Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:37]1[CH:38]=[C:39]([CH2:42][CH2:43][CH2:44][OH:45])[S:40][CH:41]=1.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:29]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14]([C:37]4[CH:38]=[C:39]([CH2:42][CH2:43][CH2:44][OH:45])[S:40][CH:41]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)OC1(C)C
Reactant: OCCCc1cc(Br)cs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2csc(CCCO)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Yield: 40.6 %

Procedure:
In a 5 mL microwave vial was added 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (55 mg, 0.131 mmol), PdCl2(dppf)-CH2Cl2 adduct (17.18 mg, 0.021 mmol), and K2CO3 (83 mg, 0.601 mmol). Then 3-(4-bromo-2-thienyl)-1-propanol (37.8 mg, 0.171 mmol) in 1,4-dioxane (3 mL) was added to give an orange solution. Water (1.5 mL) was added and the solution was heated to 100° C. at high power in the microwave for 5 min, cooled. The reaction was filtered through a thiol paladium extraction column. The column was washed with CH2Cl2 and the combined filtrates were concentrated and purified on a Gilson HPLC(NH4OH buffer), giving 23 mg (41%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1)(O)[CH3:3].OS(O)(=O)=O.[OH-].[Na+]>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:3])[C:5]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]2[N:13]=[CH:14][CH:15]=[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]1[C:21]=23
Reactant: CC(C)(O)c1c(F)cccc1-c1nccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Product: CC1(C)c2c(F)cccc2-c2nccc3cccc1c23
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
26.1 g (92.82 mmol) of 1-[2-(1-methyl-1-hydroxyethyl)-3-fluorophenyl]isoquinoline were added to a mixture at 150° C. of 260 ml of o-dichlorobenzene and 104.2 ml of H2SO4, and stirred for 60 min. The reaction solution was subsequently poured onto 1000 ml of ice and adjusted cautiously to pH=12 with solid NaOH with ice cooling. Subsequently, the mixture was extracted with 500 ml of dichloromethane, dried over MgSO4 and concentrated under reduced pressure. The crude product was dissolved in 100 ml of toluene and air was introduced at 50° C. for 4 h. Subsequently, purification was effected by column chromatography with dichloromethane. 18.45 g of a solid were obtained, corresponding to 75.5% of theory, with a purity of 99.6%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[CH:7]=1)=[O:5])[CH3:2].[I:13]I.O.S(=O)(O)[O-].[Na+]>CC([O-])=O.ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[I:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)nn1C
Reactant: II
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)c1c(I)c(C)nn1C

Procedure:
1,3-Dimethyl-5-pyrazolcarboxylic acid ethyl ester (185 g, 1.1 mol), iodine (140 g, 0.55 mol) and HIO3 (38.7 g, 0.22 mol) are heated, under reflux, in acetic acid glacial (450 ml), water (150 ml) and 1,2-dichloroethane (150 ml) for 1.5 hours. The mixture is discoloured with saturated sodium bisulfite, evaporated under reduced pressure and the product extracted with ether. The organic phase is washed with sodium bisulfite and aqueous sodium bicarbonate solution.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:26])[C@@H:6]([CH3:25])[CH2:7][CH:8]([NH2:24])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:12][CH:11]=1)[CH3:3].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1.C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:26])[C@@H:6]([CH3:25])[CH2:7][CH:8]([NH:24][C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:12][CH:11]=1)[CH3:3]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2ccccc2OC)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2ccccc2OC)cc1)NC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-4-amino-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloric acid salt (240 mg, 0.703 mmol) in pyridine/DCM (1 ml/1 ml) was added succinic anhydride (84 mg, 0.843 mmol) and stirred at room temperature for 1 hour. Then, the mixture was concentrated under reduced pressure, and the residue was purified by RP-HPLC to give (S)-4-(3-Carboxy-propionylamino)-5-(2′-methoxy-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester. HPLC Retention time 1.29 minutes (condition A): MS 442.4 (M+1)
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([C@H:14]2[S:18][C@H:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[CH2:16][S:15]2)=[CH:7][C:6]=1[O:31][CH3:32])[CH:2]=[CH2:3].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Zn]>[CH2:1]([O:4][C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C@H:14]2[S:18][C@H:17]([C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[CH2:16][S:15]2)=[CH:7][C:6]=1[O:31][CH3:32])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: C=CCOc1c(N)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1OC

