Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].CC#N.C([O-])(=O)C.[NH4+].C1C(=O)N([Br:26])C(=O)C1>>[Br:26][C:8]1[CH:9]=[C:2]([F:1])[C:3]([OH:10])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(F)c1O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: O=Cc1cc(Br)cc(F)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
This material was prepared as reported in J. Molecular Catalysis A, 2007, 30-33. Commercial 3-fluoro-2-hydroxybenzaldehyde (0.280 g, 2 mmol) was dissolved in MeCN (10 mL, 191 mmol) and ammonium acetate (0.015 g, 0.200 mmol) and NBS (0.392 g, 2.200 mmol) were added at rt. The mixture was stirred at rt for 1 h. The reaction mixture was then concentrated and the crude compound was dissolved in a small amount of dichloromethane and charged to a 12 g silica gel cartridge which was eluted with a 25 min gradient of from 0% to 30% ethyl acetate in hexanes at 30 mL/min. Fractions containing product were pooled and concentrated in vacuo to give 5-bromo-3-fluoro-2-hydroxybenzaldehyde (0.43 g, 1.963 mmol, 98% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 10.89 (s, 1H) 9.87 (s, 1H) 7.39-7.65 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:12]([C:22]([F:25])([F:24])[F:23])[CH:11]=2)=[CH:4][C:3]=1[N+:27]([O-])=O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C.C(OCC)(=O)C>[NH2:27][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[C:12]([C:22]([F:25])([F:24])[F:23])[CH:11]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)c(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccc(N3CCOCC3)c(C(F)(F)F)c2)cc1N
Temperature: 25 °C
Yield: 40.3 %

Procedure:
N-(4-methyl-3-nitrophenyl)-4-morpholino-3-(trifluoromethyl)benzoamide (68 mg, 0.17 mmol) was dissolved in ethanol (1.7 mL), tin chloride (190 mg, 0.83 mmol) was added thereto, and the mixture was subjected to a reaction with reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and then washed with an aqueous sodium hydrogen carbonate solution. The organic layer was washed with distilled water (10 mL×3), dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated solution was crystallized using ethyl acetate (2 mL) and n-hexane (20 mL) to obtain the title compound as a bright yellow solid (26 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]([C:24]2[CH:41]=[CH:40][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])=[CH:26][CH:25]=2)[CH2:21][CH2:22][CH3:23])[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([CH3:18])[C:12]=2Cl)=O)=[CH:4][CH:3]=1.O.[NH2:43][NH2:44]>CS(C)=O.[Na+].[Cl-]>[Cl:17][C:15]1[CH:16]=[C:11]2[C:12](=[C:13]([CH3:18])[CH:14]=1)[NH:44][N:43]=[C:9]2[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:20]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])=[CH:40][CH:41]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(Cl)cc(C)c1Cl)c1ccc(Cl)cc1
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1n[nH]c2c(C)cc(Cl)cc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a solution of the major diastereomer of the product of Step A (271 mg, 0.439 mmol) in DMSO (25 mL) was added hydrazine hydrate (60 wt %, 0.90 mL, 11 mmol). The mixture was stirred at 100° C. for two days in a sealed tube. The mixture was diluted with saturated NaCl (aq) then extracted twice with ethyl acetate. The combined organic layers were then washed with 2 N HCl (aq), saturated NaHCO3 (aq), and saturated NaCl (aq). The organic layer was dried over sodium sulfate, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford the major diastereomer of the title compound as a solid. This diastereomer was resolved to provide enantiopure material by supercritical fluid chromatography on a ChiralPak OJ-H column (2 cm×25 cm) eluting with 50 mL/min of 20% (MeOH+0.1% Et2NH) and 80% CO2 at 35° C. and 100 bar. LC1 2.58 min. (M-tBu+H)+ 538.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:21]=[O:22])C>C(Cl)Cl>[CH:21]([C:9]1[NH:10][CH:11]=[CH:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2cc[nH]c2)cc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2cc[nH]c2C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Following a standard procedure (Balasubramanian, T. et al, J. Org. Chem. 2000, 65, 7919-7929), a solution of 7 (472 mg, 3.00 mmol) in DMF (0.96 mL) and CH2Cl2 (30 mL) under argon was cooled to 0° C. and then POCl3 (340 μL, 3.60 mmol) was added dropwise. After 1 h, the flask was warmed to room temperature and stirred overnight (˜18 h). The reaction was quenched at 0° C. with 2.5 M NaOH (25 mL). The mixture was poured into water (50 mL), extracted with CH2Cl2, and the combined organic layers were washed with water, brine, dried (NaSO4), and concentrated. The residue was chromatographed [silica, CH2Cl2/ethyl acetate (9:1)] to give a brown solid. 1H NMR spectroscopy showed two regioisomers in ˜13:1 ratio. Cooling of the solution (ethyl acetate/hexanes) at ˜−16° C. resulted in precipitation of an orange solid, which proved to be a single regioisomer (354 mg, 64%): mp 149-150° C.; 1H NMR δ 2.41 (s, 3H), 6.42-6.44 (m, 1H), 7.10-7.13 (m, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 9.63-9.64 (m, 1H), 9.52-9.78 (br, 1H); 13C NMR δ 21.4, 111.6, 126.2, 128.9, 129.3, 129.7, 130.9, 137.7, 137.9, 180.2; FAB-MS obsd 186.0907, calcd 186.0919 (C12H11NO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:37])([F:36])[F:35])=[CH:18][N:17]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:40])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([NH2:33])=[O:32])[C:19]([C:34]([F:35])([F:36])[F:37])=[CH:18][N:17]=1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reaction time: 2 h
Yield: 95 %

