Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].I[CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.O>O1CCCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Reactant: ICCOCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: ClCCC(=C(c1ccccc1)c1ccc(OCCOCCOC2CCCCO2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenol (0.33 g, 0.001 mol) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere. Sodium hydride (0.036 g, 0.0015 mol) was added to the solution and the mixture was stirred at room temperature for an hour. 2-[2-(2-iodo-ethoxy)-ethoxy)-tetrahydropyran (0.6 g, 0.002 mol) was added and the mixture was refluxed for 3 hours. After cooling and adding water the mixture was extracted three times with ethyl acetate. The organic phase was dried with sodium sulphate and evaporated to dryness. The residue was used in the next reaction step without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.[OH-].[Na+:33]>O>[Na+:33].[Na+:33].[NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[O:18])=[CH:29][CH:30]=3)[C:5]=2[C:4](=[O:31])[N:3]=1
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1

Procedure:
2.5 grams of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (purity 99.6% by HPLC) were dissolved in 0.5 L of distilled water with the addition of 5.849 mL of a 2.0M standard solution of sodium hydroxide. The pH of the solution was adjusted to 7.14 by adding a diluted solution of sodium hydroxide in water and a suspension of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid in the same solvent. The obtained solution was dried in a freeze-drier affording the title compound as a white solid (2.8 g, purity 99.6% area by HPLC). Acidimetric titrations of the final product confirmed the absence of residual sodium hydroxide and pemetrexed diacid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[O:46]1[CH:50]=[CH:49][N:48]=[C:47]1[CH2:51][NH2:52]>CC(O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:52][CH2:51][C:47]2[O:46][CH:50]=[CH:49][N:48]=2)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Reactant: NCc1ncco1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2NCc2ncco2)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
To a solution of 1-tert-butyl 3-methyl (3R,5S)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (0.55 g) and diisopropylethylamine (0.87 ml) in 2-propanol (5 ml) was added 2-oxazolylmethylamine hydrochloride (0.34 g), and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and the fraction eluted with hexane to ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (525 mg).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:17][C:18]([F:26])([F:25])[C:19](=[CH2:24])[C:20]([O:22][CH3:23])=[O:21]>>[F:17][C:18]([F:26])([F:25])[CH:19]([CH2:24][N:11]1[CH2:12][CH2:13][O:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10]1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: C=C(C(=O)OC)C(F)(F)F
Reactant: FC(F)(F)c1cccc(C2CNCCO2)c1
Product: COC(=O)C(CN1CCOC(c2cccc(C(F)(F)F)c2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
In a 5 mL round-bottomed flask, 2-(3-(trifluoromethyl)phenyl)morpholine (650 mg, 2.81 mmol) was combined with methyl 2-(trifluoromethyl)acrylate (650 mg, 4.22 mmol; added slowly) to give a colorless solution and stirred at room temperature for 50 min. The crude reaction mixture was concentrated in vacuo to give an oil. The crude material was purified by flash chromatography (silica gel, 40+S, 0% to 30% ethyl acetate in hexanes) to afford 850 mg (78%)(methyl 3,3,3-trifluoro-2-((2-(3-(trifluoromethyl)phenyl)morpholino)-methyl)propanoate as a clear liquid. MH+=386.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:13]1[C:17](B(O)O)=[CH:16][CH:15]=[N:14]1.C([O-])(O)=O.[Na+]>COCCOC.O>[F:12][C:9]1[CH:10]=[CH:11][C:2]([C:15]2[NH:14][N:13]=[CH:17][CH:16]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccn[nH]1
Reactant: COC(=O)c1cc(F)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(F)ccc1-c1ccn[nH]1
Temperature: 23 °C
Yield: 44.9 %