Procedure:
Trans-2-(4-allyloxy-3-methoxy-5-nitrophenyl)-4-(3,4,5-trimethoxy-phenyl)-1,3-dithiolane (24) 2.60 g, 5.43 mmole) was predissolved in 33 ml absolute ethanol. To this solution was added calcium chloride (0.602 g, 5.43 mmole) predissolved in 7 ml H2O followed by freshly activated zinc dust (7.09 g, 108 mmole). The reaction was refluxed for 12 hours. The solid was removed by vacuum filtration through celite and was washed with ethyl acetate. The filtrate was washed with 10% NaHCO3, dried over MgSO4, and
Reaction SMILES: Cl.[CH2:2]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20]OC2=O)=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(OC(C)C)(C)C.[BrH:30]>C(O)(=O)C>[BrH:30].[BrH:30].[CH2:2]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][NH:17][CH2:21][CH2:20]2)=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCc1ccc(NCCN2CCOC2=O)cc1
Agent: Br
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: CCCCCCc1ccc(N2CCNCC2)cc1

Procedure:
A solution of 3-[2-(4-Hexylphenylamino)ethyl]-2-oxo-oxazolidine hydrochloride (2.131 g) in 25% hydrobromic acid in acetic acid (13.04 ml) was stirred for 96 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration and added to ethanol (15 ml). The solution was refluxed for 5 hours and pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-n-Hexylphenyl)piperazine dihydrobromide (2.413 g).
Reaction SMILES: N([O-])=[O:2].[Na+].[CH2:5]([O:12][C:13]1[C:14]([CH3:21])=[CH:15][C:16]([F:20])=[C:17]([CH:19]=1)N)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.C(O)(=O)C.S(=O)(=O)(O)O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[Cu]=O>[CH2:5]([O:12][C:13]1[C:14]([CH3:21])=[CH:15][C:16]([F:20])=[C:17]([OH:2])[CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(F)c(N)cc1OCc1ccccc1
Reactant: O=N[O-]
Agent: O=[Cu]
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(F)c(O)cc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 26.9 %

Procedure:
A solution of sodium nitrite (1.68 g, 24 mmol) in water (3.5 ml) was added to a solution of 5-benzyloxy-2-fluoro-4-methylaniline (4.7 g, 20 mmol) in acetic acid (25 ml) and 70% sulphuric acid (25 ml) at 10° C. The mixture was stirred at 10° C. for 20 minutes and a solution of copper(II)nitrate trihydrate (481 g, 2 mol) in water (790 ml) followed by copper(II)oxide (3 g, 19 mmol) was added. The mixture was stirred for 3 hours then extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with petroleum ether/ether (85/15) to give 5-benzyloxy-2-fluoro-4-methylphenol (1.25 g, 27%) as an orange oil.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[C:36]4[C:41]=3[N:40]=[CH:39][CH:38]=[CH:37]4)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.CC(=O)OCC.CO>C(Cl)Cl>[NH2:18][C@H:19]([C:28]([N:30]([C@@H:42]([CH3:50])[CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2)=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CO
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
(S)-tert-Butyl 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-4-oxobutanoate (Compound III-17) 18.4 g (27 mmol) and piperidine 22.7 g (270 mmol) were added in DCM (90 ml). The mixture was stirred for 1.5 h at room temperature. The mixture was diluted with DCM (200 ml) and washed with water (150 ml×3). The solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=50:1 to DCM:MeOH=10:1 to give the title compound 10.5 g, (yield 85%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][N:8]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])[N:7]=1)=[O:5])C.[OH-].[K+]>C(O)C.O.O>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[N:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:9]1
Reactant: CCOC(=O)c1nn(-c2c(Cl)cccc2Cl)nc1COc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nn(-c2c(Cl)cccc2Cl)nc1COc1ccccc1
Yield: 87.3 %

