Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[O:16][CH:17]=[CH:18][C:13]3=[CH:12][C:11]=2[C:19]([OH:21])=[O:20])=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)C.[H][H]>[Pd].O>[CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[O:16][CH2:17][CH2:18][C:13]3=[CH:12][C:11]=2[C:19]([OH:21])=[O:20])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)C1(C)N=C(c2nc3c(cc2C(=O)O)CCO3)NC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 5.9 %

Procedure:
A solution of 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[2,3-b]pyridine-5-carboxylic acid (1.7 g 0.056 mol) and 1.0 g (0.0072 mol) potassium carbonate in 200 mL 9:1 ethanol:water is added to 100 mg 5% palladium on carbon catalyst in a 500 mL pressure bottle. The bottle is fitted to a Parr hydrogenation apparatus, pressurized to 30 psi, with hydrogen, then shaken at room temperature for 10 hours. The catalyst is removed by filtration through a sintered glass funnel, and the filtrate concentrated in vacuo to 10 mL. Acidification of the residue to pH 2 gives a white precipitate which is removed by filtration, washed with water and air dried to give 1.0 g (63%) of 2,3-dihydro-6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[2,3-b]pyridine-5-carboxylic acid as an off-white solid, mp 189°-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[OH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15]2.C(=O)([O-])[O-].[Cs+].[Cs+].CC(=O)OCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15]3)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: O=C(O)c1cnc2ccc(O)cc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cnc2ccc(Oc3ccnc(Cl)c3)cc2c1
Temperature: 150 °C

Procedure:
A mixture of 2-chloro-4-nitropyridine (0.228 g, 1.44 mmol), 6-hydroxyquinoline-3-carboxylic acid (Int-15, 0.3 g, 1.58 mmol), and cesium carbonate (1.41 g, 4.32 mol) in N,N-dimethylformamide (3 mL) was heated at 150° C. for 2 h in a microwave reactor. The reaction was cooled to room temperature and filtered to remove solids. The filtrate was acidified with hydrochloric acid (1 M in water) until pH 1.5. The product precipitated cleanly and was isolated by suction filtration. LC-MS: (FA) EA+ 301; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.31 (d, J=2.1 Hz, 1H), 8.98 (d, J=2.0 Hz, 1 H), 8.34 (d, J=5.7 Hz, 1H), 8.21 (d, J=9.1 Hz, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.79 (dd, J=9.1, 2.8 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.09 (dd, J=5.7, 2.3 Hz, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:20][CH2:21][O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:27]3[CH:26]([CH2:25][C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:31][CH2:30][CH2:29][C:28]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(OC)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methoxyphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound is prepared.
Reaction SMILES: C(OC([C@@H:11]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:12]([C@H:21]1[CH2:25][C@@H:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH2:23][N:22]1C(OC(C)(C)C)=O)[O:13][Si](C(C)(C)C)(C)C)=O)C1C=CC=CC=1.[C:46]([NH:49][C@:50]1([C@@H:105]([CH2:107][CH3:108])[CH3:106])[CH2:54][CH2:53][N:52]([C@@H:55]([CH2:96][CH2:97][C:98]2[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=2)[C:56]([NH:58][C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2C[C@H](OC3C=CC=CN=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:57])[C:51]1=[O:104])(=[O:48])[CH3:47].OOS([O-])=O.[K+]>CO.O>[C:46]([NH:49][C@:50]1([C@@H:105]([CH2:107][CH3:108])[CH3:106])[CH2:54][CH2:53][N:52]([C@@H:55]([CH2:96][CH2:97][C:98]2[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=2)[C:56]([NH:58][C@@H:11]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:12]([OH:13])[C@H:21]2[CH2:25][C@@H:24]([S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH2:23][NH:22]2)=[O:57])[C:51]1=[O:104])(=[O:48])[CH3:47]
Reactant: CCCS(=O)(=O)[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccn3)CN2C(c2ccccc2)c2ccccc2)C1=O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCS(=O)(=O)[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@](NC(C)=O)([C@H](C)CC)C2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Step 22 (D): (2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-phenylpropyl)-4-(propylsulfonyl)pyrrolidine-1-carboxylate. A solution of 130 mg (0.2 mmol) of the compound of step 22 (C) dissolved in 2 mL of methanol was treated with a solution of 240 mg (0.4 mmol) of oxone dissolved in 0.4 mL of water. After stirring at rt for 30 min, the reaction solution was partitioned between ethyl acetate and water, the organic layer was concentrated, and the crude product was purified by chromatography eluting with a gradient of 20 to 80% ethyl acetate in hexanes to provide 86 mg (64%) of the desired sulfone and 37 mg (28%) of the sulfoxide intermediate as a lower-eluting compound. 1H NMR (500 MHz, CDCl3) δ 0.06 (s, 3 H) 0.11 (s, 3 H) 0.96 (s, 9 H) 1.07 (t, J=7.32 Hz, 3 H) 1.47 (s, 9 H) 1.87 (dd, J=13.43, 6.71 Hz, 3 H) 2.03 (s, 1 H) 2.26 (t, J=12.21 Hz, 1 H) 2.38 (s, 1 H) 2.68 (s, 1 H) 2.90 (s, 2 H) 3.46 (m, 2 H) 3.75 (s, 1 H) 4.09 (m, 2 H) 4.26 (d, J=7.02 Hz, 1 H) 4.77 (m, 1 H) 4.95 (m, 1 H) 7.18 (m, 10 H) MS (ESI) (M+H−Boc)+=575.25
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=[N:21]3)[C:17]([Cl:29])=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6].Cl>C1COCC1.O>[N:20]1([C:18]2[C:17]([Cl:29])=[CH:16][N:15]=[C:14]([NH:13][C@H:10]3[CH2:9][CH2:8][C@H:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]3)[N:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: COC(=O)C1CCC(Nc2ncc(Cl)c(-n3nnc4ccccc43)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](Nc2ncc(Cl)c(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution of NaOH (2 M, 10 mL) was added to a colorless solution of 4-(4-benzotriazol-1-yl-5-chloro-pyrimidin-2-ylamino)-cyclohexanecarboxylic acid methyl ester (482 mg, 1.25 mmol) in THF (10 mL) at RT. The reaction mixture was stirred at RT overnight; it was then diluted with water (15 mL) and acidified until pH 3 by addition of HCl (2 M). The white precipitate formed was collected by filtration, washed with water and air dried to give 435 mg (85% yield) of trans-4-(4-benzotriazol-1-yl-5-chloro-pyrimidin-2-ylamino)-cyclohexane-carboxylic acid as a white solid. MS: 373.12 (M+1)+, 345.15 ((M+1)+−28).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[N:3]=1.[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC>[O:19]1[C:15]2([CH2:20][CH2:21][CH:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:32]4[CH:33]=[CH:34][C:29]([O:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:30][CH:31]=4)=[N:3]3)[CH2:13][CH2:14]2)[O:16][CH2:17][CH2:18]1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.8 %

