Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]([CH3:10])([CH3:9])[C:6](Cl)=[O:7])(=O)C.[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH2:21])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH:21][C:6](=[O:7])[C:5]([OH:4])([CH3:9])[CH3:10])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
1-Chloro-2-methyl-1-oxopropan-2-yl acetate (215 mg, 1.30 mmol) in dry dichloromethane (2 mL) was added dropwise to a solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg, 1.087 mmol; Example 1, Step H) and triethylamine (550 mg, 0.757 mL, 5.43 mmol) in dry dichloromethane (10 mL) cooled on an ice-bath. The resulting solution was stirred at room temperature for 1 hour. The solvent was evaporated. The residue was then stirred in THF (10 mL), treated with an aqueous 2N LiOH solution (3 mL), and stirred at room temperature for 18 hours. The mixture was evaporated under reduced pressure, and the residue dissolved in EtOAc and washed with water (3×20 mL). The organic layer was dried over MgSO4, filtered and concentrated to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamide (289 mg, 84% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.03 (br s, 1H), 9.27 (s, 1H), 8.36 (d, 1H), 7.69 (d, 1H), 5.84 (s, 1H), 1.37 (s, 6H); LCMS (APCI+) m/z 317.9 (M+H)+, Retention time=2.51 minutes.
Reaction SMILES: [OH-].[Li+].[C:3]([C:7]1[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[N:9]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)[N:8]=1)([CH3:6])([CH3:5])[CH3:4]>O1CCOCC1.O.CCO>[C:3]([C:7]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[CH:20]3)[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2ncccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(C(=O)O)n(-c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
Lithium hydroxide (62 mg, 2.6 mmol) was added to a solution of ethyl 3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-5-carboxylate (0.21 g, 0.65 mmol) in dioxane-H2O-EtOH (1:1:1, 6 mL). The reaction mixture was stirred overnight at RT. The solution was concentrated and the residue was dissolved in H2O (2 mL). 3M HCl was added and the precipitate was collected by filtration and washed with water. The solid was dried under vacuum to obtain 3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazole-5-carboxylic acid (0.18 g, 94% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (dd, J=2.0, 4.0 Hz, 1H), 8.47 (dd, J=1.2, 8.4 Hz, 1H), 8.09 (m, 1H), 8.06 (s, 1H), 7.82 (dd, J=2.8, 9.2 Hz, 1H), 7.61 (dd, J=4.8, 8.8 Hz, 1H), 7.01 (s, 1H), 1.33 (s, 9H); MS (ESI) m/z: 296.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([O:13][CH3:12])[CH:15]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COc1cccc(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N=Cc2cccc(OC)c2)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture solution of 4-amino-benzoic acid methyl ester (10.0 g, 66.2 mmol), 3-methoxy-benzaldehyde (10.1 g, 72.7 mmol) and p-toluenesulfonic acid (225 mg, 1.32 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(3-methoxy-benzylidene)-amino]-benzoic acid methyl ester (17.8 g, quant.) as a pale-white solid: MS calcd. for C16H15NO3 (M+H)+: 270.3, obsd. (ESI+) [(M+H)+] 270.1.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=1
Reactant: CCOC(=O)COc1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)COc1ccc(O)cc1
Yield: 75.1 %

Procedure:
A solution of ethyl (4-methoxyphenoxy)acetate (2.0 g, 9.5 mmol), ethanethiol (2.8 mL, 38 mmol) and aluminum chloride (5.1 g, 38 mmol) in dichloromethane (20 mL) was stirred under ice-cooling for 40 min. The reaction mixture was poured into a mixture of chloroform and saturated aqueous sodium hydrogencarbonate, and filtered through celite. