°. To the filtrate are added 200 ml of 2N sodium hydroxide and the solution is then washed twice with ether. Acidification to pH 1 with 2N hydrochloric acid, followed by filtration furnishes 10 g of p-methoxycinnamic acid (56% yield), top: 167°; no depression with an authentic sample is observed, the NMR data are as in example 8.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([N:10]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][S:25]([N:28]2[CH2:49][CH2:48][C:31]3([N:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]([F:46])([F:45])[F:44])[CH:37]=4)[NH:33][C:32]3=[O:47])[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:19]([CH3:50])[CH:18]=1)[CH2:11][CH2:12][O:13]C(=O)C)(=[O:9])[CH3:8].O>CO.C(Cl)Cl>[OH:13][CH2:12][CH2:11][N:10]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][S:25]([N:28]2[CH2:49][CH2:48][C:31]3([N:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]([F:45])([F:46])[F:44])[CH:37]=4)[NH:33][C:32]3=[O:47])[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:19]([CH3:50])[CH:18]=1)[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)OCCN(C(C)=O)c1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(c2cccc(OC(F)(F)F)c2)NC3=O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(=O)N(CCO)c1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(c2cccc(OC(F)(F)F)c2)NC3=O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
K2CO3 (9.1 mg, 66.0 μmol) was added to a solution of acetic acid 2-[acetyl-(3-methyl-4-{2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-amino]-ethyl ester (28.1 mg, 44.0 μmol) in MeOH (0.5 mL). The mixture was stirred at room temperature for two hours. H2O was then added and the mixture was diluted with CH2Cl2. The organic layer was washed with saturated brine, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (CH2Cl2/MeOH=15/1) to give N-(2-hydroxy-ethyl)-N-(3-methyl-4-{2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-acetamide as a white amorphous (24.0 mg, 92%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([N:33]([CH2:47][C:48]([NH:50][NH2:51])=[O:49])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([F:46])([F:45])[F:44])(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:26]([N:33]([CH2:47][C:48]([NH:50][NH:51][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)=[O:49])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([F:44])([F:45])[F:46])(=[O:36])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NNC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(C(=O)NNC(=O)CN(Cc2ccccc2)S(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
To a stirred solution of 3-methylsulfonylbenzoic acid (60 mg) in N,N-dimethylacetamide (1.3 mL) was added 1,1′-carbonyl-diimidazole (52 mg). The mixture was stirred at 50° C. for 20 min. After cooling to r.t., N-benzyl-N-hydrazinocarbonylmethyl-2-trifluoromethyl-benzenesulfonamide (100 mg) was added and the mixture was stirred at 100° C. overnight. After cooling to r.t. the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, dichloromethane to dichloromethane/methanol 95:5) to give N-benzyl-N-{2-[N′-(3-methanesulfonyl-benzoyl)-hydrazino]-2-oxo-ethyl}-2-trifluoromethyl-benzenesulfonamide (111 mg) as a colorless oil. MS: 570.3 ([M+H]+)
Reaction SMILES: C(C1[N:17]2[C:8]([C:9](=[O:25])[NH:10][C:11]3[C:12]([CH2:23][CH3:24])=[N:13][C:14]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)=[N:15][C:16]=32)=[CH:7]N=1)CC=C.Br[N:27]1[C:31](=O)[CH2:30][CH2:29][C:28]1=[O:33].[C:34](O)(=[O:36])C.O>C(O)(=O)C.C([O-])(=O)C.[Ag+]>[OH:33][CH:28]([CH2:34][OH:36])[CH2:29][CH2:30][C:31]1[N:17]2[C:8]([C:9](=[O:25])[NH:10][C:11]3[C:12]([CH2:23][CH3:24])=[N:13][C:14]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)=[N:15][C:16]=32)=[CH:7][N:27]=1
Reactant: CC(=O)O
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCCc1ncc2c(=O)[nH]c3c(CC)nc(-n4ccnc4)nc3n12
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: O
Product: CCc1nc(-n2ccnc2)nc2c1[nH]c(=O)c1cnc(CCC(O)CO)n12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 5.25 g (15.7 mmol) of the product of Example 9i in 100 mL of acetic acid at 0° C. Add 2.79 g (15.7 mmol) of N-bromosuccinimide and 2.61 g (15.6 mmol) of silver acetate, and stir the mixture at ambient temperature for 24 hours. Add 500 mL of 9/1 acetic acid/water and heat to 90° C. for 16 hours. Filter the mixture through Celite, evaporate the solvent, and dissolve the residue in 1 N HCl. Treat the solution with charcoal, filter, and make basic with concentrated NH4OH. Collect the precipitate and wash with water and acetonitrile. Suspend the precipitate in 200 mL of 3/1 methanol/concentrated NH4OH and heat to reflux for 8 hours. Evaporate the mixture, dissolve the residue in 2N HCl, and precipitate with concentrated NH4OH. Collect the precipitate and wash with water and acetonitrile. Triturate the precipitate with boiling methanol, DMF and then again with methanol to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.F[C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[NH:22][C:21]2=[O:28])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O.O>[CH3:26][C:23]1([CH3:27])[C:24](=[O:25])[N:20]([C:17]2[CH:16]=[CH:15][C:14]([O:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=3)=[N:19][CH:18]=2)[C:21](=[O:28])[NH:22]1
Reactant: CC(C)c1cc(O)ccc1C#N
Reactant: CC1(C)NC(=O)N(c2ccc(F)nc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)c1cc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cn2)ccc1C#N
Temperature: 120 °C
Reaction time: 40 h
Yield: 19.2 %