Procedure:
3-bromo-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Intermediate X) (4.0 g, 11.3 mmol), 4-phenoxyphenylboronic acid (Intermediate V) (2.66 g, 12 mmol), sodium carbonate (2.87 g, 27 mmol), palladium tetrakis(triphenyphosphine) (0.78 g, 0.6 mmol) in dimethoxyethane (120 mL)/water (60 mL) mixture was heated at 85° C. under nitrogen for 4 hrs. Cool to room temperature and stand for 72 hrs. The solid which precipitated was filtered and washed with water and diethylether (100 mL of each). Dry in vacuo for 3 hrs to furnish 4.2 g of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as a beige solid (87%). 1H NMR (400 MHz, d6-DMSO) 8.24 (1H, s), 7.67 (2H, m), 7.45 (2H, m), 7.19 (5H, m), 4.78 (1H, m), 3.90 (4H, m), 2.25 (2H, m), 1.71-1.84 (6H, m) Mass Spec.: MH+=444.2
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH2:14][CH2:15]Br>>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13]([CH2:14][CH2:15][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])[CH:17]=[CH:18][CH:19]=1
Reactant: CCc1ccncc1
Reactant: FC(F)(F)c1cccc(CCBr)c1
Product: CC(CCc1cccc(C(F)(F)F)c1)c1ccncc1
Yield: 15.3 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.37 g (9.35 mmol) of 3-trifluoromethylphenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 0.40 g of the desired compound (yield: 15.3%).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22](C)[CH:21]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)C.[OH-].[Na+].[CH2:31]1COCC1.CO>>[CH3:15][CH:13]([CH3:14])[CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:28])=[CH:6][CH:7]=1)[NH:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:31]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C(CC(C)C)Nc2cnc3cc(C)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc2cc(NC(CC(C)C)c3ccc(C(=O)O)cc3)cnc12
Yield: 100 %