Procedure:
Methyl 2-bromo-5-fluorobenzoate (1.0 gram, 4.2 mmol) and (1H-pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 ml) then treated with NaHCO3 (706 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (243 mg (0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction mixture was cooled to 23° C., filtered, and solid rinsed with EtOAc. The organic layers were separated, dried and concentrated. Purification via FCC (ethyl acatate/hexanes, 0-30%) afforded methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 44%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([NH:31][C:32]([N:36]([CH2:38][CH2:39][OH:40])[CH3:37])=[N:33][C:34]#[N:35])[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([NH:31][C:32]([N:36]([CH2:38][CH2:39][OH:40])[CH3:37])=[N:33][C:34]#[N:35])[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(NC(=NC#N)N(C)CCO)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(C)cc(NC(=NC#N)N(C)CCO)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1d from methyl 4'-[[2-n-propyl-4-methyl-6-[2-cyano-3-(2-hydroxy-ethyl)-3-methylguanidino]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.C[O:8][C:9](OC)([N:11]([CH3:13])[CH3:12])[CH3:10].CN(C)C(OC)=C>>[CH3:12][N:11]([CH3:13])[C:9](=[O:8])[CH2:10][C:2]([CH3:6])([CH3:1])[CH:3]=[CH2:4]
Reactant: CC(C)=CCO
Reactant: COC(C)(OC)N(C)C
Agent: C=C(OC)N(C)C
Product: C=CC(C)(C)CC(=O)N(C)C
Yield: 90 %

Procedure:
147 g of 3-methyl-but-2-en-1-ol are added to 180 g of a mixture of 72.5% by weight of N,N-dimethylacetamide-dimethylacetal and 27.5% by weight of 1-dimethylamino-1-methoxyethylene, and the batch is brought to 144° C. in the course of 80 minutes, whilst at the same time distilling the resulting methanol from the reaction mixture. The batch is then heated for 100 minutes at 144°-154° C. Distillation through a short column gives 205 g (90%) of 3,3-dimethyl-pent-4-enoic acid N,N-dimethylamide (of boiling point 70° C./2.6 mbar), corresponding to a yield of 90% of theory.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[C:12]1([C:18]#[C:19][C:20](O)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:20](=[O:21])[C:19]#[C:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4]2
Reactant: O=C(O)C#Cc1ccccc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(C#Cc1ccccc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 3-phenylpropynoic acid; MS (ES+) 255 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S([O-])(=O)(=O)C.[CH2:21]([N:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26]O)[CH3:22].CS(Cl)(=O)=O>CS(C)=O>[CH2:21]([N:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCN(CC)CCCO
Reactant: O=Cc1ccc(O)cc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCN(CC)CCCOc1ccc(C=O)cc1
Temperature: 90 °C

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (20 mmol) in DMSO (80 mL) at rt, solid Cs2CO3 (50 mmol) was added. The mesylate prepared from 3-diethylamino-1-propanol and methanesulfonyl chloride, General Procedure P2 (30 mmol) was added to the reaction mixture and heated to 90° C. until the reaction was complete. After cooling to rt, the reaction was quenched by cold H2O (100 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (3×50 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography (eluting with 10% MeOH in DCM+0.5% Et3N) to afford 4-(3-diethylaminopropoxy)benzaldehyde.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([CH3:33])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]2[C:9](=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=2)[C:8]=1[C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])C.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC#N.CCOC(C)=O.O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]2[C:14]3[C:9](=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=3)[C:8]([C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:7]2[CH2:6][C:5]([CH3:34])([CH3:33])[C:4]([OH:35])=[O:3])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2nc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(n1)c(C(=O)CC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
3-[1-(4-Chloro-benzyl)-3-(3,3-dimethyl-butyryl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionic acid ethyl ester (0.020 g, 0.04 mmol) was dissolved in MeCN (1 mL). 1N LiOH (0.16 mL, 0.16 mmol) was added and the reaction was heated to 60° C. overnight. Once no starting material was seen by LCMS, the reaction was cooled to room temperature and diluted with EtOAc and water. The mixture was neutralized with solid citric acid to ˜pH 5, the aqueous layer was extracted three times with EtOAc, the combined organics were washed twice with water, once with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by HPLC to give the desired acid. LCMS (ESI) M+H 471.
Reaction SMILES: [Br:1]Br.[N:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[N:4]1>CC(O)=O>[Br:1][C:6]1[CH:5]=[N:4][N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: c1ccc(-n2cccn2)nc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1cnn(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Bromine (10.8 mL, 210 mmol) in AcOH (50 mL) was added carefully to a solution of 2-(1H-pyrazol-1-yl)pyridine (11 g, 70 mmol) in AcOH (100 mL) to give a brown precipitate. After stirring at ambient temperature for 3 h, the resulting reaction mixture was poured into ice and saturated aqueous Na2SO2O5 was added until the liquid phase became clear. The precipitate was removed by filtration and recrystallized from EtOH:H2O to give 2-(4-bromo-1H-pyrazol-1-yl)pyridine as beige crystals. 1H NMR (CD3Cl, 300 MHz) δ 8.61 (1H, s), 8.42 (1H, br. s), 7.94-7.96 (1H, m), 7.84 (1H, ddd), 7.69 (1H, s), 7.21-7.28 (1H, m). MS (ESI) 225 (M+H)+
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][CH:15]([CH2:17][CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])[S:14][C:13]=2[C:26]=1[CH3:27])(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[OH:8][C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][CH:15]([CH2:17][CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])[S:14][C:13]=2[C:26]=1[CH3:27]
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SC(CCCC(C)(C)C(=O)O)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCC(C)(C)C(=O)O)O2

