Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:6]=1[O:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[CH2:15][C:16]2[NH:28][N:27]=[N:26][N:17]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)ccc1OC1CCN(C(=O)CC#N)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(F)ccc1OC1CCN(C(=O)Cc2nnn[nH]2)CC1
Temperature: 25 °C
Yield: 15.2 %

Procedure:
3-[4-(2-tert-Butyl-4-fluorophenoxy)piperidin-1-yl]-3-oxopropanenitrile (400 mg, 1.26 mmol) obtained in Example 237, ammonium chloride (101 mg, 1.89 mmol) and sodium azide (123 mg, 1.89 mmol) were stirred in DMF (15 mL) at 120° C. for 16 hr. The reaction mixture was cooled to room temperature, and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 40:60-0:100) and by preparative HPLC (device: Gilson Inc., High Throughput Purification system; column: YMC Combiprep ODS-A, S-5 μm, 50×20 mm; solvent: SOLUTION A; 0.1% trifluoroacetic acid-containing water, SOLUTION B; 0.1% trifluoroacetic acid-containing acetonitrile; gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=90/10), 1.00 min (SOLUTION A/SOLUTION B=90/10), 4.20 min (SOLUTION A/SOLUTION B=10/90), 5.40 min (SOLUTION A/SOLUTION B=10/90), 5.50 min (SOLUTION A/SOLUTION B=90/10), 5.60 min (SOLUTION A/SOLUTION B=90/10); flow rate: 25 mL/min; detection method: UV 220 nm) to give the title compound (69 mg, 15%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:27])[CH3:26])=[O:5])C.[OH-].[Na+].O.Cl>C(#N)C>[CH3:25][S:22]([C:18]1[CH:17]=[C:16]([CH:11]2[CH2:10][C:9]([CH3:27])([CH3:26])[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(S(C)(=O)=O)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(c2cccc(S(C)(=O)=O)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A mixture of 2-(3-methanesulfonyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.3 g, 8.53 mmol), sodium hydroxide (3.41 g, 85.3 mmol), water (10 mL) in acetonitrile (30 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 mol/L aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-methanesulfonyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.76 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=360.3.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>O1CCCC1>[C:27]([O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])(=[O:29])[CH3:28]
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)On1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Yield: 90.6 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.3 ml (2.18 mmol) dry triethylamine and 0.15 ml (2.10 mmol) acetyl chloride. The mixture was refluxed for 3 h, and then evaporated in vacuo. The residue was stirred with water to give 0.42 g (92%) of 1-acetoxy-7-cyano-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 230° C. 1H-NMR (DMSO-d6): 8.16 (1H, s), 7.53 (1H, s), 2.37 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH2:22](O)[CH:23]=[CH2:24].S(=O)(=O)(O)O>O>[CH2:24]([O:12][C:11](=[O:13])[CH2:10][CH2:9][C:8]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:14])[CH:23]=[CH2:22]
Reactant: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CCOC(=O)CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 20 h

Procedure:
A mixture of 85.8 grams of 4,4-bis-(4-hydroxyphenyl)pentanoic acid, 200 ml. of allyl alcohol and 2 ml. of concentrated sulfuric acid was heated to 50° C. and maintained at the temperature, with stirring, for 20 hours. The mixture was then poured into 1500 ml. of water, with stirring. The oily layer was allowed to settle and the aqueous layer was removed by decantation. The oily layer was washed with water two additional times. Finally, a 1500 ml. portion of water was added to the oil and the mixture was stirred until the viscous oil solidified. The solid was separated from the water, pulverized and stirred one hour with 1000 ml. of water containing 16.8 grams of sodium bicarbonate. The product was filtered and washed with water until the filtrate was neutral. Yield: 86.6 grams (88.5%) of off white solid, m.p. 83°-85° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH:12]1[CH3:21].Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH:12]2[CH3:21])=[CH:25][CH:26]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)N1CCC(Nc2nc3ccccc3[nH]2)C(C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)C(C)C1
Temperature: 70 °C
Yield: 38 %

Procedure:
A mixture of 19 parts of methyl 4-(1H-benzimidazol-2-ylamino)-3-methyl-1-piperidinecarboxylate, 11 parts of 1-(chloromethyl)-4-fluorobenzene, 6 parts of sodium carbonate and 135 parts of N,N-dimethylformamide is stirred and heated overnight at 70° C. The reaction mixture is cooled and poured onto water. The product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 8 parts (38%) of methyl 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-3-methyl-1-piperidinecarboxylate; mp. 172.5° C.
Reaction SMILES: [CH:1]1([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][N:16]([CH2:23][CH:24]4[CH2:28][O:27]C(C)(C)[O:25]4)[C:17](=[O:22])[C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(Cl)Cl>CCOCC>[CH:1]1([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][N:16]([CH2:23][CH:24]([OH:25])[CH2:28][OH:27])[C:17](=[O:22])[C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OCC(Cn2ccc3c(C(=O)NCC4CCCCCC4)cccc3c2=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NCC1CCCCCC1)c1cccc2c(=O)n(CC(O)CO)ccc12