Procedure:
A mixture of 4-[3-Methyl-1-(7-methyl-quinoline-3-ylamino)-butyl]-benzoic acid ethyl ester (48 mg, 0.13 mM) and 1N aqueous NaOH solution (0.318 mL, 0.318 mM) in THF-MeOH (1:1, 1.5 mL) was heated to 50° for 5 h. The reaction was cooled, concentrated to remove organic solvent. The aqueous solution was diluted with DCM (5 mL), acidified by 1N HCl solution to pH=3-4. The organic solution was separated and the aqueous solution was extracted with DCM (3×5 mL). The combined organic solution were dried (Na2SO4) and concentrated to give a yellow solid product (44 mg, −100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.97 (d, J=6.44 Hz, 3H) 1.02 (d, J=6.44 Hz, 3H) 1.54-1.67 (m, 1H) 1.73-1.91 (m, 2H) 2.43 (s, 3H) 4.57-4.65 (m, 1H) 7.14 (d, J=2.54 Hz, 1H) 7.28 (dd, J=8.49, 1.27 Hz, 1H) 7.46-7.58 (m, 4H) 7.97 (d, 2H) 8.44 (d, J=2.34 Hz, 1H), two protons (COOH and NH) were exchanged. LC-MS: m/z 349.1 (M+1). This material will be used for the next step reaction without further work-up.
Reaction SMILES: Br[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+].O>CN(C=O)C>[N:10]([C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ncccc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncccc1N=[N+]=[N-]

Procedure:
A solution of 3-bromo-2-cyanopyridine (Chem. Pharm. Bull, 1985, 33, 565) (2.6 g, 14.2 mmol) and sodium azide (1.0 g, 15.3 mmol) in DMF (30 ml) was heated at 90° C. for 16 h. The resulting mixture was cooled, water was added and the whole was extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over magnesium sulphate. Evaporation of the solvent gave the product as an oil, which was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petrol (1:3 to 1:1) as eluent to afford the product. MS (EI) m/z 145; 1H NMR (d6-DMSO) 8.50 (1H, d), 8.09 (1H, d), 7.77 (1H, dd).
Reaction SMILES: [C:1]([N:8]([CH3:27])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:38])[CH:36]=[O:37])=[CH:31][CH:30]=1>>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:29]3[CH:34]=[CH:33][C:32]([N:35]([CH:36]=[O:37])[CH3:38])=[CH:31][CH:30]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:27])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(NCc2cc(B(O)O)ccc2F)CC1
Reactant: CN(C=O)c1ccc(Br)cc1
Product: CN(C=O)c1ccc(-c2ccc(F)c(CNC3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1

Procedure:
The title compound was prepared from boronic acid (247) (300 mg, 0.79 mmol) and aryl bromide (51) (200 mg, 0.95 mmol) in accordance with Method B.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)=[O:4].[CH2:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:24]1([CH2:23][N:30]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)=[O:4])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C(CBr)c1cccc(OCCCOCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CN(Cc1ccccc1)Cc1ccccc1)c1cccc(OCCCOCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-bromo-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanone (13.17 g), dibenzylamine (6.4 g) and dichloromethane (25 mL) was added a solution of sodium carbonate (7.6 g) in water (50 mL). The reaction mixture was stirred at ambient temperature overnight. The organic layer was separated and concentrated to a minimum and tert-butyl methyl ether was added. The organic layer was washed with dilute acetic acid (4 times) and 0.1N sodium hydroxide once and brine once. The organic solution was concentrated to dryness. The oil was washed with methanol and purified by chromatography to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([CH3:12])=[N:10][CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:11]([CH2:12][Br:13])=[N:10][CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nccnc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nccnc1CBr
Reaction time: 1 h

