Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]1.[C:20](Cl)(=[O:22])[CH3:21].O>C(Cl)Cl>[CH3:16][C:12]1[C:13]([C:20](=[O:22])[CH3:21])=[CH:14][C:15]2[C:6]([CH3:19])([CH3:5])[CH2:7][CH2:8][C:9]([CH3:18])([CH3:17])[C:10]=2[CH:11]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (2.88 g; 21.6 mmol) in methylene chloride (5 ml) was added over 15 minutes a solution of 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphthalene (4.0 g; 20 mmol) and acetyl chloride (1.6 ml; 21.6 mmol) in methylene chloride (20 ml) at 0° C. The reaction mixture was stirred for 30 minutes and ice cooled water (50 ml) was added. The organic phase was separated and the water phase was further extracted with methylene chloride (3×30 ml). The combined organic phases were first washed with brine then dried before evaporated. The residue was purified by column chromatography using hexane:methylene chloride (1:1) to give the title compound in 4.9 g (100%) yield.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COc1cccc(O)c1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Product: CCCCOC(=O)c1nc(Oc2cccc(OC)c2)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 3-methoxy phenol in analogy to Example D-20 d); MS-(+)-ion: M+1=368.1.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([CH2:18][OH:19])[N:14]=[CH:15]2)=[CH:10][N:9]=1>O.[OH-].[Na+]>[Cl:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]([OH:2])=[O:19])[N:14]=[CH:15]2)=[CH:10][N:9]=1
Reactant: OCc1cc2cnc(Cl)cc2cn1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2cnc(Cl)cc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
Potassium permanganate (280 mg, 1.8 mmol) was added in small portions to a slurry of (7-chloro-2,6-naphthyridin-3-yl)methanol (105 mg, 0.54 mmol) in water (2 mL). The mixture was stirred for 30 minutes at room temperature, and was then diluted with sodium hydroxide (1.0 M solution in water, 5 mL) and filtered over Celite. The filtrate was acidified to a pH of ˜3 via addition of citric acid, and the resulting precipitate was collected by vacuum filtration and washed with water (2×5 mL) to afford the title compound as a white solid (55 mg, 50%). 1H NMR (400 MHz, DMSO) δ 13.40 (s, 1H), 9.54 (s, 1H), 9.51 (s, 1H), 8.82 (s, 1H), 8.36 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>>[CH2:1]([C:3]1[N:4]([CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: COCCOCCCl
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1CCOCCOC
Yield: 77 %

Procedure:
2-Ethyl-1-[2-(2-methoxyethoxy)ethyl]-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-ethylbenzimidazole was used instead of benzimidazole and an equimolar amount of 2-chloroethyl 2-methoxyethyl ether was used instead of 2-chloroethyl methyl ether. Yield 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(Cl)c2)CCNC1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2ccc(F)c(Cl)c2)C1

Procedure:
Preparation according to Example 22: 3-(3-chloro-4-fluorophenyl)pyrrolidin-3-ol (0.8 g, 3.72 mmol), potassium carbonate (1.03 g, 7.45 mmol), iodopropane (0.83 mg, 4.86 mmol), acetonitrile (20 mL). Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1 to 0:1). Yield: 520 mg. The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether: M.p. 157.9° C.; MS m/z (relative intensity, 70 eV) 257 (M+, 8), 228 (bp), 198 (30), 157 (15), 84 (88).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:32])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:23])=[N:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([N:21]([CH3:32])[C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:23])=[N:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCCCCCCNC(=O)N(C)c1ncc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1ncc(-c2ccc(C[C@H](OCC)C(=O)O)cc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
0.07 g (0.15 mmol) of methyl 2(S)-ethoxy-3-{4-[2-(3-heptyl-1-methylureido)thiazol-5-yl]phenyl}propanoate is placed in 3 ml of tetrahydrofuran and 0.2 ml (0.2 mmol) of aqueous 1M lithium hydroxide solution. The reaction medium is stirred at room temperature for 18 hours. 0.07 ml of aqueous 1M lithium hydroxide solution is added and the medium is heated for a further 5 hours. The reaction medium is diluted with water, acidified to pH 4-5 and then extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. 55 mg (82%) of 2(S)-ethoxy-3-{4-[2-(3-heptyl-1-methylureido)thiazol-5-yl]phenyl}propanoic acid are obtained in the form of a white solid with a melting point of 97° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CS(C)=[O:22]>>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]([OH:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCN=C1C(c1ccccc1)c1ccccn1
Reactant: CS(C)=O
Product: CN1CCN=C1C(O)(c1ccccc1)c1ccccn1

