Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[C:6](=[C:10]([I:14])[CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=O)C.[ClH:15]>>[ClH:15].[I:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:5]([NH2:4])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1cccc(I)c1C(=O)O
Agent: Cl
Product: Nc1cccc(I)c1C(=O)O

Procedure:
Charge a 12 L, 3-neck flask, equipped with a stirrer, condenser, heating mantle and thermometer with N-Acetyl-6-Iodo-Anthranilic acid (400 grams) and 2.5 L concentrated HCl. Adjust the temperature to 50-55° C. and maintain for 24 hours. Higher temperatures may decompose the product. Chill the reaction to less than 5° C. in an ice bath, filter the product, wash the filter “cake” with acetone, then diethylether. Air dry the product. Yield was 340 grams. (Theoretical yield=374.4 grams). Melting point (m.p.) at 176-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:8]([CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17]
Reactant: C1CNCCN1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Reaction time: 5 h
Yield: 45.6 %

Procedure:
2.45 g of 6,7-dichloro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 3.1 g of piperazine and 30 cm3 of pyridine were heated under reflux for 8 hours. The dihalogeno-acid went rapidly into solution; after 5 hours, a precipitate appeared which consisted principally of the hydrochloride of the reaction product. The solvent was evaporated off, the residue was taken up in 100 cm3 of water, and 20 cm3 of N sodium hyxroxide solution were then added to the mixture. The solution, which was slightly turbid, was brought to pH 7.5, by the addition of acetic acid. The precipitate was filtered off and suspended in 100 cm3 of water; the addition of 10 cm3 of N HCl led to almost total dissolution. A slight amount of insoluble material was removed by filtration. The solution was brought to pH 7.5 by the addition of N NaOH. The solid was filtered off and recrystallised from a mixture of DMF (1 volume) and methyl cellosolve (2 volumes). 1.32 g of 6-chloro-1-methyl-4-oxo-7-piperazinyl-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 288° C., were obtained.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH2:48][C@H:49]([C:54]([NH:56][C@H:57]([C:65]([N:67]1[CH2:78][CH2:77][CH2:76][C@H:68]1[C:69]([NH:71][CH2:72][C:73]([NH2:75])=[O:74])=[O:70])=[O:66])[CH2:58][CH2:59][CH2:60][NH:61][C:62](=[NH:64])[NH2:63])=[O:55])[CH2:50][CH:51]([CH3:53])[CH3:52].CC(O)=O.CC(O)=O.C(N1CCOCC1)C>CN(C)C=O>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([NH:48][C@H:49]([C:54]([NH:56][C@H:57]([C:65]([N:67]1[CH2:78][CH2:77][CH2:76][C@H:68]1[C:69]([NH:71][CH2:72][C:73]([NH2:75])=[O:74])=[O:70])=[O:66])[CH2:58][CH2:59][CH2:60][NH:61][C:62](=[NH:63])[NH2:64])=[O:55])[CH2:50][CH:51]([CH3:52])[CH3:53])=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Boc-D-Trp-OH (5.5 g), dicyclohexylcarbodiimide (4.05 g) and 1-hydroxybenzotriazole (3.6 g) in dimethylformamide (70 ml) was stirred at ice-bath temperature for 90 min. A solution of H-Leu-Arg-Pro-Gly-NH2 diacetate (10 g, described by H. U. Immer et al., U.S. Pat. No. 3,835,108, cited above) in dimethylformamide (60 ml) was adjusted to pH 8 with N-ethylmorpholine and added to the above solution. The resulting mixture was stirred at room temperature overnight and filtered. The filtrate was evaporated and the residue was dissolved in methanol. Diethyl ether was added and the precipitate was collected and chromatographed on silica gel using chloroform-methanol-35% aqueous acetic acid (5:3:1 v/v). The pure fractions were collected and evaporated. The residue was dissolved in methanol and diethyl ether was added. The precipitate was collected and dried to give 7.8 g of Boc-D-Trp-Leu-Arg-Pro-Gly-NH2 ; nmr (DMSO-D6)δ 0.80 (m, 6H) and 1.30 (s, 9H); uv max (methanol) 289 (ε=4433) and 281 nm (ε=5015); and amino acid analysis: Gly (1.00), Pro (0.98), Leu (0.97), Arg (0.95) and Trp (0.63); and [α]D25 -16.89° (c=1, 1% acetic acid).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into the solution of 1-methyl-4-(3-nitrophenyl)-piperazine (123 mg, 0.556 mmol) in ethanol (5 mL) was added Pd (10% on carbon, 12.0 mg). The mixture was degassed for 5 min and was then was stirred under H2 atmosphere (balloon pressure) at rt for 24 h. After that time, the reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain the title compound as light yellow oil. 1H NMR (CDCl3, 400 MHz): δ=2.35 (s, 3H), 2.56 (t, 41H, J=5.2 Hz), 3.18 (t, 41H, J=5.0 Hz), 3.60 (brs, 2H), 6.21-6.23 (m, 1H), 6.27 (t, 1H, J=2.2 Hz), 6.36-6.39 (m, 1H), 7.05 (m, 1H). MS (ES+): m/z 192.31 (100) [MH+]. HPLC: tR=0.39 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:2].