Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][CH:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22][CH2:21]2)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:30][Si:31]([CH3:48])([CH3:47])[CH2:32][CH2:33][O:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[CH:45]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22][CH2:21]2)[CH2:45][C:37]2[N:36]([CH2:35][O:34][CH2:33][CH2:32][Si:31]([CH3:30])([CH3:47])[CH3:48])[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(NCc1ccccn1)c1ccc(CNC2CCCc3cccnc32)cc1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1c(CN(Cc2ccc(S(=O)(=O)NCc3ccccn3)cc2)C2CCCc3cccnc32)nc2ccccc21
Yield: 39.2 %

Procedure:
Using general procedure B: Reaction of N-pyridin-2-ylmethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzenesulfonamide (97 mg, 0.24 mmol), 1-(2-trimethylsilanyl-ethoxymethyl)-1 H-benzimidazole-2-carbaldehyde (72 mg, 0.26 mmol), and NaBH(OAc)3 (151 mg, 0.71 mmol) for 1 h at room temperature followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) gave the title compound (63 mg, 50%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.77 (dd, 2H, J=7.5, 7.5 Hz), 1.73-1.74 (m, 1H), 1.95-2.06 (m, 2H), 2.20-2.25 (m, 1H), 2.66-2.86 (m, 2H), 3.29-3.35 (m, 2H), 3.78 (d, 1H, J=14.7 Hz), 3.98 (d, 1H, J=14.7 Hz), 4.05 (dd, 1H, J=9.3, 6.3 Hz), 4.13 (d, 2H, J=6.0 Hz), 4.18 (brs, 2H), 5.70 (d, 1H, J=12.0 Hz), 5.98 (d, 1H, J=12.0 Hz), 7.06-7.10 (m, 2H), 7.13-7.18 (m, 3H), 7.31-7.36 (m, 2H), 7.43 (d, 2H, J=8.1 Hz), 7.52-7.66 (m, 4H), 8.42 (d, 1H, J=4.8 Hz), 8.52 (d, 1H, J=4.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:44][C:45]1[S:46][C:47]([CH3:51])=[C:48]([CH3:50])[N:49]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:44][C:45]1[S:46][C:47]([CH3:51])=[C:48]([CH3:50])[N:49]=1)=[O:41]
Reactant: Cc1nc(N)sc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nc(C)c(C)s4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.3 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-4,5-dimethylthiazole hydrochloride (55 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 62 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([O:22]C)=[O:21])[NH:17]2)=[CH:13][CH:12]=1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([OH:22])=[O:21])[NH:17]2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc2ccc(OCCOCCOCCO)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2ccc(OCCOCCOCCO)cc2[nH]1

Procedure:
Methyl 6-[(2-(2-hydroxyethoxy)ethoxy)ethoxy]indole-2-carboxylate (V, EXAMPLE 3, 2.9 g) and potassium hydroxide (1.0 g) are dissolved in dioxane (25 ml) and water (5 ml). The reaction is warmed to 50° for 3 hours. The reaction is neutralized by the addition of hydrochloric acid (1N, 17 ml), extracted with THF/chloroform (50/50, 3×), washed with saline and concentrated under reduced pressure with heat. The material is purified by flash column chromatography eluting with methanol/chloroform/acetic acid (5/94/1). The appropriate fractions are pooled and concentrated to give the title compound, MS theory=309.1212, found=309.1208.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH2:11])[CH2:5]2.[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH:20]=O)([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)Cl>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][CH2:20][CH2:19][NH:18][C:17](=[O:22])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: NC1Cc2ccc(Br)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-Bromo-2,3-dihydro-1H-inden-2-amine (0.21 g, 1.0 mmol) in 16 mL of DCM/MeOH (7/1, v/v) was added tert-Butyl(2-oxoethyl)carbamate (160 mg, 1.0 mmol) and NaBH(OAc)3 (297 mg, 1.4 mmol), and the mixture was stirred at RT for 3 hours. DCM was added to the mixture, and then washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give the title product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl.Cl[CH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:10][C:11]1[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=1)[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1
Reactant: COCCO
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 70 °C

