Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][NH:13][C:14]1[C:19]([C:20]#[N:21])=[CH:18][N:17]=[C:16](SC)[N:15]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.O1CCCC1>[CH3:12][NH:13][C:14]1[C:19]([C:20]#[N:21])=[CH:18][N:17]=[C:16]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:37][CH:36]=2)[N:15]=1
Reactant: CNc1nc(SC)ncc1C#N
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(N3CCN(C)CC3)cc2)ncc1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
248 mg of mCPBA was added to a 3:1 toluene-tetrahydrofuran (30 mL) solution containing 130 mg of 4-(methylamino)-2-(methylsulfanyl)pyrimidine-5-carbonitrile, and the mixture was stirred at room temperature for 15 minutes. Then, 138 mg of 4-(4-methylpiperazin-1-yl)aniline, and 280 mg of DIPEA were added to the mixture, which was then stirred at 80° C. for 8 hours. The solvent was distilled away after cooling the reaction mixture. Then, water was added, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated saline, and the solution was concentrated after drying with anhydrous magnesium sulfate. The resulting crude product was purified by basic silica gel column chromatography, and 170 mg of a white solid was obtained as a subject compound.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[OH:6][C:7]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][C:8]=1[CH:9]=O>C1(C)C=CC=CC=1>[CH2:1]([N:5]=[CH:9][C:8]1[CH:11]=[C:12]([CH:15]=[CH2:16])[CH:13]=[CH:14][C:7]=1[OH:6])[CH2:2][CH2:3][CH3:4]
Reactant: C=Cc1ccc(O)c(C=O)c1
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: C=Cc1ccc(O)c(C=NCCCC)c1
Yield: 78.7 %

Procedure:
74 g (1 mole) of butylamine were added to a solution of 74 g (0.5 mole) of 2-hydroxy-5-vinylbenzaldehyde in 750 ml of toluene, and this mixture was refluxed for 2 hours. It was then extracted with twice 500 ml of ice water and the toluene was distilled off. 80 g (79%) of 2-butyliminomethyl-4-vinylphenol were obtained as a yellow oil.
Reaction SMILES: [O:1]1[C:24]2=[C:25]3[C@:20]([CH3:27])([CH2:21][CH2:22][C@@H:23]2[OH:26])[C@@H:19]2[C@H:4]([C@H:5]4[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:8]([CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH2:7][CH2:6]4)[C@@H:3]2[O:29][C@:2]123.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([O:26][C@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:27])[C:25]3[C@:2]4([O:1][C:24]1=3)[O:29][C@H:3]4[C@@H:4]1[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:28])[C@H:5]1[CH2:6][CH2:7][C@@H:8]2[CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4OC(C)=O)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
To a mixture of 0.202 g (0.50 mmole) of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3β-ol, 0.5 ml (6.18 mmoles) of dry pyridine and 10 ml of methylene chloride was gradually added 0.1 ml (1.06 mmoles) of acetic anhydride dropwise at a temperature of 0° C. and the resulting solution was stirred at room temperature for 14 hours. The reaction mixture was then worked up in the same manner as Example 10 to recover 0.185 g of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-ene-3β-yl acetate (yield: 83%).
Reaction SMILES: [C:1]([C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=1)([CH3:5])[CH3:4])#[N:2].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([C:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: CCOC(=O)c1csc(C(C)(C)C#N)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.6 %