[OH-].[Na+].[CH3:25]OS(OC)(=O)=O>CO.O>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1ccccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(c1ccccc1C=O)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A solution of N-(2-formylphenyl)-4-(trifluoromethyl)benzenesulfonamide (2.2 g, 6.6 mmol) in methanol (11 mL) is treated with a solution of sodium hydroxide (275 mg, 6.9 mmol) in water (2.4 mL). To this is added dimethylsulfate (0.64 mL, 6.8 mmol). The reaction is stirred at rt overnight, evaporated, and chromatographed on silica gel in 5% and 10% ethyl acetate-methylene chloride. The product fractions are further purified by crystallization from toluene-hexane to afford N-(2-formylphenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide in 68% yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.[CH3:22][NH:23][CH3:24]>C(O)C>[CH3:22][N:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1)[CH3:24]
Reactant: COC(=O)c1cccc2oc(-c3ccc(CBr)cc3)nc12
Reactant: CNC
Solvent: CCO
Product: COC(=O)c1cccc2oc(-c3ccc(CN(C)C)cc3)nc12
Temperature: 30 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
Methyl 2-(4-(bromomethyl)phenyl)benzo[d]oxazole-4-carboxylate (100 mg, 0.29 mmol) and dimethylamine (26 mg, 0.58 mmol) were added into ethanol (30 ml) and the mixture was stirred at 30° C. for 12 h. The resulting mixture was evaporated under reduced pressure. 60 mg of methyl 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-4-carboxylate solid was obtained, yield: 44.5%. LC-MS (ESI) m/z: 311 (M+1)+.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1>CS(C)=O>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1)[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Cc1ccc(Br)nc1
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(C)cn1
Reaction time: 2.5 h
Yield: 56 %

Procedure:
To a stirred suspension of Cu(0) (12.2 g, 0.19 mmol, 2.2×) in DMSO (87 mL) at RT under argon was added ethyl bromodifluoroacetate (13.4 mL, 0.10 mol, 1.2×) (see Eto, H., et al.; Chem. Pharm. Bull. 48: 982-990, 2000; and Ashwood, M. S., et al.; Tetrahedron Lett. 43: 9271-9273, 2002). After 2.5 h, 2-bromo-5-methylpyridine was added in one portion, the flask resealed, re-evacuated, and purged with argon. After 48 h, the reaction was partitioned between EtOAc (200 mL) and saturated NH4Cl (150 mL). The organic phase was rewashed with saturated NH4Cl (100 mL) until the blue color dissipated. The organic phase was dried over Na2SO4 and concentrated in vacuo to afford a yellow/green non-viscous oil. Purification via flash chromatography (30% EtOAc/hexanes) afforded the product as a clear oil (10.5 g, 0.05 mol, 56% yield). 1H NMR (300 Hz, CDCl3) δ 8.47 (s, 1H), 7.63 (m, 2H), 4.37 (q, J=7.3 Hz), 2.40 (s, 3H), 1.33 (t, J=7.3 Hz, 3H); LC/MS (m/z) [M+1]+ 216.2 (calculated for C10H12F2NO2, 216.2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[H-].[Na+].[CH2:14]([NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O.O>[CH2:14]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])=[O:36])=[CH:38][CH:39]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 3 h

Procedure:
A solution of 34.25 g. of p-toluenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise over 30 minutes to a stirred and cooled (water bath) suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide. Stirring is continued at room temperature for 3 hours until foaming subsides. In the meantime, a mixture of 36.2 g. of p-hexadecylaminobenzoic acid in 1200 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated to an oil which is co-evaporated twice with added dioxane to remove excess thionyl chloride. To the resulting oily residue of p-hexadecylaminobenzoyl chloride is added, in one portion, the previously prepared mixture of sodium p-toluenesulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes, without cooling, and is filtered through a bed of diatomaceous earth. The filtrate is poured into 2 l. of water and the resulting suspension is coagulated by the addition of 250 ml. of saturated sodium chloride solution. The gummy solid is decanted and the product is dissolved in 700 ml. of methylene chloride. The mixture is filtered through diatomaceous earth and brine is added to break the emulsion. The layers are separated and the organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated on the steam bath to approx. 