Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cc(Cl)ccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,5-dichlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:26]3[CH2:30][CH2:29][S:28][CH2:27]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:26]3[CH2:30][CH2:29][S:28](=[O:39])[CH2:27]3)=[O:25])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1
Solvent: ClCCl
Product: O=C(c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
102 mg (0.23 mmol) of the compound of Example 59 is dissolved in 5 ml of dichloromethane, mixed with 57 mg (0.23 mmol, 70% purity) of meta-chloroperbenzoic acid, and stirred for 16 hours at room temperature. The reaction mixture is concentrated by evaporation in a rotary evaporator, mixed with some acetonitrile, filtered over a Millipore spray filter, and then separated by means of preparative HPLC (mobile solvent: acetonitrile/water gradient). 87 mg (82% of theory) of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([NH:26][O:27]C2CCCCO2)=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10]1.O.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>CO>[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:40][CH:41]=1.[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:40][CH:41]=1.[F:1][C:2]1[CH:3]=[C:4](/[CH:22]=[CH:23]/[C:24]([NH:26][OH:27])=[O:25])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10]1
Reactant: CCCCCC#CCN1CC[C@@H](Nc2ncc(/C=C/C(=O)NOC3CCCCO3)cc2F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCCCCC#CCN1CC[C@@H](Nc2ncc(/C=C/C(=O)NO)cc2F)C1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of (2E)-3-(5-fluoro-6-{[(3R)-1-(2-octyn-1-yl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (155 mg) in methanol (3.5 ml) was added 4-methylbenzenesulfonic acid hydrate (122 mg) at 25° C. and then stirred at the same temperature for 1 hour. The mixture was concentrated under reduced pressure. The resulting residue was triturated with a mixed solvent of ethyl acetate, diisopropyl ether and methanol. Title compound (178 mg, 73%) was obtained as colorless powder.
Reaction SMILES: [C:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C>[C:23]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(c1ccccc1)c1ccccc1O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(c1ccccc1)c1ccccc1OC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
Cumylphenyl benzoate is prepared in accordance with the following procedure: one mole of cumylphenol was dissolved in 600 ml of benzene containing 1.2 moles of triethylamine in a 2-liter stirred glass reactor equipped with external heating and cooling devices. The reaction mass was cooled to and maintained at 15°-20° C. during the addition of 1.1 moles of benzoyl chloride over a period of 1.5 hours. After completion of addition, the resulting slurry was heated to and maintained at 40°-45° C. for 1 hour, and thereafter cooled to ambient temperature and filtered. The filter cake was washed with 200 ml of toluene and the combined washings and filtrate distilled to give 214.9 g (68 mole %) of a pale yellow oil having a boiling point at 0.5 mm Hg of 261°-265° C., a specific gravity at 55° C. of 1.082, and a viscosity at 55° C. of 215 cps. On standing, the oil solidified to form a white solid having a melting point of 43°-46.5° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O[CH2:14][C:15]1([CH3:19])[CH2:18][O:17][CH2:16]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:14][C:15]1([CH2:19][O:11][C:10](=[O:12])[CH2:9][C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)[CH2:18][O:17][CH2:16]1
Reactant: CC1(CO)COC1
Reactant: CC(=O)c1ccc(CC(=O)O)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(CC(=O)OCC2(C)COC2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
(5-Acetyl-thiophen-2-yl)-acetic acid (2 g, 10.8 mmol), 3-hydroxymethyl-3-methyloxetane (1.07 mL, 10.8 mmol), and dimethylaminopyridine (221 mg, 1.08 mmol) were dissolved in 5 mL of dry THF and cooled to 0° C. Dicyclohexylcarbodiimide (2.24 g, 10.8 mmol) was added and the mixture was stirred at 0° C. for 1 hr, then warmed to room temperature and stirred overnight. The mixture was cooled to 0° C. and filtered. The white solid was washed with cold THF and the combined filtrates were concentrated. The crude product was purified via flash chromatography (hexanes/ethyl acetate gradient) to give 2.3 g of (5-Acetyl-thiophen-2-yl)-acetic acid 3-methyl-oxetan-3-ylmethyl ester (8.5 mmol, 79%). The product was dissolved in 20 mL DCM and cooled to −5° C. Boron trifluoride diethyletherate (121 μL, 1 mmol) was added dropwise, the mixture was slowly warmed to room temperature and stirred for 30 minutes. The reaction was quenched with triethylamine, concentrated and purified via flash chromatography (hexanes/ethyl acetate gradient) to give 1.44 g of 1-[5-(4-Methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-ylmethyl)-thiophen-2-yl]-ethanone (4.1 mmol, 38% over two steps).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([CH:33]1[CH2:35][O:34]1)[CH3:32]>C(O)(C)C>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:35][CH:33]([OH:34])[CH2:31][CH3:32])[CH2:21][CH2:20]2)[CH2:13][CH2:12]1
Reactant: Clc1cccc(N2CCN(CCC3CCNCC3)CC2)c1Cl