Procedure:
To a solution of ethyl 2-(1-cyano-1-methylethyl)-1,3-thiazole-4-carboxylate (0.9 g, 4.0 mmol) in tetrahydrofuran/methanol/water (=12 mL/4.0 mL/4.0 mL) was added lithium hydroxide monohydrate (330 mg, 8.0 mmol), and the reaction mixture was stirred at room temperature for 10 hr. The mixture was concentrated under reduced pressure, and the obtained aqueous solution was adjusted to pH 5 by adding 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure to give the title compound (256 mg, 53%) as a white powder.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH2:8]1)(=O)=O.[CH2:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][CH:20]=1)[CH3:17]>>[CH:13]1([CH2:12][N:9]2[CH2:10][CH2:11][CH:7]([CH2:6][N:18]([CH2:16][CH3:17])[C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:23][CH:24]=3)[CH2:8]2)[CH2:15][CH2:14]1
Reactant: CCNc1ccc(-n2ccnc2)cc1
Reactant: CS(=O)(=O)OCC1CCN(CC2CC2)C1
Product: CCN(CC1CCN(CC2CC2)C1)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 2, react 1-cyclopropylmethyl-3-pyrrolidinemethanol methanesulfonate with N-ethyl-4-(1H-imidazol-1-yl)benzenamine to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:24](=[O:26])[CH3:25])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-cyano-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (206 mg), acetic anhydride (0.127 mL), and triethyl amine (0.187 mL) in dichloromethane (2 mL) was stirred at room temperature for 1 h; then the mixture was concentrated, the residue was purified with column to give the title compound (201 mg). The title compound, ESI MS (m/z): 350 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(OC(=O)[NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[CH:30][C:29]=1[NH2:39])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[CH:30][C:29]=1[NH:39][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([C:6]2([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(C2(c3nccs3)CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C2(c3nccs3)CCOCC2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of 4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoic acid (0.9 g, 3.11 mmol), 2-Amino-4-thiophen-2-yl-phenyl-carbamic acid tert-butyl ester (1.08 g, 1.1 eq), HATU (1.42 g, 1.2 eq), and DIPEA (1.04 mL, 2.0 eq) were dissolved in DMF and stirred at 45° C. overnight. After the reaction was complete, it was cooled down and precipitated with water and a saturated solution of NaHCO3. The solid formed was collected and used for next step without further purification. Solid {2-[4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoylamino]-4-thiophen-2-yl-phenyl}-carbamic acid tert-butyl ester was re-dissolved in DCM/TFA (1:1) and stirred for 1 hour. After the reaction was complete, the reaction mixture was evaporated and purified by reverse phase chromatography to afford title compound, Example 64. MS found for C28H26N7FOS as (M+H)+ 461.12. 1H NMR (400 MHz, dmso-d6): 1H-NMR (DMSO) δ: 9.74 (s, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.44 (s, 1H), 7.32 (d, J=5.2 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.21 (d, J=3.6 Hz, 1H), 7.01 (q, J=3.6, 4.8 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.14 (s, 1H), 4.02-4.00 (m, 2H), 3.69-3.65 (m, 2H), 2.11-2.08 (m, 4H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[O:7][CH:6]=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[C:10](=[O:11])[CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[O:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1coc(-c2cccc([N+](=O)[O-])c2)cc1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1coc(-c2cccc(N)c2)cc1=O
Yield: 75.3 %

Procedure:
3-Acetoxy-6-(3-nitrophenyl)-4-pyrone (1.80 g, 6.5 mmol) was dissolved in methanol (50 ml) and hydrogenated at 10 psi for 1 h, using 10% palladium on carbon catalyst (0.2 g, 11% (w/w)). The reaction mixture was then filtered through "hyflo" and the filtrate evaporated in vacuo. The residue was recrystallised from ethyl acetate:hexane (2:1) to afford the desired product (1.20 g, 75%) as a beige solid. mp 127°-129° C. 1H NMR (360 MHz, CDCl3) δ 2.35 (3H, s), 3.85 (2H, brs), 6.81 (1H, dd, J=8.0 and 1.0 Hz), 6.84 (1H, s), 7.02 (1H, dd, J=1.0 and 1.0 Hz), 7.11 (1H, brd, J=8.0 Hz), 7.25 (1H, dd, J=8.0 and 8.0 Hz), 7.98 (1H, s).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:17]1[CH:22]=[N:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])(C)(C)C.[OH-].[Na+]>CO>[C:23]1([C:20]2[N:21]=[CH:22][C:17]([N:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([OH:35])=[O:5])[CH:14]([CH3:16])[CH3:15])=[N:18][C:19]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)N(CCCCOCC(=O)OC(C)(C)C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(CCCCOCC(=O)O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 85.1 %

