Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](OCCN)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a round-bottom flask were added (R)-tert-butyl 2-((S)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (280 mg, 0.63 mmol), triethylamine (0.19 mL, 1.89 mmol) and anhydrous CH2Cl2 (15 mL). The mixture was cooled in an ice bath and a solution of acetyl chloride (49.2 mg, 0.045 mL, 0.63 mmol) was added. The reaction mixture was allowed to warm slowly to rt and stirred until the reaction was complete (ca 1˜2 h). The solvent was removed by evaporation, and the residue was purified by preparative tlc to give (R)-tert-butyl 2-((S)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (202 mg, 66%). 1H NMR (300 MHz, CDCl3): δ=1.45 (s, 9 H), 1.93 (s, 3 H), 2.38 (s, 3 H), 2.87˜3.2 (m, 6 H), 3.32˜3.92 (m, 5 H), 4.28 (d, 1 H), 7.01˜7.25 (m, 3 H), 7.28˜7.37 (m, 4 H), 9.41-9.54 (s, 1 H). MS (E/Z): 487 (M+H+)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17](=[O:36])(=[O:35])[N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH:15]=2)[C:10]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[O:44][CH3:45])=[N:9][CH:8]=1)(=O)=O.[CH3:48][N:49](C=O)C.C(O)(C(F)(F)F)=O>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[C:48]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:36])=[O:35])[CH:15]=2)[C:10]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[O:44][CH3:45])=[N:9][CH:8]=1)#[N:49]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4OC)ncc(OS(=O)(=O)C(F)(F)F)c3c2)c(OC)c1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ncc(C#N)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A vial was charged with 6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-1-(4-fluoro-2-methoxyphenyl)isoquinolin-4-yl trifluoromethanesulfonate (0.140 g, 0.196 mmol), Pd2(dba)3 (0.018 g, 0.020 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.022 g, 0.039 mmol), and zinc cyanide (0.025 ml, 0.392 mmol). DMF (1.962 ml) was added, and the reaction was stirred at 80° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-50% EtOAc:Heptane). The material was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and purified via column chromatography (RediSep Gold 12 g, gradient elution 25-100% EtOAc:Heptane) to afford 4-cyano-1-(4-fluoro-2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.06 (br. s., 1H), 9.26 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.06 (dd, J=1.7, 8.9 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.44 (dd, J=6.8, 8.4 Hz, 1H), 7.32 (d, J=4.6 Hz, 1H), 7.20 (dd, J=2.3, 11.4 Hz, 1H), 7.00 (dt, J=2.4, 8.4 Hz, 1H), 6.92 (d, J=4.6 Hz, 1H), 3.68 (s, 3H). m/z (ESI) 441.2 (M+H)+.
Reaction SMILES: [C:1](OC)(=O)C=C.C(O)(=O)C(C)=C.N[C@@H:14]([CH2:18][CH2:19][C:20]([NH:22][C@H:23]([C:26](NCC(O)=O)=O)[CH2:24]S)=O)C(O)=O.CC(C)=O>O.CO.CCCCCC>[CH3:26][C:23]1[CH:24]=[CH:1][C:19]([CH:18]=[CH2:14])=[CH:20][N:22]=1
Reactant: C=CC(=O)OC
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: C=C(C)C(=O)O
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: O
Product: C=Cc1ccc(C)nc1