Procedure:
3.6 g of 5-(5-t-butyldimethylsilyloxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)-2,2-dimethylpentanoic acid (prepared as described in Example 80), 14.2 g of tetrabutylammonium fluoride trihydrate and 4.9 g of acetic acid were dissolved in 50 ml of tetrahydrofuran, and the mixture was reacted for 20 hours at room temperature. The reaction mixture was then condensed by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and dried over anhydrous sodium sulfate, after which the ethyl acetate was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography. The title compound was obtained from the fraction eluted with a 9:1 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[N:1]1[CH:6]=[C:5]([C:11]2[CH:12]=[C:13]([NH2:14])[CH:15]=[CH:16][CH:17]=2)[CH:4]=[N:3][CH:2]=1
Reactant: OB(O)c1cncnc1
Reactant: Nc1cccc(Br)c1
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: COCCOC
Product: Nc1cccc(-c2cncnc2)c1
Temperature: 25 °C
Yield: 31 %

Procedure:
5-pyrimidinyl-boronic acid (0.108 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.031 g in 31% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][CH:24]([CH3:26])[CH3:25].O>CN(C)C(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)CN(Cc1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of N-[(4-bromophenyl)methyl]-1-phenyl-methanesulfonamide (Example 5, Step 1) (2 g, 5.82 mmol) in N,N-dimethylacetamide (20 mL) was added sodium hydride (60% in mineral oil) (353 mg, 8.8 mmol) and the reaction was stirred at ambient temperature for 30 minutes. 1-Bromo-2-methyl-propane (0.96 mL, 8.81 mmol) was then added and the reaction was stirred for 16 hours. Water was added and the reaction was diluted with EtOAc. The reaction was then washed with water (3×) and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-50% EtOAc in heptane) to give N-[(4-bromophenyl)methyl]-N-isobutyl-1-phenyl-methanesulfonamide (1.20 g, 52% yield). LCMS (m/z) ES+ 418.1 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([CH:17]([OH:24])[CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:14]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17](=[O:24])[CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:14]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:11]2=[N:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc2c(c1)cc(C(O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cnc2c(c1)cc(C(=O)CC1CCCC1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of [1-benzenesulfonyl-2-(2-cyclopentyl-1-hydroxy-ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-carbamic acid tert-butyl ester (0.57 g, 1.18 mmol) in dichloromethane (10 mL) was added a solution of Dess-Martin periodinane in dichloromethane (0.3 M, 7.87 mL, 2.36 mmol) at 25° C. The mixture was stirred at 25° C. for 1 h and then quenched with a saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (3×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 25% ethyl acetate/hexanes) afforded [1-benzenesulfonyl-2-(2-cyclopentyl-acetyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-carbamic acid tert-butyl ester (0.375 g, 66%) as a light yellow solid: LC/MS m/e calcd for C25H29N3O5S [M+H]+ 484.59, observed 484.2.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:18]=[C:19]([NH:21][CH:22]4[CH2:27][CH2:26][N:25]([C:28]5[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=5)[CH2:24][CH2:23]4)[N:20]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:8]=[CH:9][CH:10]=1.C(N(CC)C(C)C)(C)C.Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46]>ClCCl>[CH3:17][C:15]1[CH:16]=[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[CH2:4][NH:3][C:45](=[O:46])[O:47][CH2:48][CH3:49])[C:12]2[N:13]([N:18]=[C:19]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=4)[CH2:26][CH2:27]3)[N:20]=2)[CH:14]=1
Reactant: Cc1cc(-c2cccc(CN)c2)c2nc(NC3CCN(c4cc(C)ncn4)CC3)nn2c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NCc1cccc(-c2cc(C)cn3nc(NC4CCN(c5cc(C)ncn5)CC4)nc23)c1
Temperature: 25 °C