Procedure:
A solution of the product from step b (1.43 g, 3.65 mmol) and potassium hydroxide (632 mg, 11.3 mmol) in ethanol/water (14 mL/2 mL) was heated at reflux for 2 h. The reaction mixture was allowed to cool and diluted with water (30 mL). The reaction mixture was washed with ether (30 mL) and the organic phase was discarded. The pH of the aqueous phase was adjusted to 1 with aqueous 2M hydrochloric acid and extracted twice with chloroform (40 mL). The combined chloroform extracts were dried (MgSO4) and the filtrate evaporated at reduced pressure to afford the title compound (1.16 g, 87%). 1H NMR (CDCl3) 7.52 (3H, m), 7.33-7.27 (2H, m), 7.08-6.99 (3H, m), 5.54 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:15])[C:12]([OH:14])=[O:13].[OH-].[Na+:22].O>C(O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:15])[C:12]([O-:14])=[O:13].[Na+:22]
Reactant: O=C(O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6.24 g of 2-(2,6-dichloroanilino)phenylglycolic acid in 30 ml of ethanol were added 10 ml of a 5 N aqueous sodium hydroxide solution and the mixture was stirred at room temperature for 1 hour. Then, 20 ml of water were added, and the mixture was concentrated to have a volume of 30 ml. The concentrate was cooled and the solid thus deposited was recovered by filtration. Recrystallization from water gave sodium 2-(2,6-dichloroanilino)phenylglycolate. m.p. 101°-104° C.
Reaction SMILES: [I:1][CH:2]1[CH2:7][CH2:6][NH:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH3:11]O>S(=O)(=O)(O)O>[CH3:11][O:9][C:8](=[O:10])[CH:4]1[CH2:3][CH:2]([I:1])[CH2:7][CH2:6][NH:5]1
Reactant: O=C(O)C1CC(I)CCN1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CC(I)CCN1
Yield: 86 %

Procedure:
To a solution of 13a prepared in method Q (5 g, 13.26 mmol) in methanol (500 mL) was added a few drops of conc. sulfuric acid. The reaction mixture was refluxed overnight. The solvent was evaporated and the residue was purified by chromatography to give 4-iodopipecolinic acid methyl ester 14a as a yellow solid (3.0 g, 86%): 1H NMR (300 MHz, CDCl3) δ 8.49 (d, J=1.5, 1), 8.37 (d, J=5.4, 1), 7.85 (dd, J=1.6, 5.2, 1), 4.00 (s, 3); MS (ESPOS): 264.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:7]1)=[O:5])[CH3:2].CC(C[AlH]C[CH:20]([CH3:22])[CH3:21])C.CO.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH:8]1[N:7]2[CH:6]1[CH:4]([OH:5])[O:3][CH:1]2[CH:2]1[CH:8]([C:9]2[S:10][CH:22]=[CH:20][CH:21]=2)[NH:7]1
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CCOC(=O)[C@@H]1N[C@H]1c1cccs1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: OC1OC(C2NC2c2cccs2)N2C(c3cccs3)C12
Temperature: -78 °C