Procedure:
N-(Cycloheptylmethyl)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-oxo-1,2-dihydroisoquinoline-5-carboxamide (110 mg, 0.00028 mol), hydrogen chloride (5 mL, 0.006 mol) as 2M solution in ether and methylene chloride (5 mL, 0.08 mol) were stirred at room temperature for 2 hours. The volatiles were removed under vacuum, the residue was purified via flash chromatography (12 g of silica gel, 0-10% MeOH/CH2Cl2) to give a white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][OH:14])[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:4]1)[CH3:2].Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22]Cl.[H-].[Na+]>>[CH2:1]([C:3]1([CH2:13][O:14][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH2:7][CH2:6][C:5]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:4]1)[CH3:2]
Reactant: ClCc1ccccn1
Reactant: CCC1(CO)CCC2(CCOCC2)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCC1(COCc2ccccn2)CCC2(CCOCC2)O1
Yield: 62.5 %

Procedure:
Following procedures similar to Embodiments XVII-XIX, 1.10 g of 2-ethyl-1,8-dioxaspiro[4.5]decane-2-methanol was treated with 1.35 g of 2-picolinyl chloride hydrochloride in the presence of sodium hydride to yield 1.00 g of the desired product as pale yellow liquid.
Reaction SMILES: O.NN.[CH3:4][N:5]([CH:25]1[CH2:28][O:27][CH2:26]1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH:22]([CH3:24])[CH3:23])[CH:13]=2)[CH2:7]1>C(O)C.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([N:5]([CH3:4])[CH:25]3[CH2:28][O:27][CH2:26]3)[CH2:7]2)=[CH:13][C:14]=1[O:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)Oc1cc(N2CCC[C@@H](N(C)C3COC3)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(N2CCC[C@@H](N(C)C3COC3)C2)ccc1N
Temperature: 90 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
24 mg of palladium-on-carbon (10%) and then 0.269 ml of hydrazine hydrate are added to a solution of 161 mg of (3R)—N-methyl-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-amine in 4 ml of ethanol. This mixture is heated at between 85° C./90° C. with magnetic stirring for 1 h 30, then 24 mg of palladium-on-carbon (10%) are added while continuing the refluxing for 2 h. 24 mg of palladium-on-carbon (10%) and 0.269 ml of hydrazine hydrate are again added. The mixture is heated for 1 h at 85° C./90° C., and then allowed to return to ambient temperature and the mixture is filtered through a Whatman AutoCup sintered glass funnel. The filtrate is concentrated under vacuum so as to obtain 136 mg of (3R)-1-[4-amino-3-(propan-2-yloxy)phenyl]-N-methyl-N-(oxetan-3-yl)piperidin-3-amine in the form of an orangey-yellow solid which is used for the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:15][CH:14]=[CH2:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1cc(C(=O)OC)cc(Cl)c1O
Yield: 83.3 %

Procedure:
To a 250 mL rb flask equipped with a magnetic stir bar and a reflux condenser was added a solution of 10.33 g (55.4 mmol) of methyl 3-chloro-4-hydroxybenzoate dissolved in 110 mL of acetone and 5.27 mL (60.9 mmol) of allyl bromide and 15.30 g (0.111 mol) of powdered potassium carbonate was added. The reaction was stirred and refluxed for 6 hours, then cooled and filtered. The tiltrate was evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 10% EtOAc-hexane to afford 10.462 g (84%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)[CH3:14]>>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccc(N)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: CCc1ccc(Nc2nc(C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (100 mg, 0.56 mmol), 4-ethyl-phenylamine (0.07 ml, 0.56 mmol) by a procedure similar to Example 78. 1H NMR (CDCl3): 7.85-7.78 (m, 2H), 7.76-7.71 (m, 3H)), 7.49 (t, J=7.5 Hz, 1H), 7.36 (brs, 1H), 7.24 (s, 2H), 2.70-2.69 (m, 5H), 1.26 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[CH2:9]1[O:11][C@H:10]1[CH2:12]Cl.C[O-].[Na+]>C(O)C>[O:11]1[CH:10]([CH2:12][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:9]1
Reactant: C1COCCN1
Reactant: ClC[C@H]1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: C1CN(CC2CO2)CCO1
Temperature: 250 °C
Yield: 96.4 %