Procedure:
1.1 g (0.015 mol) of 2-methoxyethanol was dissolved in 50 ml THF. To this solution 1.5 g (0.03 mol, 50% oil dispersion) NaH, (0.015 mol) 2-(3-chloromethylphenoxymethyl)quinoline hydrochloride, was added slowly. After the addition was completed, the mixture was heated at 70° C. bath temperature for overnight. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with water, dried and concentrated to dryness under reduced pressure. The residue was passed through a silica gel column using hexane/ethylacetate (3:1) as eluent. Evaporation of eluent gave light yellow oil (1.1 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([NH2:15])[CH:14]=2)[CH:5]=1.CC1(C)[O:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[CH:23][C:22](=O)[O:21]1>>[C:29]([C:28]1[CH:27]=[C:26]([C:24](=[O:25])[CH2:23][C:22]([NH:15][C:13]2[CH:14]=[C:9]([N:6]3[CH:7]=[CH:8][C:4]([CH2:3][O:2][CH3:1])=[CH:5]3)[CH:10]=[CH:11][C:12]=2[N+:16]([O-:18])=[O:17])=[O:21])[CH:33]=[CH:32][CH:31]=1)#[N:30]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: COCc1ccn(-c2ccc([N+](=O)[O-])c(N)c2)c1
Product: COCc1ccn(-c2ccc([N+](=O)[O-])c(NC(=O)CC(=O)c3cccc(C#N)c3)c2)c1

Procedure:
The title compound was prepared from 5-(3-methoxymethyl-pyrrol-1-yl)-2-nitro-phenylamine (Example F7) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as a yellow solid (102 mg).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]=O.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.Cl>C(O)(C)C.C(O)C>[C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH2:13][CH2:19][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: C=O
Reactant: CC(=O)c1c(-c2ccccc2)oc2ccccc12
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: O=C(CCN1CCCCC1)c1c(-c2ccccc2)oc2ccccc12

Procedure:
To a solution of 47.2 grams of 2-phenyl-3-acetylbenzofuran in 120 milliliters of isopropanol were added 6 grams of paraformaldehyde, 29.1 grams of piperidine hydrochloride and 6 milliliters of a saturated solution of hydrogen chloride in ethanol and the mixture was heated under reflux for a period of 10 hours. The solvent was evaporated from the resulting mixture under vacuum and the residue was triturated with ethyl ether. The portion of the residue that was insoluble in ether was separated from the ether extract and was dissolved in water. The aqueous solution was then made alkaline by addition thereto of a 5% aqueous solution of sodium hydroxide and the base that thus precipitated was extracted with ethyl ether and the extract was dried by addition of anhydrous sodium sulfate thereto. Upon addition to the ether extract of a solution of hydrogen chloride in ethanol, the hydrochloride of the compound named in the heading of this example precipitated, and it was separated by suction filtration and dried. it weighed 22.7 grams and, after recrystallization from ethanol, had a melting point of 173°-174°C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].N[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O>>[C:14]([CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[C:7]([OH:9])=[O:8])(=[O:16])[CH:13]=[CH:12][C:11]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCC(=O)O
Reactant: NCCCCCC(=O)O
Product: NCCCCC(C(=O)O)C(=O)C=Cc1ccccc1
Yield: 77 %