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (1.4 g, yield 75%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CS(C)=O.C1(C)C=CC=CC=1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23](=[O:31])[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)Cc3ccccn3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)CC(C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A mixture of sodium hydride (0.21 g, 8.8 mmoL) in 10 mL of DMSO was stirred under N2 as 4-[4-(2-pyridine-2-yl-acetyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (3.50 g, 8.83 mmol) in 15 mL of DMSO was added dropwise. After 30 min, a solution of ethyl bromoacetate (1.47 g, 8.83 mmol) in 8.0 mL of toluene was added dropwise. The reaction was stirred at rt for 2 h and then quenched with saturated NH4Cl solution, and the solvent was evaporated. The residue was extracted with CH2Cl2 (3×20 mL), combined, washed with saturated NaHCO3, saturated NaCl solution and dried over Na2SO4. The crude product was purified by Combiflash chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to give the product (4.0 g, 94%): Mp 118-120° C.; MS m/z 483 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:40]=[C:41]=[O:42])(=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[C:31]([NH:40][C:41](=[O:42])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCCCCC(=O)N=C=O
Agent: NC(=O)[O-]
Product: CCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 56 %

Procedure:
The compound 89 (101-1048 (816 mg, 2.00 mmol) was converted to the carbamate with octanoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 91 (650 mg, 56%) as crystals. Mp. 139-141° C. Rf 0.34 (EtOAc).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:36][CH:35]=1
Reactant: Cn1ccnc1-c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2nccn2C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(1-methyl-imidazol-2-yl)-aniline Rf value: 0.6 (silica gel, methylene chloride/methanol=5:1) C27H22N4O3
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9](Cl)=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)(=O)C(Cl)=O.C1(C)C=CC=CC=1.Cl.[CH3:33][NH:34][OH:35]>O1CCCC1.O.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([N:34]([CH3:33])[OH:35])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNO
Reactant: CC(C(=O)Cl)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C(=O)N(C)O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
2-(2-Fluorobiphenyl-4-yl)propionic acid chloride (prepared in the normal manner from 1.75 g of acid, ca 1 ml of oxalyl chloride, toluene, and 3 drops of N,N-(dimethylformamide) was dissolved in tetrahydrofuran (30 ml) and added over 5-10 minutes to a solution of N-Methylhydroxylamine hydrochloride (ca 2 g) in water (5 ml) containing triethylamine (5 ml) at 0°. Solvent was evaporated, and neutral material was isolated with ethyl acetate. Recrystallization from ether-light petroleum (b.pt. 40°-60°) afforded 2-(2-fluorobiphenyl-4-yl)-N-methylpropanohydroxamic acid (1.25 g), m.pt. 125°-126° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.C([O-])(=O)C.[K+].Br[C:22]1[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:13]([C:4]1[CH:3]=[C:2]([C:22]2[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11])([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: CC(C)COc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(OCC(C)C)c([N+](=O)[O-])c2)s1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
Under an argon atmosphere, 820 mg of 4-bromo-1-isobutoxy-2-nitrobenzene and 830 mg of bispinacolatodiboron were dissolved in toluene and the resulting solution was heated and refluxed for 15 hours in the presence of 60 mg of dichlorodi(triphenylphosphine)palladium, 50 mg of triphenylphosphine, and 350 mg of potassium acetate. After cooling to room temperature, 660 mg of methyl 5-bromothiophene-2-carboxylate, 150 mg of tetrakis(triphenylphosphine)palladium, and 7.5 ml of a 2M aqueous sodium carbonate solution were added to the solution, followed by heating at 100° C. for 6 hours. After cooling to room temperature, the solution was extracted with ethyl acetate and the resulting organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10) to obtain 790 mg of methyl 5-(3-nitro-4-isobutoxyphenyl)thiophene-2-carboxylate. (2) Then, 570 mg of the compound was dissolved in a mixed solution of 10 ml of ethanol and 10 ml of THF, and 3 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 60° C. for 18 hours. After cooling to room temperature, the resulting solution was diluted with water and ethyl acetate and an aqueous layer was separated. The aqueous layer was neutralized with 1M hydrochloric acid and then extracted with ethyl acetate. The resulting organic layer was dried and concentrated under reduced pressure to obtain 350 mg of 5-(3-nitro-4-isobutoxyphenyl)thiophene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12]>C(O)C>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH3:12]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CCO