Procedure:
In a flame dried 100 ml Schlenk tube equipped with a magnetic stirring bar was placed 1c (0.6 g, 3.05 mmol) in 10 ml toluene. The solution was cooled to −78° C. and a 1.5M solution of DIBAL in toluene (4 ml, 6 mmol) was added dropwise along the wall of the vessel. Once the addition was complete, the reaction was allowed to stir at −78° C. for another hour at which point ESI MS showed the lack of starting material. MeOH was slowly added along the wall of the vessel at −78° C. The reaction mixture was then allowed to stir for 30 minutes while warming to room temperature. Saturated Na2SO4 was then added and the solution was allowed to stir for another 15 minutes. The reaction was then filtered and water and ether was added. The organic later was extracted from the partition three times, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting white solid may be crystallized from EtOAc or MeOH to afford the title compound in 92% (428 mg) yield as a white solid. Silica column chromatography is not recommended. Mp=149-153° C. (decomp.) 1H NMR (CDCl3, 200 MHz) (δ: 7.66 (d, J=11.6 Hz, 1H), 7.23-7.18 (m, 2H), 7.02-6.94 (m, 4H), 5.48 (d, J=11.6 Hz, 1H), 3.27 (dd, J=7.0 Hz, 3.4 Hz, 1H), 2.99 (dd, J=9.0 Hz, 3.4 Hz), 2.90 (d, J=2.6 Hz, 1H), 2.75 (d, J=2.6 Hz, 1H), 1.17 (t, J=6.6 Hz, 1H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 141.5, 121.4, 127.7, 127.3, 125.9, 125.1, 124.8, 124.6, 96.9, 94.4, 54.0, 41.5, 37.5, 32.5 ppm. HRMS (EI) of aldehyde monomer: 152.9561
Reaction SMILES: C(N[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)C=C.[OH:25][C@@H:26]1[C@@H:30]([OH:31])[CH2:29][NH:28][CH2:27]1>>[OH:25][C@@H:26]1[C@@H:30]([OH:31])[CH2:29][N:28]([C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:27]1
Reactant: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Reactant: O[C@H]1CNC[C@@H]1O
Product: COc1ccc2c(N3C[C@H](O)[C@@H](O)C3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (3S,4S)-3,4-dihydroxypyrrolidine in place of allylamine, the title compound was synthesized.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](N(OC)C)=[O:9])=[N:6][CH:7]=1.[CH3:14][CH2:15][Mg+].[Br-]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:9])[CH2:14][CH3:15])=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1ccc(O)cn1
Reactant: CC[Mg+]
Agent: [Br-]
Product: CCC(=O)c1ccc(O)cn1
Yield: 48 %

Procedure:
Following the same procedure as described in example 11, step B, 5-hydroxy-N-methoxy-N-methylpicolinamide (0.5 g, 1.0 eq) was reacted with EtMgBr (6.0 mL, 4.0 eq) to get the desired product (0.2 g, 48% yield).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[C:59]([S:63][S:64][CH2:65][C@@H:66]([C:68]([OH:70])=[O:69])[NH2:67])([CH3:62])([CH3:61])[CH3:60].Cl>ClCCl.C(OCC)(=O)C>[CH2:3]([C@@H:2]([C:10](=[O:11])[NH:67][C@H:66]([C:68]([OH:70])=[O:69])[CH2:65][S:64][S:63][C:59]([CH3:62])([CH3:60])[CH3:61])[NH:1][C:13](=[O:14])[O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)SSC[C@H](N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)SSC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.7 %