Procedure:
21.07 g of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid tert-butyl ester was dissolved in 200 ml of methanol and 60 ml of 1N sodium hydroxide solution was added. After the mixture was heated at reflux for 2 hours, the solvent was evaporated under reduced pressure and the residue was dissolved in water. After washing with diethyl ether, the aqueous layer was neutralized with 60 ml of 1N hydrochloric acid and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, and then the residue was washed with diisopropyl ether to obtain 15.82 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]1([CH3:43])[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[C@H:17]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:25]2[CH:24]=[CH:23][C:22]([N:18]3[C@@H:17]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:16]([CH3:15])([CH3:43])[O:20][C:19]3=[O:21])=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@H]1c1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3ccc(N)nc3)cc2)[C@H]1c1ccccc1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
2-Amino-5-bromopyridine (commercially available from Sigma-Aldrich, Milwaukee, Wis.)(0.114 mL, 5.09 mmol), sodium carbonate (5.09 mL, 10.17 mmol), (S)-5,5-dimethyl-4-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one (Intermediate J)(2.0 g, 5.09 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (415 mg, 0.509 mmol) were combined in dioxane (10.200 mL) and stirred at 115° C. overnight. LC-MS indicated good conversion to desired product. After cooling to room temperature, the reaction mixture was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide (S)-3-(4-(6-aminopyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (1 g, 2.78 mmol, 54.7% yield) as an off-white solid. m/z (ESI) 360.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.O.[NH2:21][NH2:22]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH:2]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NCc2cccnc2)s1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(C(=O)NCc2cccnc2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Methyl 5-(3-picolylcarbamoyl)thiophene-2-carboxylate (860 mg, 3.11 mmol) in ethanol (34 mL) was stirred with hydrazine monohydrate (1.57 m, 31.1 mmol) at 85° C. for 12 hours. The reaction solution was concentrated and stirred with diethyl ether at 0° C. for 1 hour. The precipitated solid was recovered by filtration and washed with a liquid mixture of diethyl ether and ethanol and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-picolylamide (yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([OH:13])[CH2:11][OH:12])[CH:5]=[N:6][C:7]=1Cl.CCO.CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]=2)O1>C1COCC1.O.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>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][C:25]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([CH2:9][CH:10]([OH:13])[CH2:11][OH:12])=[CH:5][N:6]=2)=[CH:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: OCC(O)Cc1cnc(Cl)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC=C(c2ncc(CC(O)CO)cc2Cl)CC1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To a solution of 3-(5,6-dichloropyridin-3-yl)propane-1,2-diol 59 (255 mg, 1.148 mmol) in THF (1.8 ml)-EtOH (0.7 ml)-3M K2CO3 aq. (0.842 ml, 2.53 mmol) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2 H)-carboxylate 33 (391 mg, 1.263 mmol) and PdCl2(PPh3)2 (24.18 mg, 0.034 mmol) at room temperature under N2. The mixture was stirred at 85° C. for 1.5 hr. The reaction mixture was diluted with H2O, then extracted with EtOAc (3×10 mL). The organic layers were combined and washed with brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel chromatography column and was eluted with CHCl3/MeOH (10:1) Collected fractions were evaporated to afford 60 (404 mg 1.095 mmol 95%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([CH3:11])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:5]1[C:6]2[CH:7]=[CH:8][O:9][C:10]=2[C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(F)c2occc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c2ccoc12
Yield: 108 %

Procedure:
A mixture of 7-fluoro-4-methyl-benzofuran (14.2 g), N-bromosuccinimide (19.7 g), benzoyl peroxide (0.5 g) and carbon tetrachloride (600 ml) was heated under reflux under the illumination of an 80 W flood lamp for 20 h. The mixture was cooled, and filtered and the filtrate evaporated to dryness to give the title compound as a pale orange oil (23.4 g)
Reaction SMILES: [N+](C1C=C(C=CC=1)C(O)=O)([O-])=O.C(Cl)C.N(CC(O)=O)C.[CH2:22]([O:24][C:25](=[O:40])[CH2:26][N:27]([C:29](=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[CH:31]=1)[CH3:28])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:40])[CH2:26][N:27]([C:29](=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1)[CH3:28])[CH3:23]
Reactant: CCOC(=O)CN(C)C(=O)c1cccc([N+](=O)[O-])c1
Agent: CCCl
Agent: CNCC(=O)O
Agent: O=C(O)c1cccc([N+](=O)[O-])c1
Product: CCOC(=O)CN(C)C(=O)c1cccc(N)c1

Procedure:
3-Nitro-benzoic acid was reacted with sarcosine ethyl hydrochloride and the resulting [(3-nitro-benzoyl)-methyl-amino]-acetic acid ethyl ester was hydrogenated to afford [(3-amino-benzoyl)-methyl-amino]-acetic acid ethyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The ethyl ester was hydrolysed using the same procedure as in Example 247, step b to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 10.79 (1H, br s), 7.83 (2H, m), 7.44 (1H, m), 7.14 and 7.01 (1H, 2×m), 4.15 and 3.97 (2H, 2×s), 2.94 (6H, m), 2.03-1.25 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.14; H, 8.24; N, 8.97%. C39H59N5O9.2.0 mols H2O requires: C, 60.21; H, 8.16, N 9.00%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[C:16]([F:26])=[C:17]([C:22]([F:25])=[CH:23][CH:24]=3)[C:18](=[N:20]O)[NH2:19])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.C1COCC1>CC(O)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[C:16]([F:26])=[C:17]([C:22]([F:25])=[CH:23][CH:24]=3)[C:18](=[NH:19])[NH2:20])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3)ns2)c1F
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N=C(N)c1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3)ns2)c1F
Reaction time: 4 h