Procedure:
4-hydroxy-2-(1-methylethyl)benzonitrile (30 mg) was dissolved in 1 mL of dimethylformamide. 3-(6-fluoro-3-pyridinyl)-5,5-dimethyl-2,4-imidazolidinedione (Intermediate 106, 41.5 mg) and potassium carbonate (51.4 mg, 0.372 mmol) were added. The reaction mixture was stirred at 120° C. during 40 hours. Some diethylether (4 mL) and water (4 mL) were added. The aqueous layer was extracted 4 times with diethylether. The gathered organic layers were dried over sodium sulphate and evaporated giving a residue which was purified by mass directed purification (METHOD H). After evaporation of the fraction, addition of a solution of saturated NaHCO3 (3 mL) and extraction with dichloromethane (four times 4 mL), evaporation afforded the title compound (13 mg).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:38])[CH2:33][S:34]([CH3:37])(=[O:36])=[O:35]>>[CH3:37][S:34]([CH2:33][C:32]1[N:38]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:31]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)CC(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: CS(=O)(=O)Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 40.9 mg (0.269 mmol) of N′-hydroxy-2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 1. Yield: 31.2 mg (24% of theory).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:29])[C:9]=1[N:10]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4]>CCOCC>[CH2:22]([N:10]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:9]1[C:8]([CH3:29])=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1scc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C)csc2C(=O)O)cc1
Yield: 106 %

Procedure:
In the same manner as described in Example 11, 1.366 g (2.622 mmol) of the product of Example 8 provided 1.16 g (87%) of the desired carboxylic acid as a white solid after trituration with ether. Electrospray Mass Spec: 416 (M-H)-.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:17]12CC(C=C1)C=[CH:18]2>O1CCOCC1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][N:1]3[CH:18]=[CH:17][N:3]=[N:2]3)[O:9][N:8]=2)=[N:11][CH:12]=1
Reactant: [N-]=[N+]=NCC1CC(c2ccc(Br)cn2)=NO1
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: Brc1ccc(C2=NOC(Cn3ccnn3)C2)nc1