Procedure:
A solution of Fmoc-Phe-OH (4 g, 10.32 mmol) and N-hydroxysuccinimide (1.19 g, 10.32 mmol) in dichloromethane (20 ml) was cooled to 0° C., after which 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl, 1.98 g, 10.32 mmol) was added and the reaction solution was stirred at room temperature for 6 hours. The reaction solution was cooled to 0° C., after which N,N-diisopropylethylamine (1.80 ml, 10.23 mmol) and S-(t-butylthio)-L-cysteine (H-Cys(StBu)-OH) (2.16 g, 10.32 mmol) were added and the reaction solution was stirred at room temperature for 12 hours. Ethyl acetate and 2 M hydrochloric acid were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with 25 wt % brine and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure, and the concentration residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (5S,8R)-5-benzyl-1-(9H-fluoren-9-yl)-12,12-dimethyl-3,6-dioxo-2-oxa-10,11-dithia-4,7-diazatridecane-8-carboxylic acid (Compound SP663, Fmoc-Phe-Cys(StBu)-OH) (4.22 g, 71%).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][C:19]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[C:24]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:34])[CH3:32])[C:25]([F:27])=[CH:26][C:18]=3[Cl:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Reactant: CC(C)(C)C(=O)NCc1cc(C(=O)O)c(Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3cc(CNC(=O)C(C)(C)C)c(F)cc3Cl)cccc12
Yield: 8.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 2-chloro-4-fluoro-5-(pivalamidomethyl)benzoic acid (Intermediate-63, 159 mg, 0.56 mmol), oxalyl chloride (117 mg, 0.93 mmol), DMF (1 drop) and DIPEA (178 mg, 1.38 mmol) in CH2Cl2 (5 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.18 (s, 1H), 8.69-8.66 (d, J=7.2 Hz, 1H), 8.47 (s, 1H), 8.16-8.11 (m, 2H), 7.62-7.57 (m, 2H), 7.52-7.45 (m, 2H), 4.31-4.29 (d, J=5.7 Hz, 2H), 1.53 (s, 9H), 1.10 (s, 9H); MS [M+H]+: 486.45.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=2)[CH:13]=1)=[O:6].O.[OH-].[Li+].C1COCC1.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:24])=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)[CH:13]=1)=[O:6]
Reactant: COC(=O)c1ccc(-c2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)O)cc1
Yield: 73.3 %

Procedure:
Methyl 5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylate (1.63 g, 4.28 mmol) and lithium hydroxide monohydrate (376 mg, 9.0 mmol) were mixed in water (5 ml) and THF (10 ml) and stirred at room temperature for 90 h. The pH was adjusted to pH3 by addition of hydrochloric acid (2N) and the mixture extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (75 ml), brine (75 ml), dried (magnesium sulphate) and concentrated under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/ethanol/ammonia (30:8:1 then 20:8:1). The solvents were evaporated under vacuum to give 5′-[(2-chloroisonicotinoyl)amino]-2′-methyl-1,1′-biphenyl-4-carboxylic acid (1.15 g, 73%). LCMS: retention time 3.53 min, MH+367.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C[Sn](C)(C)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: COC(=O)Cc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(-c2ccccn2)cc1

Procedure:
7.85 g (34.3 mmol) of methyl 4-bromophenylacetate are introduced under argon into 95 ml of toluene and, at room temperature, 7.97 g (61.7 mmol) of diisopropylethylamine, 9.50 g (37.7 mmol) of 2-trimethylstannylpyridine and 0.4 g (0.3 mmol) of tetrakis(triphenylphosphane)palladium(0) are added. The mixture is then heated under reflux for 18 h. Cooling is followed by washing with 100 ml each of 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic phase was discarded. The acidic and the basic aqueous phase were neutralized and each extracted with 100 ml of dichloromethane, and the combined organic phases were dried over magnesium sulfate and freed of solvent in vacuo. Example VII is obtained after silica gel chromatography (toluene/ethyl acetate gradient 5: 1-1:1) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[CH:23][CH:22]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4](OCC)=[O:5].[NH3:38]>CO>[CH3:1][N:2]([CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[CH:23][CH:22]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4](=[O:5])[NH2:38]
Reactant: CCOC(=O)CN(C)C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reactant: N
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CC(N)=O)c3ccccc32)cc1
Temperature: 100 °C

Procedure:
5-(N-Methyl-N-ethoxycarbonylmethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.6 g) is dissolved in saturated solution of ammonia in methanol (20 ml), and the mixture is heated at 100° C. for 8 hours in a sealed tube. The reaction solution is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1) to give 5-(N-methyl-N-carbamoylmethylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) as colorless amorphous.