Procedure:
Add 5 g. of 1-methyl-2-(2-pyridylbenzyl)imidazoline and 25 ml. of dimethyl sulfoxide to a solution of potassium t-butylate (prepared from 1.4 g. of potassium and 200 ml. of t-butanol) and stir the resulting solution in a stream of dry air for 30 hrs. Add 2.1 ml. of acetic acid to the resulting mixture and remove the alcohol in vacuo. Shake the residue with 200 ml. of benzene and 50 ml. of cooled 5 sodium carbonate. Separate the benzene phase, water-wash, dry, filter and evaporate in vacuo. Recrystallize the residue from isopropanol acetate to yield 1-methyl-2[α(-2-pyridyl) hydroxybenzyl]imidazoline, m.p. 105°-108° C.
Reaction SMILES: [CH3:1][CH:2]([NH2:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:22]([O:24]C=O)C>>[CH3:1][CH:2]([NH:21][CH:22]=[O:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:19])([F:20])[C:10]([F:17])([F:18])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(N)c1ccccc1C(F)(F)C(F)(F)c1ccccc1
Reactant: CCOC=O
Product: CC(NC=O)c1ccccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
α-Methyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine, 1.06 g. (0.00357 mole), in 50 ml. of ethylformate is stirred and heated to refluxing for about 21 hours. Evaporation of the solution to dryness and trituration of the residue with hexane gives N-[α-methyl-2-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide, m.p. 94.5°-99° C. Recrystallizations from ether-petroleum ether and isopropyl alcohol-water afford a purified sample, m.p. 103°-105° C.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1.N1CCCCC1>C(O)C>[O:16]=[C:12]1[C:11](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:22]=2[CH2:21][CH2:20][NH:19][C:18]3=[O:17])[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 6-phenyl-1,3-dihydro-indol-2-one (41.8 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([CH:22]=1)[C:20]#[N:21].O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: OCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OCCCCc1ccccc1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
4-Phenylbutanol (0.834 g) was dissolved in N,N-dimethylformamide (10 ml), and sodium hydride (60%, 0.638 g) was added. After stirring for 30 min, 5-bromo-2-fluorobenzonitrile (0.640 g) was added, and the mixture was further stirred at 40-50° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (1.04 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:26][C:13]2=[CH:14][C:15]3[C:16](=[O:25])[N:17]([CH:22]([CH3:24])[CH3:23])[C:18](=[O:21])[C:19]=3[CH:20]=[C:12]2[N:11]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:10]1[NH:11][C:12]2=[CH:20][C:19]3[C:18](=[O:21])[N:17]([CH:22]([CH3:23])[CH3:24])[C:16](=[O:25])[C:15]=3[CH:14]=[C:13]2[N:26]=1
Reactant: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)C)C3=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O

