Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C(F)(F)F)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(C(F)(F)F)cnc3[nH]2)cc1
Yield: 31.2 %

Procedure:
A solution of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (190 mg, 0.44 mmol) in methanol (70 mL) was passed through a H-Cube reactor (10% palladium on activated carbon, 50° C., 50 bar of hydrogen pressure, 1 mL/minute). The reaction solution was concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 41%) as a white solid: LC/MS m/e calcd for C22H23F3N2O2S [M+H]+ 437.50, observed 436.9; 1H NMR (400 MHz, CD3OD) δ ppm 8.44 (s, 1H), 8.23 (s, 1H), 7.93-7.98 (m, J=8.3 Hz, 2H), 7.63-7.69 (m, J=8.3 Hz, 2H), 6.59 (s, 1H), 4.40 (t, J=7.8 Hz, 1H), 3.14 (s, 3H), 2.30-2.38 (m, 1H), 2.15-2.24 (m, 1H), 1.65-1.92 (m, 5H), 1.49-1.61 (m, 2H), 1.21-1.38 (m, 2H).
Reaction SMILES: NC(C)/[CH:3]=[CH:4]/[C:5]([NH:7][C@@H:8]1[CH2:13][C@H:12](C)[C@H:11](C/C=C(\C)/C=C/[C@H]2O[C@H](CC(N)=O)C[C@]3(OC3)C2)[O:10][C@@H:9]1C)=O.NC(C)/C=C\C(N[C@@H]1C[C@H](C)[C@H](C/C=C(\C)/C=C/[C@H]2O[C@H](CC(N)=O)C[C@]3(OC3)C2)O[C@@H]1C)=[O:40].[P:69]([O-:73])([O-:72])([O-:71])=[O:70].[Na+].[Na+].[Na+].C(N)(C)C>CS(C)=O.P([O-])([O-])([O-])=O>[CH3:9][C:8]1[N:7]=[CH:5][C:4]([CH2:3][O:70][P:69]([OH:73])([OH:72])=[O:71])=[C:12]([CH:11]=[O:10])[C:13]=1[OH:40].[P:69]([O-:73])([O-:72])([O-:71])=[O:70]
Reactant: CC(/C=C/[C@@H]1C[C@]2(CO2)C[C@@H](CC(N)=O)O1)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C/C(C)N)C[C@@H]1C
Reactant: CC(/C=C/[C@@H]1C[C@]2(CO2)C[C@@H](CC(N)=O)O1)=C\C[C@@H]1O[C@H](C)[C@H](NC(=O)/C=C\C(C)N)C[C@@H]1C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(C)N
Product: Cc1ncc(COP(=O)(O)O)c(C=O)c1O

