Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:6][C@H:5]1[C:7]([OH:9])=O)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.C([O:44][C:45](=[O:65])[CH2:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=1[C@@H:55]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57][NH:56]1)C>CN(C=O)C.C(O)=O>[Cl:54][C:51]1[CH:52]=[CH:53][C:48]([O:47][CH2:46][C:45]([OH:65])=[O:44])=[C:49]([C@@H:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:58][CH2:57][N:56]2[C:7]([C@@H:5]2[CH2:6][C@H:4]2[CH:1]([CH3:2])[CH3:3])=[O:9])[CH:50]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1[C@H]1NCCc2ccccc21
Reactant: CC(C)[C@@H]1C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O=CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1C[C@H]1C(=O)N1CCc2ccccc2[C@H]1c1cc(Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-trans-2-isopropyl-cyclopropanecarboxylic acid (39 mg, 0.31 mmol, 1.3 eq.) in DMF (2 mL), DIPEA (4 eq.) and TBTU (98 mg, 0.31 mmol, 1.3 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 min. ((S)-4-Chloro-2-1,2,3,4-tetrahydro-isoquinolin-1-yl-phenoxy)-acetic acid ethyl ester hydrochloride (90 mg, 0.24 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac). To a solution of the ethyl ester derivative in DMF (1 mL), 1M aq. NaOH (0.5 mL) was added. The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL) and then purified by prep. HPLC (column: Waters XBridge, 19×50 mm, 5 um, UV/MS, acidic conditions) and concentrated in vacuo (Genevac) to give {4-Chloro-2-[(S)-2-(trans-2-isopropyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 1) (LC-MS 1FA: tR=1.13 min; [M+H]+=428.3) and {4-Chloro-2-[(S)-2-(trans-2-isopropyl-cyclopropanecarbonyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl]-phenoxy}-acetic acid (diastereoisomer 2) (LC-MS 1FA: tR=1.15 min; [M+H]+=428.3)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:20]([C@H:24]1[CH2:25][CH2:26][C@H:27]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:4][N:3]=2)[CH2:28][CH2:29]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: Clc1ncc(CCc2cccnc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](Nc2ncc(CCc3cccnc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under a N2 atmosphere, 300 mg (1.11 mmol) of 1-chloro-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline (step 1.6) and 520 mg (3.3 mmol) 4-tert-butyl-cyclohexylamine (cisitrans mixture) are stirred at 120° C. After 2 days, a further 520 mg of 4-tert-butyl-cyclohexylamine are added, followed by 1 g after a total of 4 days. Stirring continues for 3 days at 150° C., then the reaction mixture is cooled to RT and diluted with EtOAc and NaHCO3 solution. The water phase is separated off and extracted twice with EtOAc. The organic phases are washed 3 times with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; toluene/EtOAc 3:1) and elution (toluene/EtOAc 3:1+1% EteN) yields trans 1-(4-tert-butyl-cyclohexylamino)-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline (crystallised from DIPE), followed by cis 1-(4-tert-butyl-cyclohexylamino)-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline. trans derivative: m.p. 124-125° C.; 1H NMR (CDCl3) δ 8.47 (m, 2H), 7.83 (d, 1H), 7.77 (m, 2H), 7.64 (t, 1H), 7.47 (m, 2H), 7.19 (m, 1H), 4.98 (d, HN), 4.05 (m, 1H), 3.14 (t, 2H), 2.98 (t, 2H), 2.27 (m, 2H), 1.86 (m, 2H), 1.25 (m, 4H), 1.07 (m, 1H), 0.90 (s, 9H). cis derivative: 1H NMR (CDCl3) δ 8.47 (m, 2H), 7.85 (d, 1H), 7.77 (m, 2H), 7.66 (t, 1H), 7.50 (m, 2H), 7.20 (m, 1H), 5.40 (d, HN), 4.45 (m, 1H), 3.14 (t, 2H), 2.98 (t, 2H), 2.13 (m, 2H), 1.7 (m, 4H), 1.28 (m, 2H), 1.13 (m, 1H), 0.92 (s, 9H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:11]1[O:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=1>>[OH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:13]2[CH:12]=[CH:11][O:15][C:14]=2[CH:16]=[O:17])[CH2:3][CH2:2]1
Reactant: OCCN1CCNCC1
Reactant: O=Cc1ccc(Br)o1
Product: O=Cc1occc1N1CCN(CCO)CC1
Yield: 61.1 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from 1-piperazineethanol (3.91 g) was introduced into 5-bromo-2-furaldehyde (1.75 g), to thereby yield 5-[(4-(2-hydroxy-ethyl)-piperazin-1-yl)-furan-2-carbaldehyde (yield: 1.37 g, 61%). The produced 5-[(4-(2-hydroxy-ethyl)-piperazin-1-yl)-furan-2-carbaldehyde (1.12 g) was condensed with 3,4-dimethoxybenzyl cyanide (888 mg) through Method A (production step 2), to thereby yield the target product (yield: 1.32 g, 69%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:3]1=[O:27].Br[CH:29]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:34]([O:33][C:31]([CH:30]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C:3]1=[O:27])[CH2:29][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:32])[CH3:35]
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccc3ccccc23)SCC(N)C1=O
Reactant: CCOC(=O)CC(Br)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccc3ccccc23)CN(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of a mixture of 803 g of t-butyl α-[6-amino-2-(1-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] and 1.13 g of ethyl 3-bromo-4-phenylbutyrate in 10 ml of dimethylformamide was added 0.66 g of sodium carbonate. The reaction mixture was stirred at 80° C. for 15 hours and then dissolved in a mixture of ethyl acetate and an aqueous solution of sodium chloride. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was then evaporated off. The residue was subjected to silica gel column chromatography using a 1:30 by volume mixture of ethyl acetate and methylene chloride as eluent, which separated the product into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][S:21][CH2:22][CH2:23][CH2:24][CH2:25]O.C(C=P(CCCC)(CCCC)CCCC)#N.CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:25][CH2:24][CH2:23][CH2:22][S:21][CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSCCCCO
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CSCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 64.7 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (0.94 g, 3.1 mmol) obtained in Example 5 was dissolved in toluene (15 ml). After addition of 4-(methylthio)-1-butanol (0.25 ml, 2.1 mmol) and cyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol), the resulting mixture was heated under reflux for 14 hours under an argon atmosphere. The reaction mixture was allowed to cool down. Then, 4-(methylthio)-1-butanol (0.25 ml, 2.1 mmol) was added, followed by heating under reflux for 6 hours under an argon atmosphere. The reaction mixture was allowed to cool down and then, concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to yield a colorless oil. The resulting colorless oil was solidified with hexane, whereby the title compound (0.55 g, 44%) was obtained as a white powder.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:9]=[C:10]([CH2:16][C:17]#[N:18])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].Br[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Br>CN1C(=O)CCC1.CCOCC>[Br:7][C:8]1[CH:9]=[C:10]([C:16]2([C:17]#[N:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(CC#N)cc1Br
Reactant: BrCCOCCBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COc1ccc(C2(C#N)CCOCC2)cc1Br
Temperature: 0 °C
Yield: 62.5 %