Procedure:
A mixture of 3-methyl-pyrazine-2-carboxylic acid ethyl ester (Example 1.1) (0.5 g), N-bromosuccinimide (“NBS”) (0.536 g) and 2,2′-azobis(2-methylpropionitrile) (“AIBN”) (0.487 g) in carbon tetrachloride (2.5 ml) was heated to reflux. After 1 hour thin layer chromatography showed a mixture of starting material and the desired product. Further NBS (0.536 g) and AIBN (0.243 g) were added and the reaction mixture heated for a further 1 hour. The percentage of product increased and impurities began to form. The reaction mixture was cooled to ambient temperature and then to 0° C. The cold mixture was filtered and the filtrate concentrated. The residue was purified by chromatography on silica gel (eluent: 0-10% v/v ethyl acetate in iso-hexane) to give 3-bromomethyl-pyrazine-2-carboxylic acid ethyl ester (640 mg) contaminated with 3-methyl-pyrazine-2-carboxylic acid ethyl ester (due to co-elution, ˜3:2). MH+=245, RT=1.26 min (Method A).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:24]=2[CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([N:31]3[CH2:32][CH2:33][N:28]([C:25]4[C:24]5[CH:34]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=5[O:27][CH:26]=4)[CH2:29][CH2:30]3)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C1CCN(c2ccc(F)c3cccnc23)CC1
Reactant: Fc1ccc2occ(N3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc2occ(N3CCN(C4CCN(c5ccc(F)c6cccnc56)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
To a solution of 0.200 g of 1-(5-fluoro-quinolin-8-yl)-piperidin-4-one (Example C, Step 3, 0.20 g) and 5-fluoro-3-piperazino benzofuran (Step 2, 0.20 g) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (0.224 g) and 0.02 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ML of silica gel using 50% Ethyl acetate/Hexanes then 100% Ethyl acetate to give 0.100 g of the desired product. Mp: 187-189° C.; MS (ES) m/z (relative intensity): 449 (M++−H, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:14][CH2:15][N:16](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]([NH:16][CH2:15][CH3:14])=[O:13])=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)c1c[nH]c(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.075 g, 0.368 mmol) in DMF (1 ml) was added DIPEA (0.193 ml, 1.105 mmol), HATU (0.168 g, 0.442 mmol), and ethyl amine (0.045 g, 0.553 mmol) and the reaction stirred at RT for 2 h. Purification was accomplished by HPLC to afford methyl 3-chloro-4-[(ethylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.035 g, 41% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (br. s., 1H) 7.81 (t, 1H) 7.48 (d, 1H) 3.80 (s, 3H) 3.20 (dd, 2H) 1.08 (t, 3H). MS: m/z 231.0 (M+1).
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13])([CH3:8])[CH3:7].[C:23]1([CH3:34])[CH:28]=[CH:27][C:26]([CH2:29][S:30](Cl)(=[O:32])=[O:31])=[CH:25][CH:24]=1.CN1CCOCC1>CN(C=O)C>[Br-:1].[NH2:20][C:19]1[C:14]([C:12]([NH:11][CH2:10][CH2:9][N+:6]([CH3:7])([CH3:8])[CH2:5][CH2:4][CH2:3][NH:2][S:30]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([CH3:34])=[CH:24][CH:25]=2)(=[O:32])=[O:31])=[O:13])=[N:15][C:16]([Cl:22])=[C:17]([NH2:21])[N:18]=1
Reactant: C[N+](C)(CCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: Cc1ccc(CS(=O)(=O)Cl)cc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(CS(=O)(=O)NCCC[N+](C)(C)CCNC(=O)c2nc(Cl)c(N)nc2N)cc1

Procedure:
A solution of (3-amino-propyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate M) (0.30 g, 0.756 mmol), p-tolyl-methanesulfonyl chloride (0.16 g, 0.76 mmol) and N-methylmorpholine (0.4 mL, 3.64 mmol) in DMF (5 mL) is shaken at RT for 16 h. The solvent is removed in vacuo and the residue is subjected to chromatography (basic alumina; 0-15% methanol in DCM) to yield the title compound. M+ 484.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:32])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[CH3:31])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:32])=[C:16]([CH3:31])[CH:17]=1)(=[O:29])=[O:28]
Reactant: Cc1cc(-c2ccccc2S(C)(=O)=O)ccc1NC(=O)C1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccccc2S(C)(=O)=O)ccc1NC(=O)C1CCCN1
Yield: 93 %

Procedure:
2-(2′-Methanesulfonyl-3-methyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.4 g, 0.87 mmol) was dissolved in 15 mL DCM and 5 mL trifluoroacetic acid and stirred at ambient temperature for 2 hour and concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO3, separated layers, washed organics with brine, dried with MgSO4, filtered and concentrated to yield title compound as an oil (0.29 g, 93%) APCI (AP−): 357.1 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)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>[CH2:15]([O:14][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([NH:23][CH3:22])[CH:25]=2)=[CH:3][CH:4]=1)[C:10]([O:12][CH3:13])=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)OCc1ccccc1
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cccc(-c2ccc(C[C@H](OCc3ccccc3)C(=O)OC)cc2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
635 mg (0.55 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 4 g (11 mmol) of methyl (S)-3-(4-bromophenyl)-2-benzyloxypropionate and 4 g (17 mmol) of methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 25 ml of dimethylformamide. 10 ml of a 2M potassium phosphate solution are added and the reaction mixture is stirred at 70° C. for 1 hour. The reaction is halted by the addition of 50 ml of water and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 2.6 g of methyl (S)-2-benzyloxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=61%.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.CC([OH:16])(C)C.CC(=CC)C.[O-]Cl=O.[Na+]>O>[O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:16])=[O:11])=[CH:2]1
Reactant: CC(C)(C)O
Reactant: O=Cc1coc2ncccc12
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: O=C(O)c1coc2ncccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of furo[2,3-b]pyridine-3-carboxaldehyde (67 mmol) [J. Heterocyclic Chem., 23, 1465 (1986)] in 52 mL H2O were added NaH2PO4 (67 mmol), 260 mL t-BuOH, 71 mL 2-methyl-2-butene followed by portionwise addition of NaClO2 (100 mmol) at 0° C. After 15 min, the cooling bath was removed and the reaction was stirred at RT for 24 h. A solution of sat. aq. NaHCO3 was added and the mixture was extracted with EtOAc. The water phase was acidified with 1N HCl solution and it was then extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired compound as beige solid.