Procedure:
To 1 L 3-neck round bottom flask, fitted with mechanical stirring, thermocouple and addition funnel, was charged morpholine (91.5 g, 91.5 ml, 1.05 mole, 1.0 eq.) and 200 ml of methanol. The solution was stirred rapidly while adding R-epichlorohydrin (10 g, 84.5 ml, 1.08 mole, 1.03 eq.) from the addition funnel over about 30 minutes. The temperature was monitored and when the pot temperature reached 27° C., the reaction was cooled with an ice water bath. The clear solution was stirred for 18 hours. The reaction was assayed by GC (dilute 5 drops of reaction mixture into 1 ml of ethanol and inject onto a 15 m DB-5 capillary GC column with the following run parameters, Injector 250° C., detector 250° C., initial oven temperature 28° C. warming to 250° C. at 10° C. per minute.) The reaction was complete with less than 3% morpholine remaining. The solution was cooled to 10° C. and a 25 wt. % solution of sodium methoxide in methanol (233 g, 1.08 mole, 247 ml) was added dropwise keeping the temperature less than 15° C. The resulting white slurry was stirred at 10-15° C. for 2 hours and checked by GC using the above conditions. None of the chlorohydrin could be observed. The mixture was concentrated on the rotoevaporator using 50° C. bath and full house vacuum. The resulting mixture was diluted with water (500 ml) and methylene chloride. The phases were separated and the aqueous phase washed with methylene chloride (500 ml). The combined organic layers were dried over sodium sulfate and concentrated to a clear, colorless oil. This provided 145 g, 97% yield of 1,2-epoxy-3-morpholin-4-ylpropane. 1H NMR (400 MHz, DMSO-d6) δ 3.3 (dd, 4 H), 3.1 (m, 1 H), 2.6 (dd, 1 H), 2.5 (dd, 1 H), 2.4 (m, 4 H), 2.2 (dd, 2 H); 13C NMR (100 MHz, DMSO-d6) δ 65.4, 60.1, 53.1, 48.9, 43.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:15](=[O:17])[CH3:16])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(CO)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(COC(C)=O)cc1
Temperature: 0 °C
Yield: 61.7 %

Procedure:
A solution of (4-hydroxymethyl-phenoxy)-acetic acid methyl ester 69 (100 grams, 509 mmol), acetic anhydride (250 mL) and pyridine (20 mL) was refluxed for 4 hours. Reaction mixture was poured in to ice water (1000 mL) and crude 70 was extracted into chloroform, dried over Na2SO4, and distilled. The crude was vacuum distilled to give pure 70 (75 grams, 61.7%) as a light yellow syrup, Bp15 206-210° C. The structure was confirmed with NMR. IHNMR (CDCl3) δ 2.05 (s, 3H, O═C—CH3), 3.78 (s, 3H, ester), 4.62 (s, 2H, OCH2), 5.02 (s, 2H, CH2), 6.88 (d, 2H, Ar), 7.33 (d, 2H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][NH:14][CH:15]=O)[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]2[C:4]=1[CH:15]=[N:14][CH2:13][CH2:12]2
Reactant: COc1cc(CCNC=O)cc2c1OCO2
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1c2c(cc3c1OCO3)CCN=C2
Temperature: 100 °C
Yield: 97.5 %