Procedure:
5-Azidomethyl-3-(5-bromo-pyridin-2-yl)-4,5-dihydro-isoxazole (1 g, 3.5 mmol) and bicyclo[2.2.1]hepta-2,5-diene (1 ml) were combined with dioxane (2 ml) and subjected to microwave radiation in a Smith Personal Synthesizer for 900 seconds at 125° C. The reaction mixture was concentrated in vacuo and ethyl acetate (5 ml) was added. The precipitate was filtered and washed with ethyl acetate (2×5 ml) to give the desired product (417 mg).
Reaction SMILES: I.CS[C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][NH2:18])[CH:13]=[CH:14][C:15]=1[CH3:16]>C1(C)C(C)=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][NH:18][C:4]2[NH:5][CH2:6][CH2:7][N:8]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(NN)cc1Cl
Reactant: CSC1=NCCN1
Agent: I
Solvent: Cc1ccccc1C
Product: Cc1ccc(NNC2=NCCN2)cc1Cl
Temperature: 120 °C

Procedure:
A mixture of 2-methylthio-2-imidazoline hydroiodide (1.83 g, 12 mmol) and 3-chloro-4-methyl-phenylhydrazine (1.87 g, 12 mmol) in xylene (10 ml) was heated to 120° C. overnight. After cooling down to room temperature the precipitate is filtered off and re-crystallised from ethanol, white solid, 0.41 g, MS (ISP): 227.3, 225.3 ([M+H]+.).
Reaction SMILES: CO.[F:3][C:4]1([F:24])[CH2:8][CH2:7][C@@H:6]([C@@:9]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:11])[CH2:5]1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH4-].[Na+]>C(OCC)(=O)C>[F:3][C:4]1([F:24])[CH2:8][CH2:7][C@@H:6]([C@@:9]([OH:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:11])[CH2:5]1
Reactant: NCCCOC(=O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCCCNCc1ccccc1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reaction time: 0.5 h

Procedure:
To a methanol solution of 87 mg of 3-aminopropyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate, 35 mg of benzaldehyde was added at room temperature, stirred for 30 minutes at the same temperature, sodium borohydride was added, and further stirred for 30 minutes. The reaction liquid was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on silica gel column chromatography (eluent: chloroform/methanol=50/1), to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([C:21]1[CH:26]=[CH:25][C:24](SC)=[CH:23][N:22]=1)([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:13][CH:14]=1)[CH2:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.O1CCC[CH2:30]1.O.O[O:36][S:37]([O-:39])=O.[K+]>C(OCC)(=O)C.CO>[CH3:1][C:2]([C:21]1[CH:26]=[CH:25][C:24]([S:37]([CH3:30])(=[O:39])=[O:36])=[CH:23][N:22]=1)([C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:13][CH:14]=1)[CH2:3][CH:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CSc1ccc(C(C)(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)nc1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(CC1CCOCC1)(c1ccc(S(C)(=O)=O)cn1)c1ccc(-c2ccccn2)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To a mixture of 2-[1-methyl-1-(5-(pyridin-2-yl)-1H-pyrrol-2-yl)-2-(tetrahydro-2H-pyran-4-yl)ethyl]-5-(methylsulfanyl)pyridine (84.0 mg), tetrahydrofuran (1 mL), water (1 mL) and methanol (1 mL) was added Oxone (registered trademark) (157 mg), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (55.5 mg, yield 61%) was obtained as white crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). melting point 135-136° C. MS: 426 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[C:27]([O:31][C:32]([N:34]1[CH2:37][CH:36]([CH:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)O)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>O1CCCC1.C(#N)C.O1CCCC1>[C:27]([O:31][C:32]([N:34]1[CH2:37][CH:36]([CH:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[I:20])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)cc2)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C(I)c2ccc(Cl)cc2)C1
Reaction time: 0.25 h