Procedure:
A mixture of sodium tert-butoxide (6.7 g, 70 mmol) in 100 mL NMP stirred at 0° C. was treated dropwise with a mixture of 2-(3-bromo-4-methoxyphenyl)acetonitrile (6.3 g, 28 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (6.5 g, 28 mmol) in 30 mL ether. The mixture was allowed to warm to room temperature and was stirred for 3 hours, M+Na=318/320. The mixture was quenched with 100 mL H2O carefully and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The organic layer was then dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5.18 g of crude product as a yellow solid. MS m/e=318/320 (M+Na)+.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[CH2:7]([NH:6][C:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C/C=C/C(N)=O
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Product: C/C=C/C(=O)NCc1ccccc1
Yield: 71 %

Procedure:
To 200 ml of N,N-dimethylformamide, were added 17 g of crotonamide, 105 g of LEVATIT MP-500, which was also used in Example 68, and 32 g of benzylchloride. They were reacted at 50° C. for 4 hours with stirring. After the reaction, the reaction solution was treated in the same manner as in Example 69, the resulting distillation residue was recrystallized from benzine, and 25 of N-benzylcrotonamide having a melting point of 112.5°-113.6° C. was obtained (yield: 71%).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:12])=O>>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([Cl:12])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCCC(=O)O
Product: CC(C)CCCC(=O)Cl
Yield: 85.9 %