Procedure:
methyl acrylate.methacrylic acid copolymer (molar ratio=2.4:1.9:1) (this copolymer being soluble in water at a pH lower than 4 or higher than 7 but not soluble in water at a pH of 4-7) and 100 g of ethylcellulose (ethoxy content: 48-50 w/w %) were dissolved in 2 liters of methanol, and 300 g of the glutathion-containing granules were dispersed therein. 2 liters of acetone and 8 liters of n-hexane were added gradually to the dispersion. The microcapsules thus formed were recovered by filtration, and washed with acetone-n-hexane (1:2) and n-hexane, successively. After said microcapsules were dried, microcapsules which passed through JIS standard sieve (500μ aperture) but did not pass through JIS standard sieve (105μ aperture) were collected. 467 g of glutathion-containing microcapsules which met the requirements of "Fine Granules" specified in THE PHARMACOPOEIA OF JAPAN 9th-Edition were thereby obtained.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].O1CCCC1.CO.C(O)(=O)C>[C].[Pd].O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 34.5 g.), tetrahydrofuran (345 ml.), 10% palladium carbon (14 g.), methanol (140 ml.), acetic acid (2.5 ml.) and water (50 ml.) was subjected to catalytic reduction under ordinary pressure at room temperature for 3 hours. The resultant mixture was filtered, and washed with tetrahydrofuran. The filtrate was concentrated in vacuo, and the residue was dissolved in a mixture of ethyl acetate and an aqueous solution of sodium bicarbonate. The insoluble substance was removed by filtration. After the ethyl acetate layer was separated and extracted with an aqueous solution of sodium bicarbonate, the aqueous layer and the aqueous extract were combined. After the aqueous solution was washed with ethyl acetate and diethyl ether in turn, the solution was adjusted to pH 2.0 with 10% hydrochloric acid and stirred for 30 minutes. The precipitates were collected by filtration, washed with water and dried over magnesium sulfate to give 7-[ 2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 18.3 g.).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH3:18].Cl[CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:20][S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:14])=[CH:11][C:10]=1[CH3:18]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: ClCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)OCSc2ccccc2)cc1C
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
Cesium carbonate (13.00 g, 40.0 mmol) is added to a solution of 4-methoxy-3-methyl benzoic acid (6.65 g, 40.0 mmol) in dry DMF (50 ml) at ambient temperature. The mixture is stirred at 65° C. for 20 minutes and cooled to 0° C., before chloromethyl phenylsulfide (5.76 g, 36 mmol) in dry DMF (10 ml) is added dropwise. Stirring is continued at 0° C. for 30 minutes, then at ambient temperature for 2 hours and finally at 70° C. for 1 hour, before water is added and the product extracted into diethyl ether. The ether solution is washed with 1M sodium hydroxide and 4 times with brine, dried (MgSO4) and evaporated. The crude product is used in Intermediate 8 without further purification.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:21])[C:11]#[C:12][C:13]([CH3:20])([O:15][Si](C)(C)C)[CH3:14])[CH:7]=[CH:6][C:5]=12.CC1C=CC(S(O)(=O)=O)=CC=1>O>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:21])[C:11]#[C:12][C:13]([OH:15])([CH3:14])[CH3:20])[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C#CC(=O)c1ccc2nonc2c1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)(O)C#CC(=O)c1ccc2nonc2c1
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a stirred solution of 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.45 g, 1.490 mmol) DCM (15 mL) was added p-TSA (0.341 g, 1.790 mmol) at RT and the reaction mixture was stirred for 3 h. The reaction mixture was then diluted with water (5 mL) and the layers were separated. The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one (0.3 g, 87%) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:11]1(=O)NCCCCC1>O>[CH3:11][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1=[O:9]
Reactant: O=C1CCCCCN1
Reactant: COC(=O)CCCCCN
Solvent: O
Product: CN1CCCCCC1=O
Yield: 4.5 %