Procedure:
2-(2-(2-(2-((2-Methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (2) (2.249 g, 4.38 mmol) was dissolved in methanol (220 mL) and 37% formaldehyde solution (0.483 mL, 17.5 mmol) was added. After five minutes sodium tris(acetoxy)borohydride (4.641 g, 21.9 mmol) was added and stirring continued at room temperature for two hours. The volatiles were evaporated and the residue suspended in 5% aqueous sodium hydroxide (200 mL). The resulting mixture was extracted with ethyl acetate (5×200 mL) then the combined organic phases were washed with brine (500 mL), dried over sodium sulfate and evaporated. The residue was evaporated from ether and the solvent traces removed under high vacuum to give the title compound (3) (2.196 g, 95% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.85 (s, 1H), 7.28-7.22 (m, overlaps with CHCl3), 6.88 (dd, J=8.3, 1.9 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 5.41 (s, 2H), 3.90 (s, 3H), 3.70 (s, 2H), 3.16-3.06 (m, 4H), 2.99 (d, J=12.1 Hz, 2H), 2.48 (tt, J=10.5, 5.9 Hz, 1H), 2.34 (s, 3H), 2.07 (td, J=11.1, 4.1 Hz, 2H), 1.89-1.77 (m, overlaps with water). LCMS Method C: rt 4.94 min; m/z 528.1 [M+H]+, 550.1 [M+Na]+; m/z 526.2 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:20])([CH3:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=1.[H-].[Na+].[CH3:23]I>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:23])=[C:4]([C:9]([CH3:19])([CH3:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=1
Reactant: CCCCCCCCCC(C)(C)c1cc(Br)ccc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)(C)c1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained above in part (a), (30.85 g, 90 mmoles), is dissolved in 100 ml of dry THF and then treated with 2.7 g (90 mmoles) of sodium hydride (80% in oil) which is added in small fractions. At the end of the addition, the mixture is stirred for 30 minutes at ambient temperature. 12.8 g (90 mmole) of methyl iodide are then added and this mixture is stirred for 2 hours at 20° C. The solvent is evaporated and the residue is purified by chromatography on a silica column (eluant: a mixture of dichloromethane, 40% and hexane, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[NH:19][N:18]=[N:17][N:16]=1.C(N(CC)CC)C.Cl.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[N:19]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:18]=[N:17][N:16]=1
Reactant: ClCc1ccccn1
Reactant: COc1cc2ncnc(-c3nnn[nH]3)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1cc2ncnc(-c3nnnn3Cc3ccccn3)c2cc1OC
Temperature: 27.5 °C
Reaction time: 0.29 h
Yield: 28 %