Procedure:
A mixture of 5-methylhexanoic acid (25 mL, 175 mmol) and thionyl chloride (50 mL, 0.69 mol) was stirred at reflux for 90 minutes. The mixture was concentrated, then distilled at reduced pressure to give the desired product (22.35 g).
Reaction SMILES: [NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[O:26][CH3:27])=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>ClC(Cl)Cl.CN(C)C1C=CN=CC=1>[C:40]([NH:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:11][C@H:10]2[O:26][CH3:27])=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1)(=[O:42])[CH3:41]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
10 parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide were dissolved in 225 parts of hot trichloromethane. After cooling to room temperature, 3.6 parts of N,N-diethylethanamine were added. Then there was added dropwise a solution of 1.7 parts of acetyl chloride in 30 parts of trichloromethane:exothermic reaction. The whole was stirred and refluxed for 22 hours. After cooling to room temperature, 0.6 parts of acetyl chloride were added and stirring was continued overnight at reflux. Another 0.6 parts of acetyl chloride were added and stirring was continued overnight at reflux. After cooling again to room temperature, there were added successively 0.6 parts of acetyl chloride and a small amount of N,N-dimethyl-4-pyridinamine. Stirring was continued for 22 hours at reflux. The reaction mixture was cooled to room temperature and washed with water. The organic phase was dried, filtered and evaporated. The residue was crystallized twice from acetonitrile, yielding 2.78 parts (25.5%) of cis-4-(acetylamino)-5-chloro-N-[1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 175.6° C. (compound 233).
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9]([C:14]([O:16]CCCCCC)=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+]>CO>[CH2:1]([O:7][C:8]1[C:9]([C:14]([OH:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOC(=O)c1ncccc1OCCCCCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCOc1cccnc1C(=O)O
Yield: 111.1 %

Procedure:
In 10 ml of methanol was dissolved 2.50 g (8.1 mmol) of hexyl 3-hexyloxypicolinate and 10 ml of a 10% potassium hydroxide solution was added thereto, followed by refluxing for 1.5 hours. The solvent was distilled off under a reduced pressure and the residue was dissolved in 30 ml of water and, after the pH of the solution was adjusted to about 2 with 6N hydrochloric acid, was extracted with dichloromethane. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 2.01 g of an oily product. Since the recrystallization cannot be effected in any solvents, the washing with hexane was repeated to obtain 0.80 g of the oily product, which was directly used in the subsequent reaction.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.ClC[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:3][N:2]([CH3:5])[CH3:1])[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN(C)C
Temperature: 80 °C
Reaction time: 72 h
Yield: 33 %

Procedure:
N,N-Dimethylformamide (2.5 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (100 mg), potassium carbonate (500 mg), sodium iodide (20 mg), and water (0.05 ml), and the mixture was stirred at 80° C. for 3 days. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (34.2 mg, yield 33%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[O-:12][CH2:13][CH3:14].[K+]>>[CH2:13]([O:12][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:14]
Reactant: Clc1cc2ccccc2cn1
Reactant: CC[O-]
Agent: [K+]
Product: CCOc1cc2ccccc2cn1
Temperature: 150 °C
Yield: 48.1 %