Procedure:
Using 6-aminocaproic acid in lieu of γ-aminobutyric acid, the title compound was synthesized following essentially the procedure described in Example 14. Yield 77%, m.p. 91.6-92.3° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].ClC1C=CC(Cl)=CC=1Cl.[Cl-].[Cl-].[Cl-].[Al+3]>C(O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccccc1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCC(=O)c1ccc(NC(C)=O)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
Acetanilide (13.94 g), propionyl chloride (14.31 g) and 1,2,4-trichlorobenzene (100 ml) were warmed to 60° C. and aluminium trichloride (40.0 g) was added over 15 minutes. The mixture was heated at 100° C. for 90 minutes, cooled at 40° C. and ethanol (200 ml) was added dropwise keeping the temperature below 60° C. by means of an ice-water bath. After stirring for 30 minutes at 40° C. a homogeneous system was obtained. This was quenched with water (100 ml) at 25°-30° C. and stirred for 15 minutes. Dichloromethane (300 ml) and water (200 ml) were added and the organic layer was separated and washed with water (2×200 ml). The organic layer was evaporated to about half-volume (about 150 ml), and petroleum ether (60° C.-80° C.) (150 ml) was added at 50° C. A solid precipitated and was collected after 60 minutes of stirring to afford p-acetamidopropiophenone (15.12 g; 79%), m.p. 169°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=O)[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH-:22].[Na+].[NH2:24]O.O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:19](=[N:24][OH:22])[CH3:20])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: [OH-]
Reactant: COc1cc(-c2nc(C)c(C(C)=O)s2)cc(OC)c1OC
Reactant: NO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(-c2nc(C)c(C(C)=NO)s2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
Into an ethanolic solution of 3.1 g (0.01 mol) of 2-(3,4,5-trimethoxyphenyl)-4-methyl-5-acetylthiazole obtained in Example 1 dissolved in 50 ml of ethanol, 27 ml of an aqueous 2% solution of sodium hydroxide (0.013 mol) and 0.93 g (0.013 mol) of hydroxylamine hydrochlorinate were added, and the mixture was heated for 3 hours under a reflux condenser. After cooling the mixture to room temperature, the cooled mixture was introduced into 800 ml of iced water.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4][C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]1[CH:15]=[C:16]([NH2:23])[C:17](=[CH:21][CH:22]=1)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[ClH:1].[F:13][C:14]1[CH:15]=[C:16]([NH2:23])[C:17](=[CH:21][CH:22]=1)[C:5]([O:4][CH3:2])=[O:11]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)cc1N
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triphosgene (3.26 g, 11 mmol) was added to 4-fluoroanthranilic acid (1.55 g, 1.0 mmol) in dry 1,4-dioxane (50 ml), and the mixture was stirred at rt. for 1 h, and then 50° C. for ca. 30 min. Solvent was removed in vacuo, dry methanol (30 ml) added, followed by potassium carbonate (4.42 g, 35 mmol). The mixture was stirred at r.t. for 30 min, and then 2.5 h at 50° C. Inorganic material was filtered off, and the residue distributed between ethyl acetate (150 ml) and the pH 7 buffer (75 ml). Aqueous layer was extracted with ethyl acetate (2×50 ml). Combined organic layers were washed with water diluted aq. sodium bicarbonate (pH ca. 8; 2×50 ml), brine (50 ml), and dried (MgSO4). The organic solution was concentrated in vacuo (to ca. 75 ml), and 1 M hydrogen chloride in ethyl ether (ca. 25 ml) added. The precipitated crystalline product was filtered off, washed with ethyl ether, hexanes, and dried in vacuo. Yield 1.00 g (49%). 1H NMR in 5% CD3OD in CDCl3 (δ, ppm): 3.83 (s, 3 H), 6.55 (m, 1 H), 6.66 (m, 1 H), 7.88 (m, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH3:18])=[N:11][N:12]([CH3:17])[C:13]=1[C:14]([NH2:16])=[O:15])=O)[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]1[NH:16][C:14](=[O:15])[C:13]2[N:12]([CH3:17])[N:11]=[C:10]([CH3:18])[C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)Nc1c(C)nn(C)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccccc1-c1nc2c(C)nn(C)c2c(=O)[nH]1
Temperature: 140 °C

Procedure:
4-(2-Ethoxybenzamido)-1,3-dimethylpyrazole-5-carboxamide (1.6 g, 5.29 mmol) was added to polyphosphoric acid (50 g) and the mixture heated to 140° C. for 6 hours. The solution was cooled, poured into ice-water (100 ml), and then the mixture was basified with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (3×100 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum. The residue was chromatographed on silica gel eluting with a 97:3 mixture of dichloromethane and methanol. Crystallisation of the crude product from aqueous ethanol gave the title compound as a colourless solid, m.p. 201°-204° C. Found: C,63.43; H, 5,57; N,19.35. C15H16N4O2 requires C,63.36; H, 5.67; N,19.71%.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6]CCC[CH2:2]1.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].Cl[C:37]([O:39][CH2:40]C)=O>>[O:39]1[CH2:40][CH2:6][CH:1]([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:37]1
Reactant: CCOC(=O)Cl
Reactant: CCCC(=O)Cl
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)NC3CCOCC3)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid (tetrahydro-pyran-4-yl)-amide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and butyryl chloride for ethyl chloroformate. Wt.: 30 mg (19%). 1H NMR (300 MHz, CDCl3) δ 8.67 (d, 1H), 8.26 (d, 1H), 8.13 (d, 1H), 7.67 (m, 2H), 7.52 (d, 1H), 6.68 (m, 1H), 5.28 (m, 1H), 4.32 (m, 1H), 4.05 (m, 3H), 3.15 (m, 1H), 2.46 (m, 1H), 2.10 (m, 4H), 1.65 (m, 4H), 1.49 (m, 2H), 1.18 (m, 1H), 9.95 (m, 1H), 0.88 (t, 3H); LC/MS m/z 488 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][C:19]([C:23](O)=[O:24])=[CH:18][C:17]=4[CH:26]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:27][N:28]([CH2:35][C:36]1[CH:42]=[CH:41][C:39](N)=[CH:38][CH:37]=1)[CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O[N:44]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH3:27][N:28]([CH2:35][C:36]1[CH:42]=[CH:41][CH:39]=[CH:38][C:37]=1[C:19]1([C:23]([NH2:44])=[O:24])[CH2:18][C:17]2[CH:26]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:8][CH:9]=3)[CH:14]=[CH:15][C:16]=2[O:22][CH2:21][CH2:20]1)[CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2OCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1C1(C(N)=O)CCOc2ccc(-c3ccc(N4CCOCC4)cc3)cc2C1)C1CCOCC1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
To a solution of 7—(4-morpholinophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4—(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.1 g) and 1-hydroxybenzotriazole (0.06 g) in dimethylformamide (15 ml) was added 1-ethyl-3—(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.12 g) under ice-cooling. Under nitrogen atmosphere, the mixture was warmed to room temperature. To the mixture were added 4-dimethylaminopyridine (catalytic amount) and triethylamine (0.18 ml), and the mixture was stirred over night. The mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4—((N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)phenyl)-7—(4-morpholinophenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 152) (0.17 g) as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7]/[C:8](=[N:10]/[OH:11])/[NH2:9])=[CH:4][CH:3]=1.[O:14]=[C:15]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][N:16]1[CH2:33][C:34](O)=O.Cl.C(N=C=NCCCN(C)C)C.CO>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]2[N:9]=[C:34]([CH2:33][N:16]3[CH2:17][CH2:18][CH2:19][C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]3=[O:14])[O:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: N/C(COc1ccc(Cl)cc1)=N\O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CO
Product: O=C1N(Cc2nc(COc3ccc(Cl)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of the product of Example 263A (148 mg, 0.738 mmol), the product of Example 68E (228 mg, 0.738 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (283 mg, 1.48 mmol) in 1,2-dichloroethane (4 mL) was stirred at ambient temperature for 3 hours, then heated to reflux for 24 hours. The cooled reaction mixture was diluted with CH2Cl2 (100 mL) and washed with 1 N aqueous HCl (2×30 mL) and saturated aqueous NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 40% ethyl acetate/hexanes) to give a viscous oil which was left standing overnight. Methanol (1 mL) was then added causing a solid to form which was collected by vacuum filtration, washed with hexanes, and air-dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40-7.33 (m, 2H), 7.31-7.07 (m, 12H), 5.32 (s, 2H), 4.87 (s, 2H), 3.58 (t, J=6.3, 2H), 2.62-2.54 (m, 2H), 1.78-1.67 (m, 2H); MS (ESI+) m/z 474 (M+H)+.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[SH:20]>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:20][C:16]1[N:15]([CH3:14])[CH:19]=[CH:18][N:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:7]
Reactant: Cn1ccnc1S
Reactant: CCCCCCC(Br)C(=O)OCC
Product: CCCCCCC(Sc1nccn1C)C(=O)OCC