Procedure:
Experimental Procedure: 50.0 ml of N,N-dimethyl acetamide and 5.0 g (0.019 mol) of 6,7-dimethoxy-4-(1H-tetrazol-5-yl)quinazoline were charged into a 250 ml of 4 necked round bottom flask, connected to a mechanical stirrer, thermometer socket, condenser and addition flask under mild nitrogen atmosphere. 3.80 g (0.038 mol) of triethyl amine was added at 25-30° C. Stirred the mass for 15-20 min at 25-30° C. Reaction mass temperature was raised to 50-55° C. Maintained the mass temperature at 50-55° C. for 15-20 min. 2-chloro methylpyridine hydrochloride solution [3.20 g (0.019 mol) 2-chloro methylpyridine hydrochloride was dissolved in 25.0 ml of N,N-dimethyl acetamide] was added slowly at 50-55° C. for 30-45 min. Maintained the mass temperature at 50-55° C. for 15-20 min. Raised the mass temperature to 80-85° C. Maintained the mass temperature at 80-85° C. for 7-8 hours. N,N-dimethyl acetamide was completely distilled off under vacuum. Crude compound was purified by the column chromatography by using hexane and ethyl acetate. Obtained 1.90 g (yield 28.0% by theory) of pure compound weight.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=1)[O:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25].[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][CH:14]3[NH:18][C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=3)[O:22][CH2:23][C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Reactant: O=C1CCc2ccc(-c3cccc(F)c3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)COc1cccc(NC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 20.4 %

Procedure:
Approximately forty oven dried 3 Å molecular sieves were added to a solution of 6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-one (66 mg, 0.292 mmol) and isopropyl 2-(3-aminophenoxyl)acetate (122 mg, 0.583 mmol) in toluene (3 mL) at room temperature. The reaction was heated in a 120° C. oil bath and allowed to stir overnight for approximately 16 hours. The reaction was cooled to room temperature and sodium borohydride (44 mg, 1.2 mmol) was added. The solution was stirred for 4 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (12 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 25 mg (20%) of isopropyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C@H:17]([CH3:21])[CH2:18][C:19]#[N:20])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.Cl.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:19]([CH2:18][C@H:17]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:1])[F:22])=[CH:9][CH:8]=2)[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)[CH2:12][CH2:13]1)[CH3:21])#[N:20]
Reactant: C[C@H](CC#N)N1CCC(Nc2ccc(OC(F)F)cc2)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CC#N)N1CCC(N(C(=O)c2cccnc2)c2ccc(OC(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
A solution of the above nitrile (0.20 g, 0.65 mmol) and nicotinoyl chloride hydrochloride (0.46 g, 2.6 mmol) in THF (6 mL) was then treated with DIPEA (0.56 mL, 3.2 mmol) and stirred at 80° C. for 16 h. The reaction was cooled to room temperature, concentrated under reduced pressure, diluted with CH2Cl2 (10 mL) and washed with brine solution (2×10 mL). The combined organic extracts were then dried (Na2SO4), filtered and concentrated and the crude material purified by flash column chromatography on silica gel (50:1:0.1 CH2Cl2/MeOH/NH4OH) to afford N-[(R)-1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-N-(4-difluoromethoxy-phenyl)-nicotinamide as a pale yellow oil (104 mg, 39%).
Reaction SMILES: [CH2:1]([C:5]1NC2C(N=1)=NC=CC=2)[CH2:2][CH2:3][CH3:4].[Br:14][C:15]1[C:16]([CH3:23])=[C:17]([NH2:22])[C:18]([NH2:21])=[N:19][CH:20]=1>>[Br:14][C:15]1[C:16]([CH3:23])=[C:17]2[NH:22][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:21][C:18]2=[N:19][CH:20]=1
Reactant: CCCCc1nc2ncccc2[nH]1
Reactant: Cc1c(Br)cnc(N)c1N
Product: CCCCc1nc2ncc(Br)c(C)c2[nH]1

