Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:13]CC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>C1COCC1>[C:16]1([C:1]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C=CCCCCCCCCC(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCCCCCCCC(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 75 h

Procedure:
To a solution of 10.6 g of ethyl undecylenate in 100 mL of THF at 0° C. was added, over 1 hr, 40 mL of 3M phenyl magnesium bromide. The mixture was warmed to room temperature and stirred for 75 hrs. Methanol, 10 mL, was added to quench the excess Grinard reagent and the solvent was distilled in vacuo. The residue was shaken with diethyl ether and dilute hydrochloric acid. The ether layer was washed with water and saturated sodium hydrogen carbonate, dried, and concentrated in vacuo to give 18.3 g of crude product, which was then chromatographed on silica gel with chloroform as the eluent, to give 13.7 g of 1,1-diphenyl-10-undecen-1-ol which is characterized by:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][N:19]=[C:20]([C:23]4[C:28]([CH2:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:31][CH3:32])[CH:21]=3)[N:16]([CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][N:19]=[C:20]([C:23]4[C:24]([CH2:31][CH3:32])=[CH:25][CH:26]=[CH:27][C:28]=4[CH2:29][CH3:30])[CH:21]=3)[N:16]([CH:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCC(CCC)n1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2cc(-c3c(CC)cccc3CC)ncc21
Agent: [Pd]
Solvent: CCO
Product: CCCC(CCC)n1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c2cc(-c3c(CC)cccc3CC)ncc21
Reaction time: 18 h

Procedure:
The 4-[5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) is dissolved in EtOH (2 mL), 10% Pd/C (5 mg) is added, and the mixture is shook in a parr-reactor under 50 psi of H2 over 18 h. Filter, remove solvents and chromatograph the residue affords 4-[5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil: 1H NMR (CDCl3) 8.80 (s, 1H), 7.36 (s, 1H), 7.27 (t, J=7 Hz, 1H), 7.13 (d, J=12 Hz, 2H), 7.04 (s, 1H), 436 (m, 1H), 4.21 (m, 1H), 2.96 (m, 1H), 2.92 (m, 1H), 2.34 (m, 4H), 2.03 (m, 1H), 1.86 (m, 4H), 1.63 (m, 2H), 1.49 (s, 9H), 1.28 (m, 4H), 1.02 (t, J=8 Hz, 6H), 0.90 (t, J=8 Hz, 6H); LCMS m/z 532.39 (2.58 min).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)[N:3]=[CH:4]2)[CH:12]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(I)c3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.23) (0.525 g, 1.09 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.286 g, 1.3 mmol) according to the general procedure VI. Obtained as a yellow solid (0.148 g, 33%). MS (ISP) 450.2 [(M+H)+]; mp 245-247° C.
Reaction SMILES: [CH:1]([C:4]1[C:19]([O:20][C:21]2([CH3:32])[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]2)=[CH:18][C:7]2[N:8]3[C@H:13]([CH3:14])[C:12](=[O:15])[NH:11][N:10]=[C:9]3[CH2:16][O:17][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH:1]([C:4]1[C:19]([O:20][C:21]2([CH3:32])[CH2:22][NH:23][CH2:24]2)=[CH:18][C:7]2[N:8]3[C@H:13]([CH3:14])[C:12](=[O:15])[NH:11][N:10]=[C:9]3[CH2:16][O:17][C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc2c(cc1OC1(C)CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of (R)-tert-butyl 3-((8-isopropyl-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)oxy)-3-methylazetidine-1-carboxylate ((enantiomer 2, SFC (Table 1, Method 24), Rt=9.756 min., 0.095 g, 0.213 mmol) in DCM (3 mL) was added TFA (0.5 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give (R)-8-isopropyl-1-methyl-9-((3-methylazetidin-3-yl)oxy)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #121-2, Enantiomer 2, SFC (Table 1, Method 24), Rt=3.331 min, 0.085 g, 97%). LC/MS (Table 1, Method 5) Rt=2.175 min.; MS m/z: 345 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:11])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[C:19](C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.IC>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH3:19])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CI
Solvent: ClCCl
Product: COCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 52.8 %