Procedure:
Synthesis of (2E)-4-amino-N-[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3S,5S,7S)-7-(2-amino-2-oxoethyl)-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-yl}-2,5-dimethyltetrahydro-2H-pyran-3-yl]pent-2-enamide (#B271) and (2Z)-4-amino-N-[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3S,5S,7S)-7-(2-amino-2-oxoethyl)-1,6-dioxaspiro[2.5]oct-5-yl]-3-methylpenta-2,4-dien-1-yl}-2,5-dimethyltetrahydro-2H-pyran-3-yl]pent-2-enamide (#B272): To 100 mM sodium phosphate buffer pH 7.4 (3.57 ml) were added #B129 (7 mg, in 0.23 ml DMSO, 1 eq.), isopropylamine (1.475 ml of a 1 M solution made in phosphate buffer pH 3, giving a solution of pH ˜7, 100 eq.), pyridoxal phosphate (0.295 ml of a 50 mM solution in phosphate buffer pH 7.4, 1 eq.), and ATA-P2-B01 enzyme preparation (33 mg, in 0.33 ml phosphate buffer pH 7.4, Codexis, lot #D11134, R-selective for acetophenone). After incubation at 30° C., 200 rpm for 19 hours, pH was adjusted to ˜12 with sodium hydroxide and the reaction was extracted seven times with equal volume of ethylacetate. The solvent was evaporated under reduced pressure, the residue resuspended in 0.25 ml acetonitrile/water 1:1, filtered and purified by reverse phase chromatography in a total of 10 runs (Method I). The fractions with retention time of 10 and 13 min were collected and neutralized with ammonium hydroxide before freeze-drying to afford #B271 and #B272, respectively, as white solids.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][CH:12]([F:26])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][C:20]=2[CH2:24][CH3:25])=[CH:15][CH:14]=1.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:27][C:22]1[O:23][C:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:12]([F:11])[F:26])=[CH:18][CH:17]=2)=[C:20]([CH2:24][CH3:25])[N:21]=1
Reactant: CCc1ncoc1-c1ccc(C(F)F)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc(Cl)oc1-c1ccc(C(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
LiHMDS (1.0 M in THF, 24 mL, 24 mmol) was added to a solution of Example 54A (4.90 g, 21.9 mmol) in THF (73 mL) at −78° C. The reaction was stirred at −78° C. for 30 min, and then solid hexachloroethane (5.20 g, 21.9 mmol) was added in one portion. The reaction was allowed to stir overnight while warming to room temperature. The reaction was quenched with water and the product extracted with EtOAc. The combined organic extract was washed with water and brine, and filtered through celite. The filtrate was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was dissolved in toluene and loaded on silica gel (Analogix® 25×115 column), and eluted with 2 column lengths of hexanes then 5% to 50% EtOAc/hexanes. The result was 4.1 g (73%) of the title compound as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=8.5, 2H), 7.58 (d, J=8.7, 2H), 6.68 (t, J=56.5, 1H), 2.77 (q, J=7.5, 2H), 1.31 (t, J=7.5, 3H). MS (DCI+) m/z 258 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:29])[C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:29][CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: Cc1cccc(C(N)c2ccccc2)c1
Product: Cc1cccc(C(NC(=O)CNC(=O)c2ccc(F)cc2)c2ccccc2)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-m-tolyl-methylamine (CA [55095-20-0]).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[N:15]=1.S(Cl)(Cl)=O.[NH2:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:30][C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=3)=[O:24])=[C:16]2[N:15]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: Cc1cccnc1N
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccnc1NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Yield: 22.4 %

Procedure:
To a suspension of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation C, 25.0 mg, 0.072 mmol) in CCl4 (1.0 mL) was added thionyl chloride (0.10 mL) and the mixture heated at reflux for 4 hours. The mixture was cooled to ambient temperature and was concentrated to a brittle foam. The foam was dissolved in pyridine (2 mL), 2-amino-3-methyl-pyridine (9.3 mg, 0.086 mmol) was added and the mixture was heated at 90° C. for 20 hours. The reaction was cooled to ambient temperature and the pyridine evaporated. The residue was partitioned into 1M NaOH and EtOAc, mixed and the EtOAc layer removed. The aqueous layer was extracted with EtOAc and combined EtOAc fractions were washed with H2O, saturated NaCl and dried over MgSO4. The solution was filtered and concentrated, and the resulting solid was washed with dry Et2O to afford the title compound as a white solid (7 mg, 29%). MS (apci) m/z=435.1 (M+H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[CH:21]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][C:23]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][C:22]=1[CH3:27])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: COc1ccc(N)c(C)c1
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccc(OC)cc1C
Yield: 76.1 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (4.95 g, 20 mmol), 4-methoxy-2-methylaniline (5.15 ml, 40 mmol) and 1,4-dioxan (20 ml) were heated at reflux for 1 hour, the solvent evaporated, the residue taken up in dichloromethane, washed with aqueous sodium bicarbonate, dried and evaporated. Recrystallisation from methanol gave 3-butyryl-4-(4-methoxy-2-methylphenylamino)-8-methylquinoline (5.30 g), m.p. 114°-115°.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1>C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([O:14][CH3:15])[C:9]([O:12][CH3:13])=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(Br)cc1OC
Solvent: CC(=O)O
Product: COc1cc(Br)c([N+](=O)[O-])cc1OC
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of concentrated nitric acid (14 mL) and acetic acid (42 mL) was cooled to 110° C. while stirring, and then 4-bromo-1,2-dimethoxybenzene (2 g, 9.21 mmol) was gradually added to the stirred mixture. The reaction mixture was warmed to 15° C., and stirring was continued for 60 minutes. The reaction mixture was cooled to 0° C. and stirred while adding ice water, and then extraction was performed with ether. The obtained organic layer was neutralized with saturated aqueous solution of sodium hydrogencarbonate and potassium carbonate, and then washed with water. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained crude product was recrystallized from ethanol to give 2.09 g of the title compound as light yellow crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1)[CH3:2].[NH4+:18].[OH-].CCO>>[NH2:18][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])[C:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])=[O:15]
Reactant: CCN(CC)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
N,N-Diethyl-3-fluoro-4-nitro-benzamide (5.1 g, 21.2 mmol) was refluxed in a 2:1 mixture of NH4OH/EtOH (150 mL) for 48 h. The solution was cooled to rt and the solvent concentrated. The solution was then extracted (3×) with EtOAc. The combined organic phases were washed with brine and dried over anhydrous MgSO4. The crude product was crystallized from EtOAc/hexanes to give the title compound (4.35 g, 86% yield). 1H NMR (400 MHz, CD3OD) δ 8.12 (d, J=8.8 Hz, 1H), 6.92 (s, 1H), 6.56 (d, J=8.8 Hz, 1H), 3.51 (q, J=7.2 Hz, 2H), 3.28 (m, 2H), 1.23 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([C:32]2[S:36][CH:35]=[N:34][C:33]=2[C:37](Cl)=[O:38])[CH:29]=[CH:30][CH:31]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:37]([C:33]1[N:34]=[CH:35][S:36][C:32]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)=[O:38])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Reactant: O=C(Cl)c1ncsc1-c1cccc(F)c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncsc2-c2cccc(F)c2)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 5-(3-fluoro-phenyl)-thiazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 2 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.20. LC-MS-conditions 02: tR=1.06 min, [M+H]+=487.91.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10](O)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:12])[CH3:11])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(=O)O
Product: CC(=O)Nc1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 94 %