Procedure:
To a solution of 3-((3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)methoxy)-2,6-difluoro-N′-hydroxybenzimidamide (0.02 g, 0.05 mmol) in AcOH (0.50 ml) was added acetic anhydride (6 μL, 0.06 mmol) followed by addition of THF (1.0 ml) under nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 h after which Pd-C (10%, 2.0 mg) was added and the resulting solution was stirred under hydrogen for 4 h. After the completion of the reaction (TLC monitoring), the reaction mass was filtered through celite bed, washed the celite bed with THF (3-4 times) and concentrated the filtrate. The residue was purified over neutral alumina (40% MeOH-DCM) to get the desired product (11 mg (58%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:7](=[O:28])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[S:16][C:17](OC4CCCCO4)=[C:18]([F:20])[CH:19]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[CH2:34]([OH:36])C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:7](=[O:28])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[S:16][C:17]([CH2:34][OH:36])=[C:18]([F:20])[CH:19]=2)[CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(F)c(OC4CCCCO4)s3)ccn2c1=O
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(F)c(CO)s3)ccn2c1=O

Procedure:
318 mg of ethyl 1-cyclopropyl-8-[4-fluoro-5-(tetrahydropyran-2-yloxy)-thiophen-2-yl]-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 101) was dissolved in 5 ml of tetrahydrofuran. 5 ml of ethanol and 43.0 mg of pyridinium p-toluenesulfonate were added to the obtained solution, and they were heated under reflux for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution. After the extraction with ethyl acetate, the organic layer was washed with water and then with saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by the silica gel column chromatography (eluent: chloroform/ethyl acetate=5/1) to obtain 230 mg of ethyl 1-cyclopropyl-8-(4-fluoro-5-hydroxymethylthiophen-2-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N:13]1([CH2:18][CH2:19]O)[CH:17]=[CH:16][N:15]=[CH:14]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O.O>[N:13]1([CH2:18][CH2:19][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: OCCn1ccnc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C

Procedure:
To a stirring mixture of the methyl 2-(4-hydroxyphenyl)acetate (1.4 g, 1 EQ) and 2-(1H-imidazol-1-yl)ethanol (1.0 g) in THF (0.5 mL, 0.5 M) at 0° C. was added PPh3 (2.9 g). To this mixture was added dropwise DIAD (2.2 mL) over 10 min. The reaction mixture was warmed to ambient temperature overnight. A normal aqueous workup with water and EtOAc was followed. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified via silica gel chromatography to give methyl 2-(4-(2-(1H-imidazol-1-yl)ethoxy)phenyl)acetate. Method[1], MS (ESI) 261.1, Retention time=0.782 min.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:18][CH:19]=3)=[CH:11][CH:10]=2)O1.I[C:34]1[CH:58]=[CH:57][C:37]2[NH:38][C:39]([C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]([CH3:50])[CH3:49])=[N:40][C:36]=2[CH:35]=1.C(=O)(O)[O-].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:54][O:53][C:52]([NH:51][C@@H:47]([CH:48]([CH3:50])[CH3:49])[C:46]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:41]1[C:39]1[NH:38][C:37]2[CH:57]=[CH:58][C:34]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[N:16]=[C:17]([C@@H:20]5[CH2:24][CH2:23][CH2:22][N:21]5[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:18][CH:19]=4)=[CH:13][CH:14]=3)=[CH:35][C:36]=2[N:40]=1)=[O:56])=[O:55]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(I)ccc2[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)OC(C)(C)C)n4)cc3)ccc2[nH]1)C(C)C
Yield: 38.8 %

Procedure:
To a solution of tert-butyl (2S)-2-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (169 mg, 0.3847 mmol) (Ref. WO 2008/021923), methyl ((S)-1-((S)-2-(5-iodo-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (180.9 mg, 0.3847 mmol) and Pd(dppf)Cl2—CH2Cl2 (47.13 mg, 0.05771 mmol) in acetonitrile (4 mL) in a sealed tube (25 mL) under nitrogen atmosphere is added aq. sodium bicarbonate (961.8 μL of 1 M, 0.9618 mmol). The resultant suspension is heated in oil bath at 100° C. for 16 hours, concentrated, diluted with water and CH2Cl2, organic solution is separated, aqueous solution is extracted with dichloromethane, combined extracts are washed with brine and dried (Na2SO4). Purification of the residue on 25+M biotage silica gel cartridge using MeOH-ethyl acetate (0:100 to 15:85) as eluent afforded tert-butyl (2S)-2-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (101 mg, 0.1491 mmol, 38.75%) as light brown solid.