Product: Cc1c(Cl)ccc(N)c1Cl
Yield: 99.4 %

Procedure:
To a solution of SnCl2H2O (140 g, 0.62 mol) in ethanol (350 mL) was added a solution of 2,6-dichloro-3-nitrotoluene (25 g, 0.12 mol) in ethanol (50 mL). The reaction mixture was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (100 mL), pH was adjusted to approximately pH 12 with 1N NaOH solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate, and concentrated to afford 2,6-dichloro-3-aminotoluene (21 g, 98%); NMR (CDCl3) 2.42 (s, 3), 6.62 (d, 1), 7.14 (d, 1) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>N1C=CC=CC=1>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:19]([NH:18][CH2:16][CH3:17])=[O:20])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=O
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Solvent: c1ccncc1
Product: CCNC(=O)N1CC(Oc2ccccc2C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
To a stirred solution of 3-(2-tert-Butylphenoxy)azetidine (0.21 g, 1.02 mmol) in pyridine (10 ml) was added ethyl isocyanate (0.078 g, 1.10 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water and saturated sodium chloride, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was triturated with heptane/ethyl acetate to provide 3-(2-tert-Butylphenoxy)-N-ethylazetidine-1-carboxamide (0.15 g, 53%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#[CH:38].C(NC(C)C)(C)C>C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:38]#[C:37][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reactant: C#Cc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3c(Cl)cc(C#Cc4ccccn4)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A solution of 4-[3-({4-[(5-chloro-7-iodo-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]-1-methylpiperazin-2-one (0.17 g, 0.27 mmol), 2-ethynyl pyridine (0.056 g, 0.54 mmol) and diisopropylamine (0.075 ml, 0.54 mmol) in ethyl acetate (5 ml) was cooled to −20 C under a nitrogen atmosphere. To this was added copper (I) iodide (0.016 g, 0.081 mmol) and bis(triphenylphospine)palladium (II) chloride (0.038 g, 0.054 mmol). The reaction mixture was allowed to warm to ambient temperature and then stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 0-8% methanol in dichloromethane to give the product as a light brown solid (0.056 g, 35%). NMR Spectrum: (DMSOd6) 2.02 (m, 2H), 2.50 (t, 2H under DMSO), 2.72 (t, 2H), 2.84 (s, 3H), 3.01 (s, 2H), 3.28 (t, 2H under H2O), 3.94 (s, 3H), 4.20 (t, 2H), 6.23 (s, 2H), 7.21 (s, 1H), 7.32 (s, 1H), 7.45 (dd, 1H), 7.68 (d, 1H), 7.86 (m, 2H), 8.35 (s, 1H), 8.64 (d, 1H), 9.54 (s, 1H). Mass Spectrum: M+H+ 601 and M+H− 599.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16][C@H:17]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:18](O)=[O:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[NH2:68][CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74]1[CH:83]=[CH:82][CH:81]=[C:80]([OH:84])[C:75]=1[C:76]([O:78][CH3:79])=[O:77]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:16][C@H:17]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:18]([NH:68][CH2:69][CH2:70][CH2:71][CH2:72][O:73][C:74]2[CH:83]=[CH:82][CH:81]=[C:80]([OH:84])[C:75]=2[C:76]([O:78][CH3:79])=[O:77])=[O:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