Procedure:
3-Chloroisoquinoline (3.0, 18 mmol) was dissolved in potassium ethoxide (24% in EtOH, 10.6 mL, 27 mmol) and heated to 150° C. in a sealed tube for 24 h. After cooling, the solvent was removed in vacuo and the residue treated with 1M HCl until the solution reaches a pH 3. Saturated NaHCO3 solution then added slowly to return the solution to pH 8 followed by extraction with CHCl3. The combined organics were washed with brine, dried over anhydrous MgSO4. The residue obtained from concentration in vacuo was purified by column chromatography on SiO2 (0-15% EtOAc, hex) to afford 1.5 g (48%) of 3-ethoxyisoquinoline. LCMS found 174.11 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[O:25]C(C)(C)[N:23]([C:28](=[O:32])[CH:29]([F:31])[F:30])[C@@H:22]3[CH2:33][F:34])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:7][CH2:8][C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C@@H:21]([OH:25])[C@H:22]([NH:23][C:28](=[O:32])[CH:29]([F:30])[F:31])[CH2:33][F:34])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)nn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (6-{4-[(4S,5R)-3-(2,2-Difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridazin-3-ylmethyl)-carbamic acid tert-butyl ester (0.25 g, 0.506 mmol) in CH2Cl2 (10 mL) is added trifluoroacetic acid (1.5 mL) at room temperature. Resulting reaction mixture is allowed to stir at room temperature for 5 h. The solvent evaporated in vacuo and the crude material is striped out with CH2Cl2 followed by washing with n-pentane and diethyl ether and dried to afford title compound (0.181 g): 1H NMR (400 MHz, DMSO-d6) 4.32-4.39 (m, 1.5H), 4.46 (m, 2.5H), 4.55-4.58 (m, 0.5H), 4.68-4.71 (m, 0.5H), 4.94 (bs, 1H), 5.99 (bs, 1H), 6.19 (t, J=53.76 Hz, 1H), 7.54 (d, J=8.28 Hz, 2H), 7.85 (d, J=8.92 Hz, 1H), 8.13 (d, J=8.32 Hz, 2H), 8.36 (d, J=10 HZ, 1H), 8.51 (bs, 2H), 8.87 (d, J=8.72 Hz, 1H). LC-MS (m/z): [M+H]=355.
Reaction SMILES: [Cl-].[CH3:2]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:34][C:35]1[C:40]([C:41]([C:43]2[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=2)=O)=[CH:39][C:38]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[C:52]([O:58][CH3:59])[CH:51]=2)=[CH:37][N:36]=1>C1COCC1>[CH3:59][O:58][C:52]1[CH:51]=[C:50]([C:38]2[CH:39]=[C:40]3[C:41]([C:43]4[CH:48]=[CH:47][C:46]([NH2:49])=[N:45][CH:44]=4)=[CH:2][NH:34][C:35]3=[N:36][CH:37]=2)[CH:55]=[CH:54][C:53]=1[O:56][CH3:57]
Reactant: COc1ccc(-c2cnc(N)c(C(=O)c3ccc(N)nc3)c2)cc1OC
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4ccc(N)nc4)c3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (166 mg, 0.485 mmol) in THF (1 ml) at 0° C. under nitrogen was added potassium bis(trimethylsilyl)amide (97 mg, 0.485 mmol). The mixture was stirred at room temperature for 30 min, then it was added to [2-amino-5-(3,4-dimethoxy-phenyl)-pyridin-3-yl]-(6-amino-pyridin-3-yl)-methanone (34 mg, 0.097 mmol) in one portion. The reaction mixture was stirred for 2 hours, then quenched with wet methanol and concentrated in vacuo. The crude was diluted with 2 ml of 1,4-dioxane and treated with 0.1 ml of aqueous 70% perchloric acid. The mixture was stirred at 80° C. for 19 hours, diluted with THF/methanol (1:1), and treated with 2.0 g of PS-trisamine (Argonaut Technologies, 4 equivalents per equivalent of acid used) for 30 minutes. The resin was filtered off and washed with THF/MeOH (1:1). Purification was accomplished by flash chromotography on silica gel with a gradient of methanol/dichloromethane afforded 5-[5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyridin-2-ylamine as a yellow solid (9.7 mg, 29% yield). 1H NMR (DMSO-d6): δ 11.8 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.77 (dd, J=2.0, 10.0 Hz, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.24 (dd, J=2.0, 7.5 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.55 (d, J=8.5 Hz, 1H), 5.90 (broad s, 2H), 3.86 (s, 3H), 3.79 (s, 3H). HPLC/MS m/z: 347.1 [MH]+.
Reaction SMILES: [C:1]1([P:7]([CH2:14][SH:15])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CSNC(=O)C.[C:24]([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:26])[CH3:25]>CN(C=O)C>[NH:27]([C:24]([CH3:25])=[O:26])[C@H:28]([C:36]([S:15][CH2:14][P:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: SCP(c1ccccc1)c1ccccc1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CSNC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)SCP(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 92 %

Procedure:
Method A (transthioesterification). Phosphinothiol 20 (500 mg, 2.2 mmol) was dissolved in dry TBF (5 mL). The solution was deoxygenated by bubbling Ar(g) for 0.5 h. To this solution was added NaH (51.6 mg, 2.2 mmol). The mixture formed a slurry to which was added DMF (2 mL0 to dissolve any precipitate. The N-methylmercaptoacetamide (NMA) thioester of N-acetylphenylalanine (63 mg, 0.22 mmol) was added, and the reaction mixture was stirred for 8 h. Unreacted Phosphinothiol 20 was removed by adding Merrifield resin (1.5 g, 1.26 mmol/g), stirring for 6 h, and removing the resin by filtration. The residue was purified by flash chromatography (silica gel, 50% ethyl acetate in hexanes). AcPheSCH2PPh2 was isolated as a white solid in 92% yield.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH2:6][NH:7]C1C=CC=CC=1)[CH3:3].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C>O.C(OCC)C.ClCCl>[C:16]1([CH:15]=[N:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CNc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN=Cc1ccccc1
Reaction time: 17 h
Yield: 131.8 %

Procedure:
To a mixture of 10.6 g of ethyl phenylglycinate hydrochloride 2 (49.3 mmol), 100 mL of dichloromethane, 5 ml of benzaldehyde (49.2 mmol) and 30 g of magnesium sulfate (249.2 mmol) were added at room temperature, under a nitrogen atmosphere, 21.25 mL of triethylamine (152.46 mmol). After stirring for 17 h the heterogeneous reaction mixture was filtered through celite and the solid was washed with 100 mL of dichloromethane. The solvents were evaporated under reduced pressure and the viscous oil thus obtained was stirred with 80 mL of diethyl ether and 80 mL of water until dissolution. After decantation, the organic layer was dried over sodium sulphate and the solvent was evaporated under vacuum. The immine ester 3 (12.4 g, 94% yield) was obtained as a yellow pale oil.