Procedure:
The title compound was prepared according to the procedure described for the preparation of 2-butylimidazo[4,5-b]pyridine starting with 5-bromo-2,3-diamino-4-picoline. Yield: 2.54 g (95%) of an amorphous solid: 1H NMR (250 MHz, CDCl3) δ 8.45 (s 1H), 3.05 (t, 2H, J=7 Hz), 2.73 (s, 3H), 2.02-1.87 (m, 2H), 1.61-1.45 (m, 2H), 1.02 (t, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[O:12]1[CH:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Cl:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:13][CH:14]([OH:12])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: CC(C)(C)C1CO1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(O)Cn1cnc2cc(Cl)c(Cl)cc21
Temperature: 160 °C
Yield: 73.3 %

Procedure:
A large (2-5 mL) microwave reactor flask was charged with 5,6-dichlorobenzimidazole (571 mg, 3.1 mmol), 1,2-epoxy-3,3-dimethylbutane (307 mg, 3.1 mmol), powdered anhydrous potassium carbonate (424 mg, 3.1 mmol) and DMF (1.5 mL). The reaction was then heated in a microwave reactor for 6 minutes at 160° C. The reaction was then diluted with ethyl acetate and extracted with water three times. The organics were dried over MgSO4 and the solvent was removed. The residue was crystallized from CH2Cl2 to afford 653 mg (73%) of product as a white solid: 1H NMR (DMSO, 400 MHz) δ 1.06 (s, 9H), 3.47 (dd, 1H, J1=2.0, J2=10.4), 4.08 (dd, 1H, J1=10.5, J2=14.4), 4.47 (dd, 1H, J1=2.0, J2=14.4), 7.75 (s, 1H), 7.79(s, 1H), 8.23 (s, 1H); HPLC-MS calcd. for C21H22Cl2N4O2 (M+H+) 287.1, Found 287.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][CH:5]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=3[C:10](I)=[CH:9]2)[CH2:4][O:3]1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:20])[O:6][CH:5]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=3[C:10]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)=[CH:9]2)[CH2:4][O:3]1
Reactant: COc1nccc2c1c(I)cn2CC1COC(C)(C)O1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2CC1COC(C)(C)O1
Temperature: 130 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a solution of 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (120 mg) in DMF (3 mL)/water (0.30 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (131 mg), tetrakis(triphenylphosphine)palladium(0) (35.7 mg) and potassium carbonate (85.4 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (32.0 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:21][C:5]2=[CH:6][C:7]3[C:8]([CH3:20])([CH3:19])[C:9](=[O:18])[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=3[CH:12]=[C:4]2[N:3]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH3:19][C:8]1([CH3:20])[C:7]2[CH:6]=[C:5]3[NH:21][C:2]([NH:1][C:29]([NH:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:30])=[N:3][C:4]3=[CH:12][C:11]=2[N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]1=[O:18]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)=O
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)Nc4ccccc4)nc3cc21
Yield: 63.3 %