300 ml. and is filtered through 300 g. of hydrous magnesium silicate using 3 l. of methylene chloride as elutant. The first approx. 600 ml. of filtrate is discarded and the remainder is evaporated to a tan, pasty solid. The solid is crystallized from 75 ml. of 2:1 toluene:hexane solution to give a colorless solid containing a less polar by-product. The mixture is crystallized from absolute ethanol in which the by-product separates out first. The mixture is filtered and the filtrate is concentrated to dryness and the residue is crystallized again from ethanol. This process is repeated until all of the by-product is removed. The product fractions were combined and crystallized twice from 2:1 toluene:hexane to give 8.3 g. of the title compound as colorless crystals, melting point 123°-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH:9][C:22](=[O:24])[CH3:23])[CH:8]=1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(C)=O)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (1.0 g) in pyridine (5 ml) was added acetic anhydride (5 ml), and the solution was stirred for 10 minutes at room temperature. An ice water was added thereto, the solution was stirred, was neutralized with a saturated aqueous solution of sodium bicarbonate, and the resulting solid was filtered and purified by silica gel column chromatography (hexane-ethyl acetate system) to provide N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (1.1 g). To a suspension of lithium aluminum hydride (400 mg) in tetrahydrofuran (20 ml) was added aluminum chloride (1.4 g) on an ice bath under a nitrogen atmosphere, the solution was stirred for 15 minutes at room temperature, then N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (1.1 g) was added thereto followed by stirring for 1 hour at room temperature. Tetrahydrofuran and aqueous ammonia were sequentially added thereto, the resulting suspension was filtered through celite pad, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (604 mg).
Reaction SMILES: [OH:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([OH:11])([CH2:10][C:4]([C:13]([OH:15])=[O:14])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:16](O)[CH2:17][CH2:18][CH3:19].S(=O)(=O)(O)O.[Cl-].[Na+].[OH-].[Na+]>>[OH:11][C:8]12[CH2:7][CH:6]3[CH2:12][C:2]([OH:1])([CH2:3][C:4]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([CH2:5]3)[CH2:10]1)[CH2:9]2.[OH:11][C:8]12[CH2:7][CH:6]3[CH2:12][C:2]([OH:1])([CH2:3][C:4]([C:13]([OH:15])=[O:14])([CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: CCCCO
Agent: O=C(O)C12CC3CC(O)(CC(O)(C3)C1)C2
Agent: O=S(=O)(O)O
Agent: [Cl-]
Product: CCCCOC(=O)C12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 0.14 mol of the obtained 3,5-dihydroxy-1-adamantanecarboxylic acid, 1.4 mol of n-butanol and 3.5 mmol of sulfuric acid was stirred at 100° C. for 8 hours. To the reaction mixture were added a saturated sodium chloride aqueous solution and a 5% sodium hydroxide aqueous solution (NaOH: 3.5 mmol), and the resultant mixture was subjected to separation. The organic layer was concentrated, and the concentrated residue was subjected to recrystallization from toluene to give n-butyl 3,5-dihydroxy-1-adamantanecarboxylate in yield of 86% at a conversion rate from 3,5-dihydroxy-1-adamantanecarboxylic acid of 99%.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>O1CCOCC1.CCOC(C)=O.O.[Cl-].[Na+].O>[CH:13]1([NH:16][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[O:11][CH3:12])[CH2:15][CH2:14]1
Reactant: COc1cccc([N+](=O)[O-])c1Br
Reactant: NC1CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc([N+](=O)[O-])c1NC1CC1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