Procedure:
Polymer supported triphenylphosphine (125 g, 370 mmol) is suspended in tetrahydrofuran: acetonitrile 9:1 (1000 ml) and treated with Iodine (95.2 g, 370 mmol) followed by stirring for 15 minutes. Imidazole (25.5 g, 370 mmol) is added followed by a solution of 3-[(4-Chloro-phenyl)-hydroxy-methyl]-azetidine-1-carboxylic acid tert-butyl ester (44.7 g, 150 mmol) in tetrahydrofuran (150 ml) and the reaction mixture stirred at ambient temperature for 20 hours. The reaction mixture is filtered through celite™ filter material and the filtrate evaporated. The residue is taken up in chloroform and washed with sodium thiosulphate solution, water and brine. The solution is dried over magnesium sulphate and evaporated to provide 3-[(4-Chlorophenyl)-iodo-methyl]-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR 400 MHz, CDCl3, δ 1.35 (9H), 3.21 (1H), 3.37 (1H), 3.60 (2H), 4.05 (1H), 5.12 (1H), 7.20 (4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=2)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[C:12]([C:13]=1[O:14][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=2)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c(O)c2cc(OC)ccc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1c(OCc2ccccc2)c2cc(OC)ccc2n1-c1ccccc1

Procedure:
A mixture of 155 g (0.52 mole) of 3-hydroxy-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester [P. C. Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1984)], 83.0 g (0.60 mole) of anhydrous potassium carbonate, and 68 ml (97.8 g; 0.57 mole) of benzyl bromide in 2250 ml of acetone was stirred at reflux for 20 hours. The mixture was cooled, filtered, and the filter cake was washed several times with fresh acetone. The combined filtrates were evaporated (vacuum) to yield a crude residue of 5-methoxy-1-phenyl-3-(phenylmethoxy)-1H-indole-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[C:5]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:4]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:54]([NH:57][NH2:58])(=[O:56])[CH3:55]>CN(C)C=O.O>[C:54]([NH:57][NH:58][C:9]([C:7]1[CH:6]=[C:5]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:4]=[C:3]([O:2][CH3:1])[N:8]=1)=[O:11])(=[O:56])[CH3:55]
Reactant: COc1ccc(CCNc2cc(C(=O)O)nc(OC)n2)cc1
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCNc2cc(C(=O)NNC(C)=O)nc(OC)n2)cc1
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
To a solution of 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid [100 mg, 0.33 mmol, Intermediate (56)] in dimethylformamide (1 mL) is added N,N-diisopropylethylamine (145 μL, 0.83 mmol) followed by TBTU (128 mg, 0.4 mmol). Stirred the reaction mixture for 5 minutes before adding acetic hydrazide (37 mg, 0.5 mmol) and continued stirring the reaction mixture overnight at ambient temperature. The reaction mixture is poured into water (25 mL) and subsequently extracted three times with 25 mL ethyl acetate. The combined organic extracts are washed three times with 25 mL water, with 25 mL brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The material obtained is subjected to flash column chromatography on silica (10 g) eluting with 0 to 5% MeOH in DCM gradient to afford 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid N′-acetyl-hydrazide (42 mg). A mixture of 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid N′-acetyl-hydrazide (42 mg, 0.12 mmol), p-toluenesulfonylchloride (34 mg, 0.18 mmol) and PS-BEMP (218 mg, 0.48 mmol) in THF (1.5 mL) is irradiated in a microwave to 140° C. for 6 minutes. The material is filtered and absorbed onto silica gel and subjected to flash column chromatography on silica gel eluting with 10 to 50% EtOAc in heptane gradient to afford [2-methoxy-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [25.1 mg, 63%, Example 44]. LCMS: RT=2.64 minutes, MS: 342 (M+H). IC50=55 nM
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][N:26]3[CH:34]=[CH:35][CH:36]=[C:25]3[CH2:24]2)=[O:22])=[C:17]([Cl:37])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Cl:37][C:17]1[CH:16]=[C:15]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:20]=[CH:19][C:18]=1[C:21]([N:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][N:26]2[CH:34]=[CH:35][CH:36]=[C:25]2[CH2:24]1)=[O:22]
Reactant: O=C(c1ccc(Br)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: OB(O)c1cccc2ccccc12
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(c1ccc(-c2cccc3ccccc23)cc1Cl)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C