Procedure:
4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (861 mg, 3.32 mmol) was dissolved in DCM (6.6 mL) then 2,6-di-tert-butyl-4-methylpyridine (1.023 g, 4.98 mmol) and AgOTf (938 mg, 3.65 mmol) were added. The reaction mixture was cooled to 0° C. and iodomethane (0.25 mL, 3.98 mmol) was added. After 4 min, the reaction mixture was diluted with DCM and it was filtered over elite. The filtrate was concentrated to a residue which was dissolved in diethyl ether. The organic solution was washed with 10% HCl and brine, then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (20% to 80% EtOAc/Hex) to afford the title compound (479 mg, 53%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:24])[N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=2)[N:13]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-96, 0.250 g, 0.678 mmol), pivaloyl chloride (0.3 mL), TEA (2.0 mL), and dry THF (5 mL) to afford 0.150 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s, 9H), 4.30 (d, J=6.0 Hz, 2H), 7.41-7.43 (m, 1H), 7.59-7.62 (m, 3H), 7.71-7.76 (m, 1H), 8.19-8.29 (m, 3H), 12.68 (s, 1H); MS (m/z): 453.38 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:19])[CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.O1CCOCC1.[I:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>O>[C:27]([CH:21]([NH:20][C:18](=[O:19])[NH:17][CH:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:5])=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:44]([C:41]1[CH:42]=[CH:43][C:38]([I:37])=[CH:39][CH:40]=1)(=[O:46])=[O:45])([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCN)C(=O)O)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCC(NC(=O)NC(CCCCNS(=O)(=O)c1ccc(I)cc1)C(=O)O)C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
In a round bottom flask 2-[3-(5-Amino-1-carboxy-pentyl)-ureido]-pentanedioic acid di t-butyl ester (300 mg, 0.62 mmol) is suspended in water (10 mL) and 1,4 dioxane (10 mL) and TEA (1.75 mL, 1.25 mmol) was added followed by 4-iodo-benzenesulfonyl chloride and the mixture stirred overnight at 50° C. The reaction mixture was evaporated to dryness, taken up in DCM and chromatographed over silica gel to afford the desired product (375 mg, 80%) as a clear oil. The compound was dcprotected using the previously described methods followed by HPLC purification to afford the desired product MIP-1097 as a whiter solid (270 grams, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, 2H), 7.68 (t, 1H), 7.53 (d, 2H), 6.35 (dd, 2H), 4.10 (m, 1H), 4.00 (m, 1H), 2.65 (m, 2H), 2.22 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H), 1.35 (m, 2H), 1.25 (m, 2H), (3 CO2H not seen). ESMS m/z: 565 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:6]3[C:7]4[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=4[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)=[N:10][CH2:11][C:5]3=[N:4][N:3]=2)[CH2:27][CH2:26]1
Reactant: Brc1nnc2n1-c1ccccc1C(c1ccccn1)=NC2
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(c2nnc3n2-c2ccccc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-(β-hydroxyethyl)piperazine to give 1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=O)=[CH:4][CH:3]=1.[CH2:19]([NH:21][CH2:22][CH2:23][NH2:24])[CH3:20]>>[CH2:19]([N:21]1[C:6]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=3)[C:8]3[C:9]([C:10](=[O:12])[N:24]2[CH2:23][CH2:22]1)=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:20]
Reactant: CCNCCN
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Product: CCN1CCN2C(=O)c3ccccc3C12c1ccc(Cl)cc1

Procedure:
Condense o-(p-chlorobenzoyl)benzoic acid (13 g.) and N-ethylethylenediamine (15 ml.) by the procedure of Example 1 to obtain 1-ethyl-9b-(p-chlorophenyl)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 114° C. (elemental analysis confirms the empirical formula C18H17ClN2O).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:12][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: Cc1ccc(C(N)=O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(C)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 617.5 %

Procedure:
A mixture of 2-hydroxy-4-methyl-benzamide (15.1 g, 0.1 mol) and K2CO3 (41.7 g, 0.3 mol) in 1000 mL of acetone was heated to reflux for 1 hour before Me2SO4 was added at that temperature. The resulting mixture was refluxed overnight. The reaction mixture was then filtered and the filtrate was concentrated. The resulting residue was dissolved in 1000 mL of methanol/ammonia (1:1) and stirred at room temperature for 3 hours. After removal of the solvent, the residue was recrystallized from EtOAc/PE to afford 102 g of 2-methoxy-4-methyl-benzamide (yield 61%). 1H NMR (400 MHz, DMSO-d6): δ 7.72 (d, J=7.6 Hz, 1H), 7.57 (br s, 1H), 7.46 (br s, 1H), 6.92 (s, 1 H), 6.81 (d, J=7.6 Hz, 1 H), 3.85 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[CH:7][CH:6]=1.[H-].C([Al+]CC(C)C)C(C)C.FC(F)(C(F)F)COC1C=CC(C=O)=CC=1.C(OP([CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])(OCC)=O)C>>[F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:51]/[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: N#Cc1ccc(OCC(F)(F)C(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Agent: [H-]
Product: CCOC(=O)/C=C/c1ccc(OCC(F)(F)C(F)F)cc1