Procedure:
2.23 g (10 mmol) of N-[2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl]formamide (C) was dissolved in 25.5 ml of methylene chloride, and to this mixture was added 1.87 ml (20 mmol) of phosphorus oxychloride. The resulting mixture was refluxed under heating for 7 hours and concentrated under reduced pressure. The residue was added with 50 ml of toluene and 50 ml of water, then further added with 14 ml of 20% sodium hydroxide aqueous solution, stirred under heating at 100° C. for one hour and cooled. The reaction mixture was separated and the aqueous layer was extracted with 25 ml of toluene. The toluene layers were combined, washed with 25 ml of water and dried over anhydrous magnesium sulfate. Distillation off the solvent gave 2.00 g of 8-methoxy-6,7-methylenedioxy-3,4-dihydroisoquinoline (D) (yield: 98%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:39][CH2:40][C@@H:41]([OH:53])[CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(Cl)Cl>[CH2:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51][CH2:52][N:43]1[CH2:42][C@H:41]([OH:53])[CH2:40][NH:39][C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)=[O:14]
Reactant: Cc1ccc2cc(C(=O)O)ccc2n1
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2cc(C(=O)NC[C@@H](O)CN3CCc4ccccc4C3)ccc2n1
Temperature: 15 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
To a solution of 2-methylquinoline-6-carboxylic acid (200 mg, 1.070 mmol) in DCM (30 mL), was added HATU (489 mg, 1.283 mmol) and TEA (324 mg, 3.208 mmol). The solution was stirred at 15° C. for 30 minutes before (R)-1-amino-3-(3,4-dihydro isoquinolin-2(1H)-yl)propan-2-ol (264 mg, 1.283 mmol) was added. The resulting solution was stirred for another 16 h at 15° C., until the reaction was complete by LCMS analysis. The mixture was then concentrated under vacuum to give the crude material which was purified by Preparative HPLC to give the title compound (118 mg, 29%). 1H NMR (400 MHz, METHANOL-d4) δ 8.33 (d, J=1.9 Hz, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.09 (dd, J=2.1, 8.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.15-7.05 (m, 4H), 4.18 (quin, J=6.1 Hz, 1H), 3.79 (s, 2H), 3.63-3.55 (m, 2H), 2.95-2.90 (m, 4H), 2.76 (s, 3H), 2.76-2.68 (m, 2H). LCMS (m/z): 376.1 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:14])[S:11][C:7]=2[C:6](I)=[CH:5][CH:4]=1.C[Sn](C)(C)[C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1>>[NH2:30][C:26]1[CH:25]=[C:24]([C:6]2[C:7]3[S:11][C:10]([NH:12][C:13]([C:15]4[S:16][C:17]([CH3:20])=[CH:18][CH:19]=4)=[O:14])=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C[Sn](C)(C)c1cccc(N)c1
Reactant: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(-c2cccc(N)c2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 56 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid [7-(3-amino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (4-methoxy-7-iodo-benzothiazol-2-yl)-amide (300 mg, 0.70 mmol) and 3-trimethylstannanyl-phenylamine (291 mg, 1.14 mmol) using the general procedure B as a light brown solid in 56% yield. MS: m/e=396 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:45])[C@@H:4]([NH:18][C:19]([C:21]1[C:30]([S:31][CH2:32][CH3:33])=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:34][C:35]3[CH:40]=[CH:39][C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:37][CH:36]=3)[CH:27]=2)[N:22]=1)=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(Cl)Cl>C(Cl)Cl.CO>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([NH:18][C:19]([C:21]2[C:30]([S:31][CH2:32][CH3:33])=[N:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:34][C:35]4[CH:36]=[CH:37][C:38]([C:41]([CH3:42])([CH3:43])[CH3:44])=[CH:39][CH:40]=4)[CH:27]=3)[N:22]=2)=[O:20])[C:3]([OH:45])=[O:2])=[CH:11][CH:10]=1
Reactant: CCSc1nc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2nc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OC
Solvent: CO
Solvent: ClCCl
Product: CCSc1nc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2nc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Yield: 75.7 %

Procedure:
3-Biphenyl-4-yl-(2S)-{[6-(4-tert-butyl-phenoxy)-3-ethylsulfanyl-quinoxaline-2-carbonyl]-amino}-propionic acid methyl ester (30 mg, 0.048 mmol) was hydrolyzed as described in general procedure C. Column chromatography over silica using DCM and 95:5 DCM-methanol as eluants gave the title compound (22 mg).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO>[NH2:30][CH:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Yield: 33.5 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (2.5 g), ammonium acetate (5.4 g) and sodium cyanoborohydride (0.96 g) in methanol (50 ml) was refluxed for 5 hours. The mixture was concentrated to dryness. The residue was dissolved in ethyl acetate, washed with water, dried, and evaporated. The residue (2.6 g) was purified by column chromatography on silica gel (70 g) eluting with a mixture of chloroform and methanol (9:1) to give a white powder of 4'-(1-aminoethyl)-2'-(2,4-difluorophenylthio)methanesulfonanilide (0.84 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O.O.[OH-].[K+]>C(O)C.[C].[Pd]>[C:13]([CH2:12][O:11][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([OH:1])[C:7]=1[C:8](=[O:10])[CH:9]=[CH:24][CH:23]1[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH2:19][CH2:18][OH:17])[CH2:22]1)([OH:15])=[O:14]
Reactant: COC(=O)COc1cccc(O)c1C(C)=O
Reactant: O=Cc1cccc(OCCO)c1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cccc(O)c1C(=O)C=CC1C=CC=C(OCCO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a suspension of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (1 g) and 3-(2-hydroxyethoxy)benzaldehyde (0.74 g) in ethanol (12 mL) were added water (3 mL) and potassium hydroxide (3 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% palladium-carbon powder (0.2 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was dissolved in water, and the solution was washed with diethyl ether. The aqueous layer was acidified by addition of concentrated hydrochloric acid, and the resulting mixture was extracted with ethyl acetate twice. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was treated with diethyl ether, and the precipitated crystals were collected by filtration. The crystals were dried under reduced pressure to give the title compound (1.6 g).