Procedure:
As presented in the following reaction formula, anhydrous acetic acid (Ac2O; 1.7 mL) was added several times in a divided manner to a mixture of 4-chloro-2-fluoroaniline (2 g, 13.8 mmol) in acetic acid (2 mL) at room temperature (about 25° C.). The resulting reaction mixture was stirred for 2 hours. After the completion of reaction, the mixture was filtered to obtain a crude product, which was washed with hexane to obtain N-(4-chloro-2-fluorophenyl)acetamide (2.4 g, yield: 94%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[NH4+].[Cl-]>C1COCC1>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[OH:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Brc1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)c1ccsc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.5M BuLi in hexanes (3.5 mL, 5.25 mmol) in THF (6.5 mL) cooled to −78° C. was added 3-bromothiophene dropwise (469 μL, 5.0 mmol). The mixture was stirred for 30 minutes and a 1.0M solution of 4-bromobenzaldehyde in THF was slowly added (5.5 mL, 5.5 mmol). The reaction was warmed to 0° C. and aged for 1 hour. The mixture was then poured into a saturated aqueous solution of NH4Cl. The resulting mixture was extracted 3 times with ethyl acetate and the organic layers were washed with brine, dried and evaporated. The crude residue was chromatographed on silica gel using a gradient of 10-25% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])=[CH:4][C:5](O)=[O:6].[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:5](=[O:6])[CH:4]=[C:3]([CH3:8])[C:2]([F:10])([F:9])[F:1])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CC(=CC(=O)O)C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(=CC(=O)N1CCN(c2ccc(C(=O)NCCC(C)C)nn2)CC1)C(F)(F)F