Procedure:
In a first step, p-chlorobenzonitrile is reacted with 2,2,3,3-tetrafluoropropanol in the presence of bases, for example sodium hydride, with exchange of the p-chlorine atom to give 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile. The second step is to reduce the 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile by metal hydrides, for example diisobutylaluminum hydride, 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde being formed. The 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde is reacted stereoselectively with ethyl diethylphosphonoacetate in a third reaction step to give ethyl (E)-4-(2,2,3,3-tetrafluoropropoxy)cinnamate.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:12][C:13](=O)[CH2:14][CH:15]([C:20](=[O:23])[NH:21][CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18].[CH2:25]([O:32][C:33](=[O:40])[CH2:34][NH:35][CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:32][C:33](=[O:40])[CH2:34][N:35]([CH2:36][CH:37]([CH3:38])[CH3:39])[C:13](=[O:12])[CH2:14][CH:15]([C:20](=[O:23])[NH:21][CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CNC(=O)C(CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)CC(C)C
Reactant: CC(C)CNCC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: CNC(=O)C(CC(=O)N(CC(=O)OCc1ccccc1)CC(C)C)CC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To an ice-cooled solution of 5-methyl-3-methylcarbamoyl-hexanoic acid 2,3,4,5,6-pentafluorophenyl ester (350 mg, 0.99 mmol) in DMF (5 ml) was added isobutylamino-acetic acid benzyl ester (110 mg, 0.49 mmol) with stirring. The reaction mixture was allowed to warm to room temperature and stirred for 2 days then for 3 h at 50° C. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed successively with 1M HCl, 1M Na2CO3 and brine. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel, 50→100% ethyl acetate in hexane) to give the title compound as a colorless oil (130 mg, 70%). 1H-NMR; δ (CDCl3, rotamers), 7.33 (5H, m), 6.17 (1H, m), 5.15 (1H, m), 4.21 (1H, m), 3.91 (1H, m), 3.41-2.95 (2H, br m), 2.81 (2H, m), 2.75 (3H, m), 2.32 (1H, m), 1.91-1.40 (3H, br m), 1.28-1.05 (1H, m) and 0.85 (12H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]([CH:22]=[C:23]([C:29]([O:31]CC)=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(=O)(O)[O-]>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:9]3[C:10](=[CH:11][C:12]([CH2:15][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[CH:13][CH:14]=3)[C:29](=[O:31])[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22]2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)C(=CN(c1ccc(CN2CCOCC2)cc1)C1CCN(C)CC1)C(=O)OCC
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)c1cn(C2CCN(C)CC2)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 130 °C
Yield: 98.8 %