Procedure:
A solution of 15.7% of methyl 6-aminocaproate and 8.2% of caprolactam in water was pumped through a 40 ml tube reactor at 270° C. and 100 bar with a residence time of 4.2 minutes. The exit stream contained according to quantitative gas chromatography 14.98% by weight of caprolactam, corresponding to a yield of 55.4%, based on methyl 6-aminocaproate. N-methylcaprolactam was formed as a by-product in a 4.5% yield.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[CH:19][C:20]([CH:25]=[O:26])=[N:21][C:22]=1[O:23][CH3:24].O>COCCOC>[CH3:24][O:23][C:22]1[N:21]=[C:20]([CH:25]=[O:26])[CH:19]=[CH:18][C:17]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1nc(C=O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(C=O)ccc1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
Tetrakistriphenylphosphine palladium (403 mg), phenylboronic acid (510 mg) and a 2 M sodium carbonate solution (3.5 mL) were sequentially added to a solution of 5-bromo-6-methoxypyridine-2-carbaldehyde (753 mg) in 1,2-dimethoxyethane (23 mL) in a nitrogen atmosphere, and the mixture was stirred at 80° C. for three hours. Water was added to the reaction solution at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→1:1) and further purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to give 6-methoxy-5-phenylpyridine-2-carbaldehyde (445 mg, 60%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][N:3]1[P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].[C:11]1([Mg]Cl)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>Cl[Cu].C1COCC1>[C:11]1([CH2:4][CH:2]([NH:3][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7])[CH3:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COP(=O)(OC)N1CC1C
Reactant: Cl[Mg]c1ccccc1
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: COP(=O)(NC(C)Cc1ccccc1)OC
Temperature: 48 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A 100 mL, 3-necked flask equipped with an overhead stirrer, reflux condenser and pressure equalizing addition funnel was charged with 2c (10.0 g, 60.5 mmol), THF (60 mL) and CuCl (70 mg, 1 mol %) and the stirrer was started. The mixture was heated to 48° C. and the pressure equalizing addition funnel was charged with PhMgCl (2M in THF, 13 mL). This solution was added slowly while maintaining an internal temperature of 48-51° C. The reaction was stirred at 48-51° C. for an additional 30 minutes until the GC analysis indicated the consumption of 2c (<1.0%) and the reaction mixture was cooled to ambient temperature. The reaction was quenched by slow addition to a cooled solution of saturated aqueous ammonium chloride in water (50/50 v/v, 100 mL) while maintaining the temperature below 20° C. Heptanes (100 mL) was used to rinse the reactor and the rinse solution was transferred to the quenched reaction mixture. The mixture was agitated for 15 minutes, allowed to separate for 30 minutes then the aqueous phase was discarded. The organic phase washed with deionized water (30 mL) and the organic phase concentrated under reduced pressure to give an oil. The residue was dissolved in heptanes (100 mL) and the solution was concentrated under reduced pressure. The residue was crystallized from methyl tert-butyl ether (1 g/3 mL), filtered and dried to give 6c as white needles (10.2 g; 74.8% yield), with 99.90% GC purity containing 0.06% 8c. Mp 86-88° C. 1H NMR (300 MHz, CDCl3) δ 7.32-7.17 (m, 5H), 3.66 (d, J=6.4 Hz, 3H), 3.50-3.83 (m, 1H), 2.71 (d, J=6.6 Hz, 2H), 2.45 (m, 1H), 1.15 (d, J=6.6 Hz, 3H).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([OH:22])[CH:24]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Oc1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(O)c3)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Cl:12][C:13]1[C:20]([Cl:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:14]=1[CH:15]=[O:16].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][N:7]1[C:11]([CH:15]([OH:16])[C:14]2[CH:17]=[C:18]([O:24][CH3:25])[C:19]([O:22][CH3:23])=[C:20]([Cl:21])[C:13]=2[Cl:12])=[CH:10][CH:9]=[N:8]1
Reactant: COc1cc(C=O)c(Cl)c(Cl)c1OC
Reactant: Cn1cccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C(O)c2ccnn2C)c(Cl)c(Cl)c1OC
Reaction time: 1 h
Yield: 90.5 %

Procedure:
18 ml of 1.6M n-butyl lithium in n-hexane is added dropwise to a solution of 2.26 g of 1-methyl-pyrazole in tetrahydrofuran at -60° C. under argon gas atmosphere and the mixture is stirred at the same temperature for 1 hour. A solution of 5.88 g of 2,3-dichloro-4,5-dimethoxybenzaldehyde in tetrahydrofuran is added dropwise to the mixture at -60° to -50° C. and the mixture is stirred at -50° C. to room temperature for 1 hour. An aqueous ammonium chloride solution is added to the reaction mixture and the mixture is concentrated to remove organic solvent. The residue is extracted with ethyl acetate, and the extract is washed, dried and evaporated to remove solvent. The residue is crystallized from isopropyl ether to give 7.18 g of α-(1-methylpyrazol-5-yl)-2,3-dichloro-4,5-dimethoxybenzylalcohol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(CCN(CCN(C)C)C)C.CN(C)[CH:29]=[O:30]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:29]=[O:30]
Reactant: CN(C)C=O
Reactant: COc1cccc(F)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(F)c1C=O
Reaction time: 2 h
Yield: 71.8 %