Procedure:
Following the procedure of Example 9, making variations only as required to use to use 4,4,4-trifluoro-3-methylbut-2-enoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (62% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.83, 7.00, 6.55, 3.86-3.83, 3.80-3.73, 3.62-3.60, 3.48, 2.01, 1.75-1.62, 1.49, 0.92. MS (ES+) m/z 414.4 (M+1).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH:1]([O:4][CH2:5][CH2:6][O:7][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])([CH3:3])[CH3:2]
Reactant: CC(C)OCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
In a round bottom flask was placed 2-isopropoxy-ethanol (700 mg, 6.72 mmol) dissolved in methylene chloride (15 mL) and cooled to 0° C. in an ice bath. To this solution was added triethylamine (1.2 mL, 8.7 mmol) and para-toluenesulfonyl chloride (1.54 g, 8.06 mmol). The resulting solution was then slowly allowed to warm to 25° C. and was stirred for 16 h. After this time, the reaction was transferred to a separatory funnel and washed with water (15 mL). The aqueous layer was then extracted with methylene chloride (2×20 mL). The organic layers were combined and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 25% ethyl acetate/hexanes) afforded toluene-4-sulfonic acid 2-isopropoxy-ethyl ester (1.41 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.OO.S([O-])([O-])=[O:13].[Na+].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N+:4]([O-:13])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1Cl
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(Cl)ccc[n+]1[O-]
Temperature: 90 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
To a solution of 3-chloro-2-cyanopyridine (40g, 0.29 mol) in 500 mL acetic acid added hydrogen peroxide (30%, 52 g, 0.45 mol) dropwise. After stirring at 90° C. for 18 h, the reaction is cooled to 25° C. and a solution of sodium sulfite (57 g, 0.45 mol) in H2O is added dropwise. The reaction is concentrated to remove the bulk of the acetic acid and the residue is partitioned between 1M NaOH and CH2Cl2. The CH2Cl2 layer is dried (MgSO4), filtered, concentrated, and recrystallized from EtOAc to provide 23 g (51%) of 3-chloro-2-cyanopyridine-N-oxide. The N-oxide from above (12.2 g, 79 mmol) was taken up in DMF (160 mL) at 0° C. Methyl thioglycolate (7.1 mL, 79 mmol) was added followed by sodium methoxide (8.5 g, 160 mmol) in portions. The RXN was stirred for 1 h. The RXN was poured onto ice and the resulting solid was collected by filtration, washed with water, dissolved in CH2Cl2, dried (MgSO4), filtered, concentrated, and recrystallized from EtOAc. 10.6 g (60%) of 3-amino-2-carbomethoxythieno[3,2-b]pyridine-4-oxide was obtained. The pyridine-N-oxide (10.6 g, 47 mmol) is mixed with phosphorous oxychloride (100 mL). The RXN is heated to 80° C. for 30 min. The RXN is concentrated and partitioned between CH2Cl2 and NaHCO3 sln. The CH2Cl2 layer is dried (MgSO4), filtered, cone, and chromatographed (5:1 hex:EtOAc). 8.3g (73%) of the 5-chloro and 2.0 g (18%) of the 7-chloro product were obtained: 1H NMR (300 MHz, CDCl3 (5-chloro)) δ3.92 (s, 3H), 6.15 (bs, 2H), 7.37 (d, 1H), 7.99 (d, 1H); MS (DCI/NH3) m/e 243 (M+H)+. 1H NMR (300 MHz, CDCl3 (7-chloro)) δ3.93 (s, 3H), 6.20 (bs, 2H), 7.41 (d, 1H), 8.54 (db, 1H); MS (DCI/NH3) m/e 243 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:25]2[CH:26]=[C:21]([C:19]([C:18]3[CH:27]=[CH:28][CH:29]=[CH:16][CH:17]=3)=[O:20])[CH:22]=[CH:23][CH:24]=2)=[CH:9][CH:8]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: OCc1ccc(CC2OCCO2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cccc(OCc2ccc(CC3OCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.8 %

Procedure:
To a cooled (0° C.) solution of (4-((1,3-dioxolan-2-yl)methyl)phenyl)methanol (0.45 g, 2.317 mmol), 3-hydroxybenzophenone (0.551 g, 2.78 mmol) and triphenylphosphine (0.729 g, 2.78 mmol) in anhydrous THF, di-iso-propylazodicarboxylate (1.027 mL, 2.78 mmol) was added dropwise. The reaction mixture was allowed to warm to RT and stirred at this temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous potassium carbonate, brine and dried (magnesium sulfate). The suspension was filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 100% iso-hexane to 25% ethyl acetate in iso-hexane to afford the title compound (1.022 g, >100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23].C(=O)(O)[O-].[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>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(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: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester (2.0 g, 5.6 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester (1.78 g, 5.6 mmol), tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.56 mmol), and sodium bicarbonate (1.4 g, 16.8 mmol) were combined in DME (30 mL) and H2O (10 mL), and the mixture was purged with N2 (g). The reaction was stirred at 80° C. overnight, and after aqueous workup, the crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19]Br)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(O)C>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:22]
Reactant: CCNCC
Reactant: BrCCCc1ccc(-c2ccc(CCCBr)cc2)cc1
Solvent: CCO
Product: CCN(CC)CCCc1ccc(-c2ccc(CCCN(CC)CC)cc2)cc1
Yield: 84.9 %

Procedure:
A solution of 515 mg of 4,4'-bis(3-bromopropyl)biphenyl and 0.95 g of diethylamine in 1.3 ml of ethanol was refluxed in a flask equipped with a balloon for 2 hours, cooled, and concentrated under a reduced pressure. To the concentrate was added 5% sodium bicarbonate aqueous solution, the mixture was extracted three times with 50 ml benzene. The extract was washed with 5% sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, concentrated under a reduced pressure to and dried in vacuo obtain 420 mg of the title compound as a yellow oil.