Procedure:
A flask containing diethyl 2-{[(1-methyl-4-piperidinyl)-4-(4-morpholinylmethyl)anilino]methylene}malonate (0.36 g) is treated with polyphosphoric acid (1.8 g). The reaction mixture is heated to 130° C. under a flow of nitrogen gas. After 4 hours the reaction is cooled to room temperature. The reaction mixture is carefully added to a vigorously stirred mixture of dichloromethane and saturated aqueous bicarbonate. The layers are separated and the basic aqueous layer is extracted with three additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.32 g of crude ethyl 1-(1-methyl-4-piperidinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate as a tan solid.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:18]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH2:33][NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])=O.[CH2:44]([NH2:47])[CH2:45][CH3:46].CO>ClCCCl>[N+:23]([C:22]1[CH:21]=[CH:20][C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH2:33][NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:36])=[O:37])=[CH:18][C:17]=1[CH2:15][NH:47][CH2:44][CH2:45][CH3:46])([O-:25])=[O:24]
Reactant: O=Cc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CCCNCc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
NaBH(OAc)3 (0.0031 mol) was added to a mixture of N-[2-(3′-formyl-4′-nitro-biphenyl-2-yl)-ethyl]-benzenesulfonamide (0.0021 mol) and propylamine (0.0023 mol) in DCE (2 mL), and the reaction mixture was stirred overnight under N2. The excess of NaBH(OAc)3 was decomposed with CH3OH, and the solvent was evaporated. The residue was purified by Biotage column chromatography (eluent: 95:5 CH2Cl2:CH3OH). The purest product fractions were collected and then the solvent was evaporated and co-evaporated with toluene to yield the title compound as a residue.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:10]([CH:13]1[CH2:15][CH2:14]1)[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(OP(OC2C=CC=CC=2)([N:72]=[N+:73]=[N-:74])=O)=CC=1>C1COCC1>[N:72]([CH2:11][C@H:10]([CH:13]1[CH2:15][CH2:14]1)[C@H:9]([C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:73]=[N-:74]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)C2CC2)COC1(C)C
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)[C@H](CN=[N+]=[N-])C2CC2)COC1(C)C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of tert-butyl (4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.3 g, 3.0 mmol) and triphenylphosphine (1.6 g, 6.1 mmol) in anhydrous THF (20 mL), DIAD (1.2 mL, 5.9 mmol) was added drop-wise under an atmosphere of nitrogen. Upon completion of addition, a precipitate was formed. The reaction mixture was stirred for 30 min. then diphenylphosphonic azide (1.3 mL, 6.2 mmol) in anhydrous THF (1.0 mL) was added. After stirring at ambient temperature for 3 h, the volatile organic solvents were removed under reduced pressure and the crude product was purified by flash column chromatography (120 g of silica gel, eluting with 0-15% EtOAc-hexanes) to afford the sub-title compound as a light yellow oil (1.18 g, 86%). LC/MS (ESI) m/z calc. for C17H35N4O2Si: 355.30 [M-Boc+H]+. found: 355.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)=O.[NH2:24][C:25]1[C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[OH:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:24]=[C:25]3[C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=[CH:27][N:26]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1cccnc1N
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CCO)NC(=O)OC(C)(C)C)cc3)nc12

Procedure:
A mixture of 1,1-dimethylethyl ((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)carbamate (1.00 g, 2.59 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.358 g, 2.59 mmol), and solid sodium bicarbonate (0.272 g, 3.24 mmol) in isopropanol (25 mL) was heated at reflux for 3.5 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried (Na2SO4), and concentrated. The resulting pale yellow solid was used in the next reaction without further purification. MS(ES+) m/e 426 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1>CO.[OH-].[Na+]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2occc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2occc2c1
Temperature: 65 °C
Yield: 100.3 %

Procedure:
A stirred mixture of methyl benzofuran-5-carboxylate (1.3 g, 7.38 mmol) in MeOH (51 mL) and sodium hydroxide (41 mL of a 5% aqueous solution) is heated to 65° C. for 4 h. The mixture is cooled to rt, and MeOH is removed in vacuo. The remaining aqueous layer is extracted with CH2Cl2. The CH2Cl2 layer is discarded, and the aqueous layer is acidified to pH=1 with concentrated hydrochloric acid. The aqueous layer is extracted with CHCl3. The organic layer is washed with water, dried (MgSO4), filtered and concentrated in vacuo to afford 1.2 g (98%) of benzofuran-5-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.9, 8.30, 8.11, 7.92, 7.69, 7.09.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.O1CCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Br:1][C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: O=C(NC1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC1CCN(c2ncnc3[nH]cc(Br)c23)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of N-{1-[5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-piperidinyl}benzamide (100 mg), D6, in methanol (1 mL) and tetrahydrofuran (2 mL) was added cesium carbonate (181 mg, 0.555 mmol) and the mixture stirred at room temperature for 3 h. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (15 mL) and the organic phase dried (phase separator) and the solvent removed in vacuo. The crude material was purified by MDAP to give the title compound E29 (32 mg) as a white solid. 1H NMR (d6-DMSO) δ 12.24 (1H, s), 8.38 (1H, d), 8.29 (1H, s), 7.87 (2H, d), 7.55 (1H, s), 7.53 (1H, t), 7.46 (2H, t), 4.18 (2H, d), 4.08 (1H, m), 3.09 (2H, t), 1.94 (2H, d), 1.81 (2H, ddd), MS(ES+) 400 [M(C18H1879BrN5O)+H]+.