Procedure:
To a solution of (2-(4-chloro-2-methoxypyridin-3-yl)-6-isopropylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (220 mg) in 50 mL of dioxane was added 1 mL of conc. (12 N) HCl. The mixture was heated to reflux and maintained for 3 h. The solvent was removed by rotary evaporation and the solid residue was triturated with n-butanol three times to give a white solid which was used directly in the next step.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:32])[CH2:28]/[CH:29]=[CH:30]/[CH3:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:32])[CH2:28]/[CH:29]=[CH:30]/[CH3:31])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: C/C=C/CC(=O)O
Agent: Cl
Product: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (77 mg, 75%), MS (ISP) m/z=411.4 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (E)-pent-3-enoic acid.
Reaction SMILES: [Li+].[OH-].[C:3]1([C:12]([O:14]CC)=[O:13])[C:8]2[CH2:9][CH2:10][CH2:11][C:7]=2[CH:6]=[CH:5][N:4]=1>O.CO>[C:3]1([C:12]([OH:14])=[O:13])[C:8]2[CH2:9][CH2:10][CH2:11][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1nccc2c1CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nccc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A 2N solution of LiOH (50 mL) in water was slowly added to the title compound of step 1 (10 g, 52.4 mmol) in MeOH (250 mL) at 0° C. The mixture was allowed to warm to rt and stirred for 30 min. The MeOH was reduced under vacuum and the residual aqueous solution was washed with EtOAc. The organic phase was re-extracted with water. The combined aqueous extracts were acidified to pH=2 with 1N HCl. The water was removed and preparative HPLC gave the title compound (5.4 g, 63%) as a white solid. 1H NMR (CD3OD, 400 MHz): δ 8.45 (d, J=5.6 Hz, 1H), 7.88 (d, J=5.6 Hz, 1H), 3.39 (t, J=8.0, 7.6 Hz, 2H), 3.16 (d, t, J=8.0, 7.6 Hz, 2H), 2.16-2.20 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[C:13]([NH2:26])=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Cl.[C:28](N)(=N)[CH3:29].C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]4[N:16]([C@H:17]([C:19]5[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=5)[CH3:18])[C:28]([CH3:29])=[N:26][C:13]4=[CH:12][CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=N)N
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)ccc1N)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc2ccc(Nc3cc(C4CC4)[nH]n3)nc2n1[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture of crude (S)—N6-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,3,6-triamine (Method 9; 0.120 g, 0.34 mmol) and acetamidine hydrochloride (0.052 g, 0.55 mmol) in EtOH (5 ml) was heated at reflux overnight. After cooling to 25° C., saturated NaHCO3 solution (10 ml) and EtOAc (30 ml) were added to the reaction mixture. The organic layer was separated, washed with brine (10 ml), dried over Na2SO4, concentrated, and purified by chromatography (EtOAc:MeOH=100:1) to give the title compound as an off-white solid (0.055 g, 43%). NMR (400 MHz, d6-Acetone) 11.14 (br s, 1H), 8.44 (br s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.44 (m, 2H), 7.11 (m, 2H), 7.00 (br s, 1H), 6.00 (m, 2H), 2.12 (s, 3H), 2.11 (d, J=7.2 Hz, 3H), 0.89 (m, 2H), 0.65 (m, 2H). MS: Calcd.: 376. Found: [M+H]+ 377.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@H:12]([CH3:17])[C:13]([O:15]C)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@@H:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][C@@H:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[C@H:12]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:17]
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Reactant: COC(=O)[C@@H](C)Oc1cccc2cccnc12
Solvent: CCO
Product: C[C@@H](Oc1cccc2cccnc12)C(=O)NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a stirred mixture of (R)-methyl 2-(quinolin-8-yloxy)propanoate (100 mg, 0.433 mmol) in EtOH (1 mL) was added (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl) propan-2-ol (89.2 mg, 0.433 mmol). The mixture was stirred in a sealed tube in a microwave apparatus at 120° C. for 0.5 hour. After cooling to room temperature the solvent was evaporated, and the residue was first purified by prep-TLC and then prep-HPLC to afford the title compound (90 mg, yield: 51%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.89 (br. S., 1H), 8.29-8.42 (m, 1H), 7.49-7.65 (m, 3H), 7.28 (d, J=5.52 Hz, 1H), 6.89-7.13 (m, 4H), 5.01-5.13 (m, 1H), 4.10-3.84 (m, 1H), 3.45-3.60 (m, 2H), 3.35-3.43 (m, 2H), 2.81 (d, J=3.01 Hz, 2H), 2.65 (br. S., 2H), 2.34-2.49 (m, 2H) 1.71 (d, J=6.78 Hz, 3H), LCMS (m/z): 406.2 [M+H]+
Reaction SMILES: [H-].[K+].[CH3:3][C:4]1[C:5]([CH2:16][Si](C)(C)C)(O)[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]2[C:12]=1[O:11][CH2:10][O:9]2.O>O1CCCC1>[CH3:3][C:4]1[C:5](=[CH2:16])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]2[C:12]=1[O:11][CH2:10][O:9]2
Reactant: CC1=C2OCOC2CC(C)(C)C1(O)C[Si](C)(C)C
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C(C)=C2OCOC2CC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
23 ml (about 1 eq.) of potassium hydride (20% in oil) were placed in a 750 four-necked sulphonation flask provided with a magnetic stirrer, dropping funnel and argon gasification, washed three times with hexane and 120 ml of tetrahydrofuran were added. A solution of 30.4 g (0.11 mol) of 4,6,6-trimethyl-5,6,7,7a-tetrahydro-5-trimethylsilylmethyl-1,3-benzodioxol-5-ol in 200 ml of tetrahydrofuran was added dropwise thereto at 0° C. Subsequently, the suspension was stirred at 20-30° C. for 2 hours. It was again cooled to 0° C. and 200 ml of water were cautiously added dropwise. Subsequent three-fold extraction with 100 ml of hexane each time, washing with saturated sodium chloride solution and drying over anhydrous sodium sulphate gave, after removal of the solvent under reduced pressure, 18.7 g of yellow oil which was subjected to short path distillation under reduced pressure. At 77-85° C./0.75 mbar (7.5 kPa) there were obtained 15.6 g (74% yield) of 4,6,6-trimethyl-5,6,7,7a-tetrahydro-5-methylidene-1,3-benzodioxol as a colorless oil. The content of desired product was 96% according to GC (area %). IR (film, cm−1): 1697, 1600; mass spectrum: 180 (M+, 50), 107 (100); 1H-NMR (C6D6, 400 MHz): inter alia 0.83 and 0.95 (2s, in each case 3H), 1.78 (bs, 3H), 3.9 (m, 1H), 4.59 (s, 1H), 4.70 (s, 1H), 4.75 (s, 1H), 4.91 (s 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[O:6][CH2:7][C:8](=[O:29])[CH2:9][N:10]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])C(=O)OCC1C=CC=CC=1)([O-:3])=[O:2].[BrH:34]>O1CCOCC1.C(O)(=O)C>[BrH:34].[N+:1]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[O:6][CH2:7][C:8]([CH2:9][NH:10][C@@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])=[O:29])([O-:3])=[O:2]
Reactant: C[C@H](c1ccccc1)N(CC(=O)COc1ccccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: Br
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: C[C@@H](NCC(=O)COc1ccccc1[N+](=O)[O-])c1ccccc1
Reaction time: 0.5 h