Procedure:
1-Naphthaleneboronic acid (0.52 g, 3.00 mmol) was added to a mixture of (4-bromo-2-chlorophenyl)-(5H, 11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone of Step A (1.27 g, 3.15 mmol) and sodium carbonate (0.53 g, 4.98 mmol) in toluene (22.5 mL), ethanol (4.5 mL) and water (9 mL). The resultant solution was purged with nitrogen for 10 minutes, then tetrakis(triphenylphosphine)palladium (0.18 g, 0.06 mmol) was added. The reaction mixture was heated to reflux for 76 hours. The solution was cooled to ambient temperature, then filtered through a pad of Celite, which was subsequently rinsed with ethyl acetate. The combined filtrate was diluted to 100 mL water/ethyl acetate (1:1). The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield a brown oil. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (5:1) resulted in a white solid which was dried under vacuum (0.62 g), m.p. 115–117.5° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:14]2[N:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=O.C([NH2:18])=O.C[O-].[Na+]>Cl>[CH3:15][C:11]1[CH:12]=[N:13][C:14]2[CH:5]([C:3]([NH2:18])=[O:2])[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: COC(=O)C1CCCc2cc(C)cnc21
Reactant: NC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cnc2c(c1)CCCC2C(N)=O
Yield: 90 %

Procedure:
A mixture of methyl-3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate (25 g. 0.13 m), formamide (11.6 g., 0.26 m) and sodium methoxide (from 2.99 g., 0.13 m sodium) was heated on a steam bath for 1 hour while bubbling nitrogen through the mixture, to blow off the methyl formate produced in the reaction. The cooled reaction mixture was diluted with 2N HCl and worked up as described in Example 21 to give the title compound in 90% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[C-:11]#[N:12].[K+]>O1CCOCC1.O.CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)cc(CBr)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1cc(F)cc(Br)c1

Procedure:
To a solution of 3-bromo-5-fluorobenzyl bromide (3.2 g, 0.0112 mole) in 1,4-dioxane (20 mL) was added a solution of KCN (0.82 g, 0.013 mole) in H2O (5 mL) and EtOH (5 mL), refluxed for 2 hours, extracted with ether, washed with brine, dried over MgSO4, and concentrated. Column chromatography was performed using hexane/ethyl acetate (19:1). 3-Bromo-5-fluorophenylacetonitrile was obtained was a colorless oil: 1H NMR (DMSO-d6) δ4.15 (s, 2H), 7.29(d, 1H, J=9.37 Hz), 7.47(s, 1H), 7.55(d, 1H, J=8.45 Hz); MS(EI) M+m/z 213; Anal. Calc. For C8H5BrFN: C, 44.89, H, 2.35, N,6.54. Found: C, 44.88, H, 2.32, N, 6.46.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1Br.C(O)(C)C.O>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(F)cc2)nc(Br)c1Br
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(Br)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
4,5-Dibromo-2-(4-fluorophenyl)-1-(2-trimethylsilanyl-ethoxymethyl)imidazole (10.8 g; 25 mmol) are dissolved in THF (108 ml) and cooled to −78 C under argon. N-BuLi (15.6 ml; 1.6 M) is added under stirring within 15 min. After 30 min at −78 C, isopropanol (7.8 ml; 0.1 mol) is introduced dropwise and the mixture warmed to room temperature. Water is added to the reaction mixture and the aqueous phase extracted three times with ethyl acetate. The combined organic phases are washed with saturated NaCl-solution, dried over Na2SO4, filtered and evaporated to dryness, yielding the title compound as colorless oil (9.1 g; 95%).