Procedure:
2-(1-methyl-lH-imidazo1-2-ylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Stardtng from ethyl 2-bromooctanoate (12.1 g, 48 mmol) and 1-methyl-2-mercapto imidazole (5 g, 43.8 mmol). Yield: 12 g (96%); clear oil; MS: 285 (M+H)+.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C@H:22]([C:24]([OH:26])=[O:25])[CH3:23]>>[C:1]([NH:21][C@H:22]([C:24]([OH:26])=[O:25])[CH3:23])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](C)C(=O)O

Procedure:
Prepared as described above in steps 2-4 using oleic acid and L-alanine. (400 MHz, MeOH-d4) δ 0.92 (t, J=5.9 Hz, 3H), 1.27-1.41 (m, 23H), 1.58-1.67 (m, 2H), 2.05 (q, J=5.9 & 12.7 Hz, 4H), 2.23 (t, J=7.8 Hz, 2H), 4.24 (q, J=6.8 & 14.2 Hz, 1H), 5.36 (t, J=4.9 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:18]I>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([I:18])[C:10]=1[OH:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(O)c1OCc1ccccc1
Reactant: II
Solvent: CC(=O)O
Product: COc1ccc(I)c(O)c1OCc1ccccc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a suspension of 2-benzyloxy-3-methoxy-phenol (3.80 g, 16.5 mmol) and cupric acetate monohydrate (3.28 g, 16.5 mmol) in acetic acid (45 mL) was added iodine (4.62 g, 18.2 mmol) and the reaction was heated to 55° C. and stirred overnight. After this time the reaction was quenched with 10% aqueous sodium thiosulphate (40 mL) and diluted with diethyl ether (150 mL). The resultant emulsion was filtered through celite and the organic layer was washed with water (4×40 mL) and brine (40 mL), dried over magnesium sulphate and the solvent removed under vacuum. The crude residue was purified by silica-gel flash chromatography (sequential elution—5% diethyl ether in hexane, 10%). Concentration of fractions containing the pure product as indicated by thin layer chromatography gave 2.85 g of the desired product. Later impure fractions were combined and re-chromatographed to yield a further 520 mg of material (combined mass=3.37 g, 57% yield). 1H-NMR (CDCl3) δ 7.40-7.33 (m, 5H), 7.34 (d, J=8.9 Hz, 1H), 6.34 (d, J=8.9 Hz, 1H), 6.06 (s, 1H), 5.06 (s, 2H), 3.86 (s, 3H).