Procedure:
The solution of 3-fluoroanisole (3.36 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to −78° C. and 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below −75° C. Upon the completion of the addition, N,N,N′,N′,N″-pentamethyldiethylenetriamine was added dropwise and the stirring at −78° C. was continued under an atmosphere of nitrogen for an additional two hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for half an hour. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2×150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was triturated in n-heptane. The precipitate was collected by filtration and dried to yield 2-fluoro-6-methoxybenzaldehyde (2.95 g, 0.0191 mol) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.S(=O)(=O)(O)[OH:11].N([O-])=O.[Na+].CCCCCC>O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(N)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
283 g of 3-chloro-4-methylaniline was added to a solution of 1000 ml of water and 500 ml of concentrated sulfuric acid, causing the temperature of the mixture to rise from ambient to 95° C. The mixture was cooled and stirred at room temperature for 30 minutes, then cooled to 5° C. and a solution of 145 g of sodium nitrite in 500 ml of water was slowly added (1.5 hours) to the stirred mixture at 5°-10° C. The mixture was stirred at about 5° C. for one hour, then added over two hours to a stirred solution of 1.2 liters of concentrated sulfuric acid in 2 liters of water, at 105°-110° C. The resulting mixture was stirred at 110° C. for one hour, then held at room temperature for 18 hours. Then 3.5 liters of hexane was added, the mixture was stirred for 30 minutes, allowed to stand, and the two liquid phases were separated. The hexane phase was filtered, washed with water, dried (MgSO4) and concentrated to dryness to give crude 3-chloro-4-methylphenol (2A).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1.[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.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>[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1)[CH3:20]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Cc1ccc(-c2nc(Br)ns2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(CC(C)C)c(C#N)c2)n1
Temperature: 120 °C
Yield: 79.8 %

Procedure:
To a solution of 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-(2-methylpropyl)benzonitrile (D60) (500 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (470 mg) and tripotassium phosphate (988 mg) in N,N-dimethylformamide (DMF) (6 mL) and water (1.5 mL) stirred under nitrogen was added Pd(Ph3P)4 (179 mg). The mixture was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulphate, concentrated and purified by column chromatography to give 5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-(2-methylpropyl)benzonitrile (D61) (500 mg). MS (ES): C24H25N3OS requires 403. found 404.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:11])[CH2:7][C:6]2[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH2:27][C:28]3[N:29]=[C:30]4[N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33][CH2:32][N:31]4[CH:43]=3)=[CH:24][C:5]=2[CH2:4][N:3]1[CH2:44][C:45]([F:48])([F:47])[F:46].[ClH:49].O1CCOCC1>ClCCl>[ClH:49].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[O:11])[CH2:7][C:6]2[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH2:27][C:28]3[N:29]=[C:30]4[NH:35][CH2:34][CH2:33][CH2:32][N:31]4[CH:43]=3)=[CH:24][C:5]=2[CH2:4][N:3]1[CH2:44][C:45]([F:47])([F:48])[F:46]
Reactant: CC(C)(C)OC(=O)N1CCCn2cc(CCOc3ccc4c(c3)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)OCCN3CCOCC3)C4)nc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O)OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 1 mL of a dichloromethane solution containing 71.7 mg (0.105 mmol) of [2-(morpholin-4-yl)]ethyl(4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetate obtained in Example 10-(a) was added 2.00 mL (8.00 mmol) of 4N hydrogen chloride/1,4-dioxane solution, and the resulting mixture was stirred under nitrogen gas atmosphere at room temperature for 12 hours.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[N:20][N:19]4[CH2:28][CH2:29][CH2:30][C:18]=34)=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1)C.[OH-].[Li+]>CO>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:17]([C:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])=[CH:8][CH:9]=3)[N:14]=[CH:13][CH:12]=2)=[C:18]2[CH2:30][CH2:29][CH2:28][N:19]2[N:20]=1
Reactant: CCOC(=O)COc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Temperature: 60 °C

Procedure:
To a solution of [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetic acid ethyl ester (250 mg, 0.6 mmol) in methanol (4 mL) at room temperature is added 1 N lithium hydroxide (1.2 mL, 1.2 mmol). The mixture is heated at 60° C. for 4 h. The mixture is cooled to room temperature and concentrated in vacuo. The residue is taken up in water and acidified to pH=6 with 1 N hydrochloric acid. The aqueous solution is extracted with dichloromethane 5 times. The combined organic extracts are dried (sodium sulfate), filtered, and concentrated in vacuo to yield the title compound, 150 mg (65%), as an off white solid. MS ES− m/e 385 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13]Br>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)nc1
Reactant: BrCCBr
Product: N#CC1(c2ccc(Cl)nc2)CC1
Yield: 43 %

Procedure:
The title compound was prepared from (6-chloro-pyridin-3-yl)-acetonitrile and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 43% of theory; LC (method 3): tR=2.71 min; Mass spectrum (ESI+): m/z=179/181 (Cl) [M+H]+.