Procedure:
To a suspension of 8-(3-(aminomethyl)phenyl)-6-methyl-N-(1-(6-methylpyrimidin-4-yl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine dihydrochloride (37 mg, 73.8 μmol) in dichloromethane (0.75 mL) was added N,N-diisopropylethylamine (38.1 mg, 51.5 μL, 295 mmol). To the resulting yellow solution was added ethyl chloroformate (8.99 mg, 7.89 μL, 81.2 mmol) and the reaction was stirred at room temperature over night. The title compound was obtained as a light yellow solid (35 mg, 95%) after column chromatography on silica gel using a gradient from methylene chloride to a mixture of methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 501.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): (ppm)=8.51 (s, 1H), 8.13 (s, 1H), 7.83 (br s, 2H), 7.44 (t, 1H), 7.36 (s, 1H), 7.33 (d, 1H), 6.41 (s, 1H), 5.08 (br m, 1H), 4.53 (br d, 1H), 4.44 (d, 2H), 4.32 (br d, 2H), 4.15 (q, 2H), 3.96 (m, 1H), 3.69 (m, 1H), 3.20 (t, 2H), 3.10 (m, 1H), 2.40 (s, 3H), 2.38 (s, 3H), 2.22 (br d, 2H), 1.25 (t, 3H).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C@@H:8]([C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][N:12]1[C@H:16]([CH3:17])[CH2:15][C@H:14]([NH2:18])[C:13]1=[O:19])[CH3:4].C(N(CC)CC)C.[N:36]1[C:45]2[NH:44][CH2:43][CH2:42][CH2:41][C:40]=2[CH:39]=[CH:38][C:37]=1[CH:46]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C@@H:8]([C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][N:12]1[C@H:16]([CH3:17])[CH2:15][C@H:14]([NH:18][CH2:46][C:37]2[CH:38]=[CH:39][C:40]3[CH2:41][CH2:42][CH2:43][NH:44][C:45]=3[N:36]=2)[C:13]1=[O:19])[CH3:4]
Reactant: O=Cc1ccc2c(n1)NCCC2
Reactant: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](N)C[C@H]1C)c1ccc(OC)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](NCc2ccc3c(n2)NCCC3)C[C@H]1C)c1ccc(OC)nc1
Reaction time: 1.5 h

Procedure:
To a stirred suspension of 4-8 (250 mg, 0.57 mmol), triethylamine (80 mL, 0.57 mmol), and 5,6,7,8-tetrahydro-[1,8]naphthyridine-2-carboxaldehyde (for preparation, see U.S. Pat. No. 6,048,861) (93 mg, 0.57 mmol) in 1,2-dichloroethane (5 mL) was added sodium triacetoxyborohydride (182 mg, 0.86 mmol) and the resulting mixture was stirred for 1.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was then washed with saturated aqueous sodium chloride, dried over magnesium sulfate, then filtered. Following evaporative removal of the solvent, the residue was purified by flash column chromatography (silica gel, 95:5:0.5:0.5% ethyl acetate/ethanol/NH4OH/H2O) to give 4-9 as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Br[CH2:24][CH:25]1[CH2:28][CH2:27][CH2:26]1>>[CH:25]1([CH2:24][O:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: BrCC1CCC1
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)cn2)cc1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(OCC3CCC3)cn2)cc1

Procedure:
N-{3-[4-(5-Hydroxypyridin-2-yloxy)phenyl]-1-methylpropyl}acetamide was reacted with bromomethylcyclobutane in analogy to example 10b.