(2S)-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-2-[(phenylsulfonyl)-amino]-propanoic acid (10.3 mg, 0.020 mmol) in DMF (1 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10.6 mg, 0.024 mmol). After stirring 5 minutes at rt a solution of N,N-diisopropylethylamine (17.4 L, 0.10 mmol) and methyl 2-(4-aminobutoxy)-6-hydroxybenzoate hydrochloride (8.27 mg, 0.030 mmol) in DMF (1 mL) was added. The solution stirred at rt for 2 h. Purification by preparative LCMS afforded product as a white solid (9.2 mg, 62%). 1H NMR (400 MHz, CD3OD): δ 7.96 (brs, 1H), 7.69–7.65 (m, 2H), 7.52–7.14 (m, 7H), 6.51–6.46 (m, 2H), 5.62–5.59 (m, 1H), 4.00–3.94 (m, 13H), 3.87 (s, 3H), 3.44–3.38 (m, 1H), 3.36–3.30 (m. 1H), 3.06–3.00 (m, 1H), 2.98–2.91 (m, 2H), 2.81–2.72 (m, 1H), 1.64–1.60 (m, 2H), 1.51–1.47 (m, 2H); LCMS found for C30H33BrN3O10S2 (M+H)+: m/z=738.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1>ClC1C=CC=CC=1Cl.[Mn]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C2=NCCc3ccccc32)c1
Agent: [Mn]
Solvent: Clc1ccccc1Cl
Product: Fc1cccc(-c2nccc3ccccc23)c1
Temperature: 165 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
266.41 g (1.183 mol) of 1-(3-fluorophenyl)-3,4-dihydroisoquinoline were dissolved in 1500 ml of o-dichlorobenzene and admixed with 901.2 g (10.37 mol, 8.7 eq.) of manganese. The mixture was stirred at 160-170° C. for 16 h. Subsequently, the reaction solution was filtered through Celite which was rinsed with dichloromethane/ethanol (25:1). Subsequently, the solvent was distilled off under reduced pressure. 264.74 g of a crystalline solid with 99% purity were obtained, corresponding to 99% of theory.
Reaction SMILES: [CH:1]([O:4][C:5]([NH:7][C@H:8]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](O)=[O:17])=[O:10])=[O:6])([CH3:3])[CH3:2].[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([NH2:37])=[N:32][CH:31]=[CH:30]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CC(O)=O>[CH:1]([O:4][C:5](=[O:6])[NH:7][C@H:8]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:17])[NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([NH2:37])=[N:32][CH:31]=[CH:30]2)=[O:10])([CH3:3])[CH3:2]
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: CC(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.1 %

Procedure:
A mixture of 1-[(R)-isopropoxycarbonylamino-phenyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid (0.20 g), 6-aminomethyl-isoquinolin-1-ylamine (0.6 mmol), N-methyl morpholine (0.2 mL) and 0.19 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 3 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. 0.120 mL CH3COOH were added, the mixture was concentrated and the remaining residue was purified by HPLC (RP-18; H2O/CH3OH 95/5→0/100) to give 0.10 g (35%) of the title compound as a colorless oil. (+)-APCI-MS: 490 (MH+).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[BrH:19]>C1CCCCC1>[Br:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: Br
Reactant: OCCCCCCCCCCCCCCCCO
Solvent: C1CCCCC1
Product: OCCCCCCCCCCCCCCCCBr
Yield: 67 %

Procedure:
1,16-Hexadecanediol (13.75 g) was dissolved in 37 ml of cyclohexane, and 57% hydrobromic acid solution (37 ml) was added to this solution. The reaction mixture was refluxed for six hours while stirring. After the reaction, the mixture was extracted three times with diethyl ether. The organic layer was neutralized with saturated sodium hydrogen carbonate solution, washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane:ethyl acetate=7:3) gave 16-bromohexadecan-1-ol as white crystals at a 67% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:20]1([C:17]2[O:16][C:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[N:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2nnc(CC3CCCCN3)o2)cc1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A solution of (RS)-2-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-piperidine-1-carboxylic acid tert butyl ester (0.175 g) in dichloromethane (4 ml) was cooled (ice bath) and treated with trifluoroacetic acid (1 ml). The mixture was stirred for 1 h, added to saturated potassium carbonate and the product extracted into dichloromethane. The organic phase was dried (MgSO4) and solvent removed at reduced pressure to give the title compound (0.115 g)