2-bromo-1-methoxy-3-nitrobenzene (10.6 g, 45.7 mmol) and cyclopropylamine (16 mL, 230 mmol) were dissolved in 1,4-dioxane (50 mL). The stirred mixture was heated mixture in sealed flask to 115 C. After 66 h, mixture was cooled to r.t. and was diluted with EtOAc (100 mL), water (100 mL) and brine (50 mL). The phases were separated and extracted with EtOAc (100 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (0-20% EtOAc in hexanes) to afford N-cyclopropyl-2-methoxy-6-nitroaniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C10H13N2O3: 209.09; found: 209.96.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.CC1(C)[O:31][CH:30]([CH2:32][NH2:33])[CH2:29][O:28]1.Cl>CO>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH:30]([OH:31])[CH2:29][OH:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC1(C)OCC(CN)O1
Agent: Cl
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CO)c2c1
Temperature: 160 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (200.0 mg, 0.54 mmol, prepared in analogy to the one in Example 2-1) and 1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.5 mL, 3.8 mmol) was heated with stirring at 160° C. for 16 hours. After being cooled to room temperature, the resulting reaction mixture was diluted with methanol (2.0 mL). Concentrated hydrochloric acid (12.0 N, 0.5 mL) was introduced to the above mixture. The resulting mixture was stirred at room temperature for 1 hour, and then extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 69.2 mg of the product as a white solid (yield was 30%). MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.89 (d, J=7.33 Hz, 1 H), 7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50-7.35 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04-3.89 (m, 1 H), 3.69 (d, J=5.56 Hz, 2 H), 3.64-3.49 (m, 4 H), 2.41 (s, 3 H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Nc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Yield: 72.7 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800 mg, 2.44 mmol), 3-amino-4-chlorophenol (422 mg, 2.93 mmol), potassium carbonate (843 mg, 6.10 mmol) and N,N-dimethylformamide (6.0 mL) was stirred using a microwave synthesizer at 180° C. for 30 min. The solvent was evaporated under reduced pressure, ethyl acetate, tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=17/83→75/25) to give the title compound (610 mg, 73%) as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(Cl)c2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1ccc(Cl)c2cccnc12)c1ccccc1
Yield: 64.3 %

Procedure:
In the similar fashion using route 14 general procedure 27, 5-chloroquinolin-8-amine (Intermediate 27) (70 mg, 0.39 mmol), benzenesulfonyl chloride (83 mg, 0.42 mmol) and DMAP (cat.) gave the title compound (80 mg, 64%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH3:13])[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)=[O:6]>Br>[Br:1][C:4]([CH3:13])([CH3:3])[C:5]([C:7]1[CH:12]=[N:11][CH:10]=[N:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: CC(C)C(=O)c1cncnc1
Agent: Br
Product: CC(C)(Br)C(=O)c1cncnc1
Reaction time: 8 h

Procedure:
At room temperature, 11.8 ml (229.8 mmol) of bromine, dissolved in 111.5 ml of hydrobromic acid, were added to 28.7 g (191.5 mmol) of 2-methyl-1-(pyrimidin-5-yl)propan-1-one dissolved in 463 ml of hydrobromic acid. After the addition had ended, the reaction mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure. This gave 50.8 g (91%) of the desired product, which was reacted without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[C:42]([NH:46][C:47](=[O:50])[CH2:48]Cl)([CH3:45])([CH3:44])[CH3:43]>C1COCC1.C(Cl)Cl>[C:42]([NH:46][C:47](=[O:50])[CH2:48][N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:18]([CH:17]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:25]=4)[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)NC(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CC(=O)NC(C)(C)C)CC3)cc1OCC2
Reaction time: 120 h
Yield: 55.7 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (300 mg, 0.61 mmol) in THF (5 mL) was added potassium carbonate (295 mg, 2.13 mmol) and N-tert-butyl-2-chloro-acetamide (100 mg, 0.67 mmol). The mixture was stirred for 5 days before being diluted with DCM and washed with water (2×30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated in diethyl ether, affording 274 as a cream solid (169 mg, 0.34 mmol, 56%). LCMS: RT=3.12 min, [M+H]+=492. 1H NMR δ (ppm) (DMSO-d): 8.29 (1H, d, J=8.29 Hz), 7.86 (1H, d, J=0.63 Hz), 7.85 (1H, s), 7.15 (1H, s), 7.03 (1H, dd, J=8.36, 1.77 Hz), 6.89 (1H, d, J=1.71 Hz), 5.90-5.80 (1H, m), 4.48-4.41 (4H, m), 2.85 (2H, d, J=11.24 Hz), 2.81 (2H, s), 2.20-2.09 (2H, m), 1.78-1.67 (2H, m), 1.70-1.58 (2H, m), 1.44 (6H, d, J=6.60 Hz), 1.25 (9H, s). 1H obscured by solvent.