Procedure:
The product from Example 1D (19 g, 42.4 mmol) in 1,4-dioxane (100 mL) at 10° C. was treated with 30% HBr in acetic acid (30 mL), stirred for 30 minutes, purged with nitrogen, poured into diethyl ether (600 mL), triturated, and filtered to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ1.60 (d, 3H), 3.98 (d, 1H), 4.20 (d, 1H), 4.38 (q, 1H), 5.14 (s, 2H), 7.16 (t, 1H), 7.25 (d, 1H), 7.40-7.55 (m, 5H), 7.63 (t, 1H), 7.91 (d,1H), 9.20-9.60 (bs, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].I[CH2:21][CH2:22][CH2:23][CH3:24]>CS(C)=O>[CH2:21]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)[CH2:22][CH2:23][CH3:24]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCn1ccc2ccc(C(=O)OC)cc21
Temperature: 25 °C

Procedure:
Methyl 1H-indole-6-carboxylate (4.17 g) was dissolved in DMSO (30 mL), and potassium tert-butoxide (2.93 g) was added. The mixture was stirred for ten min at room temperature. Iodobutane (3.0 mL) was added. The mixture was allowed to stir for three additional hours. The mixture was partitioned between ethyl acetate and water and brine, dried over sodium sulfate, filtered, and concentrated to give methyl 1-butyl-1H-indole-6-carboxylate (4.53 g). MS (ESI+) for C14H17NO2+H1 m/z 232.12 (M+H)+.
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:16][CH2:15][O:14]1)(C1C=CC(C)=CC=1)(=O)=O.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C=O)C>[C:17]1(=[O:27])[N:21]([CH2:12][CH:13]2[CH2:16][CH2:15][O:14]2)[C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OCC2CCO2)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1CCO1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A solution of 2-(tosyloxymethyl)oxetane (27 g, 111.4 mmol) (prepared according to A. O. Fitton et al., Synthesis 1987, (12), 1140-2) and potassium phtalimide (20.64 g, 111.4 mmol) in DMF (200 ml) is stirred at a temperature of 120° C. for 18 hours, then evaporated in vacuo. The residue is taken up in ethyl acetate, the organic layer washed with water and brine, dried (Na2SO4), filtered, and evaporated to dryness. The crude solid product (19.8 g, 82%) is used in the next step without further purification.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH2:43])[CH:28]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1>>[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH:43][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:14]=1[NH:13][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:11])=[O:12])[CH:28]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: COC(=O)[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 94 %

Procedure:
The title compound (48 mg, 94%) was obtained from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid and (S)-2-amino-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester as in Example 1, Part C. 1H NMR (500 MHz, CDCl3): 11.28 (s, 1H), 8.37 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.68 (d, J=1.9, 1H), 7.32-7.28 (m, 4H), 7.20-7.15 (m, 4H), 6.96 (d, J=8.5, 1H), 6.87 (dd, J=8.4, 2.0, 1H), 6.21 (br d, J=8.8, 1H), 5.50 (t, J=8.5, 1H), 4.48 (d, J=8.3, 1H), 3.63 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH2:14])[CH2:4][O:3]1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[O:26]>CCCCC.ClCCl>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:14][C@H:5]1[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:26]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Solvent: ClCCl
Solvent: CCCCC
Product: CC1(C)OC[C@H](NC(=O)Nc2ccc(Cl)cc2Cl)[C@H](c2ccccc2)O1
Yield: 59 %

Procedure:
To a solution of 102 mg (0.49 mmol) of (4S,5S)-amine 1 in pentane (3 mL) was added a solution of 74 mg (0.39 mmol) of 2,4-dichlorophenyl isocyanate in dichloromethane (0.1 mL). A white precipitate was observed and collected via filtration. The crude solid was dissolved in dichloromethane (˜4 mL) and washed with 0.1 N HCl (˜4 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to yield 91 mg (59%) of the title compound.