Reactant: CCC1CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCC(O)CN1CCC(CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A suspension of 0.41 g (1 mmol) of 1-(2,3-dichlorophenyl)-4-(2-piperidin-4-ylethyl)piperazine, dihydrochloride in 25 mL of isopropanol and 0.29 g (2.1 mmol) of potassium carbonate is stirred for 30 minutes then 0.08 g (1.1 mmol of 2-ethyloxirane is added. The suspension is stirred to reflux overnight. The precipitate is filtered and the solution is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water and with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified over 10 g of silica gel (dichloromethane/methanol 90/10) to give 0.2 g (50%) of 1-(4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)butan-2-ol as an oil that crystallizes upon standing.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=[C:11]2[C:10]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:30][O:18][C:17]([C:15]1[N:16]=[C:11]2[C:10]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]2=[N:13][CH:14]=1)=[O:19]
Reactant: O=C(O)c1cnc2c(n1)c(-c1ccc3ccccc3c1)nn2Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c(n1)c(-c1ccc3ccccc3c1)nn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
20 mg of 1-benzyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid was dissolved in 5 mL of N,N-dimethylformamide, added with 10 mg of potassium carbonate and 20 μl methyl iodide, and stirred at room temperature for 3 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was extracted and washed with water. The organic layer was dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10), to afford 20 mg the title compound as a colorless powder.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.P(=O)(O)(O)O.[N+]([O-])(O)=O.N([O-])=O.[Na+].[BrH:29]>O>[Br:29][C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: Br
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1sc(Br)nc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 4.5 g (0.0187 mole) of ethyl 2-amino-4-trifluoromethyl-5-thiazolecarboxylate in 50 ml. of 85% phosphoric acid at -10° C. was added 25 ml. of nitric acid. To this mixture was added dropwise at -10° C. to -5° C. a solution of 4.0 g (0.0579 mole) of sodium nitrite in 20 ml. of water in 30 minutes. This mixture was stirred for 10 minutes at -10° C. to -5° C. and poured into a solution of 2.70 g (0.0187 mole) of freshly prepared cuprous bromide in 20 ml. of hydrobromic acid. A vigorous evolution of gas occurred. The reaction mixture was stirred for 5 minutes and diluted with water. The solid suspension was filtered and air-dried to give 4.8 g of solid which was chromatographed on silica gel using ether/petroleum ether (1:4) as eluant. The first 1 liter of eluate gave 3.7 g of solid which was recrystallized from petroleum ether to give 2.9 g (51%) of the desired product as white needles, m.p. 75.5°-76.5° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[C:35]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.CCOCC.Cl>[C:35]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:24][C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)([CH3:23])[C:4]([OH:32])=[O:3])=[CH:8][CH:9]=3)[N:17]([CH3:22])[C:18]2=[O:21])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 45 %

Procedure:
To a mixture of 80 mg of 2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 0.08 mL of 4-tert-butylbenzyl bromide is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 45 mg (45%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.33 (d, 2H, J=8.4 Hz), 7.18, 7.16 (ABq, 4H, J=8.6 Hz), 6.96-6.92 (m, 2H), 6.88-6.85 (m, 2H), 6.77 (d, 2H, J=8.8 Hz), 4.38, 4.29 (ABq, 2H, J=14.8 Hz), 3.98 (t, 2H, J=6.0 Hz), 3.69 (bs, 1H), 3.73-3.66 (m, 1H), 3.44 (t, 1H, J=8.6 Hz), 3.25, 3.11 (ABq, 2H, J=13.8 Hz), 3.06 (t, 1H, J=8.6 Hz), 2.86 (s, 3H), 2.28-2.19 (m, 1H), 1.97-1.89 (m, 1H), 1.38 (s, 3H), 1.30 (s, 9H). HRMS (ES+) m/z exact mass calcd for C33H40N2O5F (m+1) 563.2921, found 563.2917.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.O[CH2:12][NH:13][C:14](=[O:18])[CH:15]([Cl:17])[Cl:16]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:12][NH:13][C:14](=[O:18])[CH:15]([Cl:17])[Cl:16]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: O=C(NCO)C(Cl)Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(Cl)c(CNC(=O)C(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.4 %

Procedure:
The title compound was prepared by modification of procedures previously reported in the literature (Felder et al (1965) Helv. Chim. Acta, 48: 259). To a solution of 4-chlorobenzoic acid (15.7 g, 100 mmol) in 150 ml of concentrated sulfuric acid was added N-hydroxymethyl dichloroacetamide (23.7 g, 150 mmol) in portions. The reaction mixture was stirred at room temperature for 2 days, poured onto 375 g of ice, stirred for 1 hour, the solid was collected by filtration, and washed with H2O. The moist solid was dissolved in 5% sodium bicarbonate solution, filtered, and acidified to pH 1 with concentrated HCl. The solid was collected by filtration, washed with H2O, and air-dryed overnight to give 4-chloro-3-dichloroacetylaminomethylbenzoic acid (26.2 g, 89%) as a white powder.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Al]([C:13]#[N:14])(CC)CC>C1(C)C=CC=CC=1>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:13]#[N:14])[CH2:2]1
Reactant: CC[Al](C#N)CC
Reactant: O=C1C=CCCC1
Solvent: Cc1ccccc1