Procedure:
A solution of D5 (172 mg) and phenyl isocyanate (72 mg; 0.6 mmol) in acetone (3 ml) is stirred at RT for 3 days. Acetone is evaporated and the residue is purified by flash chromatography on silica gel eluted with CH2Cl2/MeOH (20:1) to give the desired compound (154 mg).
Reaction SMILES: CC(C)=O.[C:5]([OH:9])(=[O:8])[CH2:6][OH:7].[C:10](Cl)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[C:10]([O:7][CH2:6][C:5]([OH:9])=[O:8])(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCC(=O)Cl
Reactant: O=C(O)CO
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCC(=O)OCC(=O)O
Reaction time: 1 h
Yield: 66.7 %

Procedure:
15.8 gm (0.20 mole) pyridine and 50 ml. acetone were combined in a 250 ml. round bottomed-three necked flask equipped with magnetic stir bar and two addition funnels, and cooled in an ice water bath with stirring. One addition funnel was charged with 15.5 gm (0.20 mole) glycolic acid dissolved in approximately 75 ml. acetone. The other addition funnel was charged with 32.5 gm (0.20 mole) octanoyl chloride. The contents of each addition funnel were added simultaneously to the cooled, stirred pyridine solution so that the complete addition of each component was continuous over one hour. The resultant slurry (a precipitation of pyridine hydrochloride was noted) was stirred an additional 45 minutes at ice bath temperature, and then at room temperature for another 30 minutes. Solvent was then removed by rotary evaporation at reduced pressure and 45C. The residual oil was dissolved in 200 ml dichloromethane and this was extracted with 3×150 ml. of 4% aqueous HCl. The dichloromethane layer was dried over sodium sulfate, decanted and the solvent removed by rotary evaporation. Drying on high vacuum for 4 hours left OOAA and 8.0% octanoic acid by weight, giving a crude yield for OOAA of 84%(mole). Recrystallization from 200 ml. hexane gave 27 g of a white crystalline product melting at 50 to 52° C., which was determined to be 99% wt. OOAA, giving a 67% (mole) yield of pure octanoxyloxyacetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.Cl.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[CH2:35][NH:34][CH2:33][CH2:32]2>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:34]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=3)[CH2:35]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Agent: Cl
Product: COc1ccc(C(CCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 59.6 %

Procedure:
The procedure of Example 39 is repeated using 2.12 g of 4-[6-Bromo-1-[(4-methylphenyl)thio]hexyl]-1,2-dimethoxybenzene and 2.3 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 1.6 g of the desired product as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:15][S:16]([CH2:19][CH2:20][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)(=[O:18])=[O:17]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C=CS(C)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCS(C)(=O)=O)c2)OC1(C)C
Temperature: 90 °C
Yield: 63.4 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.3 g, 27.31 mmol), methylvinyl sulfone (4.349 g, 40.97 mmol) and DBU (2.042 mL, 13.66 mmol) were suspended in dry acetonitrile (54.63 mL) in a sealed glass bomb and heated in a sand bath at 90° C. overnight. The resulting reaction mixture was concentrated to a solid and the solids were washed with hexanes to yield 5.2 g (63.4%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10](OC)=[O:11])(=[O:4])=[O:3].[NH2:15][NH2:16]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([NH:15][NH2:16])=[O:11])(=[O:4])=[O:3]
Reactant: COC(=O)c1cncc(S(C)(=O)=O)c1
Reactant: NN
Solvent: CO
Product: CS(=O)(=O)c1cncc(C(=O)NN)c1
Temperature: 70 °C
Yield: 82.9 %

Procedure:
Methyl 5-(methylsulfonyl)nicotinate (100 mg, 0.465 mmol) were added to hydrazine (17.87 mg, 0.558 mmol) in methanol (10 mL) and refluxed for 12 h at 70° C. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum and the compound was purified by flash column chromatography (3% CH3OH/CH2Cl2) afforded the title compound (83 mg, 80% yield) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.20 (d, 1H, J=2.0 Hz), 9.17 (d, 1H, J=2.0 Hz), 8.61 (s, 1H), 3.11 (s, 3H). ESI-MS: 216.1 [M+H]+.