Product: N#CC1CCCC(=O)C1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To a solution of 2-cyclohexen-1-one (6 mL, 62 mmol) in hexanes (100 mL) was added 1M Et2AlCN (160 mL) in toluene with cooling at −15° C. After stirring for 30 min, the reaction mixture was poured into an ice-cold 2M HCl solution and extracted with CH2Cl2. The extracts were washed with cold 2M NaOH and water, dried and concentrated in vacuo. Distillation of the product yielded 1.7 g (22%) of 3-oxo-cyclohexanecarbonitrile, b.p. 145-146° C. (16 mmHg).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cc(Br)ccc2OCCN1Cc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CN(Cc1ccccc1)CCO2
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
To a solution of 4-benzyl-7-bromo-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (4.20 g, 12.8 mmol) in tetrahydrofuran (400 ml) was added 1M borane-tetrahydrofuran solution (52.8 ml, 52.8 mmol) and the mixture was stirred at 80° C. for 2 hr. Under ice-cooling, methanol (240 ml) and sodium hydroxide (20.8 g, 519 mmol) were added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The residue was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (2.42 g, 59.5%) as an oil.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH2:4][N:5]([CH2:43][C:44]([O:46]C)=[O:45])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:9]=[C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:7]=1.[OH-].[Na+]>CO>[C:3]([CH2:4][N:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:9]=[C:8]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:7]=1)[CH2:43][C:44]([OH:46])=[O:45])([OH:48])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccc3ccccc3n2)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccc3ccccc3n2)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 69.7 %

Procedure:
A solution of 1.5 g (2.26 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycine methyl ester and 2.0 ml (12 mmol) of 6 N NaOH in 80 ml of methanol was stirred at reflux for 4 hours. The solvent was removed at reduced pressure, the residue was acidified and the product was removed by filtration. Recrystallization from THF-acetone gave 1.0 g (70% yield, mp 172°-174°) of N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:43][O:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][O:46]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (387 mg, 1 mmol) in DCM (15 ml) was cooled down to 0° C. EDC (383 mg, 2 mmol) and HOBT (135 mg, 1 mmol) were added, and the mixture was stirred at RT for 1 h. NH2OTHP (146 mg, 1.25 mmol) in DCM (1 ml) was added dropwise and the mixture was stirred at RT. After 4 h, the reaction mixture was washed with a saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 98:2) to give (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][C:6]1[CH:27]=[CH:26][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:24]#[N:25])=[CH:8][CH:7]=1.CC1C=CC(S(O[CH2:43][C@H:44]2[O:46][CH2:45]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[O:5][C:6]1[CH:27]=[CH:26][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:43][CH:44]4[O:46][CH2:45]4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:24]#[N:25])=[CH:8][CH:7]=1
Reactant: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1OCC1CO1

Procedure:
A solution of 4-(4-(2-methoxyphenoxy)-anilino)-3-cyano-6-methoxy-7-hydroxyquinoline (3.6 g, 8.0 mmole), prepared as described in Example 18 step 2, in DMSO (40 ml) was reacted with (2S)-(+)-glycidyl tosylate (2.3 g, 10 mmole) in the presence of potassium carbonate (2.8 g, 20 mmole) at room temperature for 18 hours. 4-(4-(2-methoxyphenoxy)-anilino)-3-cyano-6-methoxy-7-glycidyloxy quinoline was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:19]([O-])=O)=[C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH:9]=1)=[O:4]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:19])=[C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Sc2ccccc2OC)c([N+](=O)[O-])s1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Sc2ccccc2OC)c(N)s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The procedure as in Example 20: step a was followed using 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 200 mg, 0.75 mmol) and 2-methoxy-benzenethiol (109 μL, 1.25 mmol, Aldrich Chemical Company) to isolate 4-(2-methoxy-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester. 4-(2-Methoxy-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (200 mg, 0.61 mmol) was then treated with TiCl3 (20% aq. HCl solution, 5 mL, 6.1 mmol) in THF (6 mL). The reaction was stirred for 20 minutes at rt. The reaction mixture was concentrated in vacuo and then dissolved into EtOAc. The organic layer was washed several times with saturated NaHCO3. The combined organic layers were dried over sodium sulfate. Removal of the solvents in vacuo yielded 5-amino-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step e was followed using 5-amino-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester (160 mg, 0.54 mmol), t-butylnitrite (96 μL, 0.81 mmol), and copper (II) bromide (112.6 mg, 0.65 mmol) resulting in 5-bromo-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step b was followed using 5-bromo-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester (18 mg, 0.05 mmol) and m-CPBA (32 mg, 0.25 mmol) resulting in 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step f was followed using 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (45 mg, 11 mmol) and dimethyl aluminum amide (1M, 0.57 mL, 0.55 mmol) resulting in the title compound 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxamidine (4 mg, 13%). 1H-NMR (CD3OD): δ: 8.30 (s, 1H), 8.12–8.14 (d of d, J=6.1, 1.8 Hz, 1H), 7.70–7.74 (m, 1H), 7.16–7.24 (m, 2H), 3.79 (s, 3H).