Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5]1)[CH2:2][CH3:3].[Br:17]N1C(=O)CCC1=O>ClCCl>[Br:17][C:12]1[CH:11]=[C:10]([CH:6]2[O:7][CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5]2)[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCN1CCOC(c2ccc(O)cc2)C1
Solvent: ClCCl
Product: CCCN1CCOC(c2ccc(O)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 55 h
Yield: 43.3 %

Procedure:
To the phenol from example 29 (200 mg 0.9 mmol) in dichloromethane (5 ml) was added N-bromosuccinimide (161 mg, 0.9 mmol). The reaction mixture was stirred at room temperature for 55 hours, before concentrating in vacuo. The crude product was purified by column chromatography on silica eluting with dichloromethane:methanol (95:5) to give the title compound as a white foam (117.5 mg, 0.39 mmol, 44%). 1H NMR (CDCl3, 400 MHz) δ: 0.96 (t, 3H), 1.59 (q, 2H), 2.03 (t, 1H), 2.23 (t, 1H), 2.40 (t, 2H), 2.81 (d, 1H), 2.98 (d, 1H) 3.82 (t, 1H), 4.01 (d, 1H), 4.56 (d, 1H), 6.96 (d, 1H), 7.20 (d, 1H), 7.49 (s, 1H). LRMS: m/z 302 (M-H+, Br isotope).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.O.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>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][OH:7]
Reactant: Brc1nccs1
Reactant: OCc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: OCc1ccccc1-c1nccs1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a stirred solution of 2-bromothiazole (1.0 g, 6.1 mmol) in dioxane/water (20/5 mL) was added (2-(hydroxymethyl)phenyl)boronic acid (1.4 g, 9.1 mmol), sodium carbonate (1.29 g, 12.2 mmol), and Pd(PPh3)4 under nitrogen. The mixture was heated at reflux for 18 h. After cooling to rt, water (50 mL) was added and aqueous was extracted with DCM (3×50 mL). The combined organic layer was dried and evaporated. The residue was purified by column chromatography to yield (2-(thiazol-2-yl)phenyl)methanol (0.95 g, 5.1 mmol).
Reaction SMILES: COC(=O)CC1C=C(O)C2C(=CC=C(F)C=2)C=1.[F:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:25](C)=[C:26]2[C:29]([OH:31])=[O:30])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[C:24]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:25]=[C:26]2[C:29]([OH:31])=[O:30])=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)O)c1C
Agent: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Product: COC(=O)Cc1cc(C(=O)O)c2cc(F)ccc2c1

Procedure:
Starting with (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester, using the method analogous to the one described for 7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalene-1-carboxylic acid, 7-fluoro-3-methoxycarbonylmethyl-naphthalene-1-carboxylic acid (80 mg) was obtained as a light brown viscous oil. MS cald. for C14H10FO4 262, obsd. (ESI+) [(M+H)+] 263.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2.C(N(CC)CC)C.O>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[CH:16]3)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To the solution of 2,6-dichloro-3-nitropyridine (4 g) and 5-aminoindazole (2.8 g) in acetonitrile (50 ml) was added triethylamine (3.2 ml), and then the solution was reacted at 20-25° C. for 12 hr. The reaction mixture was cooled at room temperature, added H2O 30 ml slowly, and then reacted at 20° C. for 1 hr. The reaction mixture was filtered, washed with the mixture solution(15 ml) of acetonitrile: H2O=1:1 (volume ratio) and dried at 50° C. in vacuo to obtain the desired compound (4.7 g, 78%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(N(CC)CC)C>[Cl:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([I:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(Cl)cc(I)c1O
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(Cl)cc(I)c2o1
Yield: 9 %

Procedure:
A mixture of 3-iodo-5-chlorosalicylaldehyde (100 g, 0.354 mole), acetic anhydride (300 mL) and triethylamine (54 mL) was heated at reflux for 18 hours. Upon cooling, the desired coumarin precipitated as a dark brown crystalline material. The precipitate was filtered, washed with hexane/ethyl acetate (4:1, 200 mL), and air dried. [Yield: 60 g (55% yield)]. Additional quantities of the desired product (10 g, 9% yield) can be obtained from the filtrate, upon storage.
Reaction SMILES: C([C:9]1[CH2:20][N:12]2[C:13](=[O:19])[N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[N:10]=1)(=O)C1C=CC=CC=1.[H-].[Na+].I[CH2:24][CH3:25].O>CN(C)C=O>[CH2:24]([N:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]2=[N:10][CH:9]=[CH:20][N:12]2[C:13]1=[O:19])[CH3:25]
Reactant: CCI
Reactant: COc1cc2n(c(=O)n1)CC(C(=O)c1ccccc1)=N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(OC)cc2nccn2c1=O
Reaction time: 2 h
Yield: 29.1 %

Procedure:
A stirred solution of 11 g of 2-benzoyl-7-methoxyimi-dazo[1,2-c]pyrimidin-5-one in 33 ml of dry dimethylformamide was treated with 1.27 g of 80% of sodium hydride and was stirred for another hour. 8 g of iodoethane were added dropwise over 10 minutes and stirring was continued for two hours after which the mixture was poured into iced water. The mixture was filtered to obtain 2.3 g of 6-ethyl-7-methoxyimidazo[1,2-c]pyrimidin-5-one as a yellow crystalline solid melting at 159°-60° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1(O)CCCC(O)CCC1.[C:27]1([CH3:47])[CH:32]=[CH:31][C:30]([S:33]([O:36][S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])(=[O:35])=[O:34])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>ClCCl>[C:27]1([CH3:47])[CH:32]=[CH:31][C:30]([S:33]([O:16][CH2:15][C@H:13]2[CH2:12][C@@H:11]([C:8]3[N:4]4[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]4=[CH:10][N:9]=3)[CH2:14]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1.[C:43]1([CH3:46])[CH:42]=[CH:41][C:40]([S:37]([O:36][CH2:15][C@H:13]2[CH2:14][C@H:11]([C:8]3[N:4]4[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]4=[CH:10][N:9]=3)[CH2:12]2)(=[O:38])=[O:39])=[CH:45][CH:44]=1
Reactant: OCC1CC(c2ncc3c(Cl)nccn23)C1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: OC1CCCC(O)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3ncc4c(Cl)nccn43)C2)cc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3ncc4c(Cl)nccn43)C2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
cis-3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate and trans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate were prepared as follows: To a solution of [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol (˜5:1 mixture of cis- and trans-isomers, contaminated with unknown amount of cyclooctane-1,5-diol from the previous reaction, 118.8 mg, 0.5 mmol) and p-toluenesulfonic anhydride (244.8 mg, 0.75 mmol) in dichloromethane (2.0 mL) was added i-Pr2NEt (0.26 mL, 1.5 mmol). The resulting mixture was stirred at rt for 15 h. Solvents were removed and the residue was purified by silica gel chromatography (hexanes/EtOAc: 4/1 to 1/1) to afford the respective cis- and trans-title compounds:
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=2[O:10]1.CI.[NH4+].[Cl-]>C1COCC1>[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13]([CH:18]([CH3:2])[C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=2[O:10]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc2c(c1)OCO2
Temperature: -15 °C
Yield: 63 %

Procedure:
To a solution of LDA in THF (60 mL) was added methyl 3,4-methylenedioxyphenylacetate (2 g, 10.3 mmol) at -78° C. and the solution was warmed to -15° C. for 45 min. MeI (4.39 g, 30.9 mmol) was added and the reaction was warmed to room temperature for 16 h. The reaction mixture was then poured to a separatory funnel containing NH4Cl (80 mL) and the product was extracted with EtOAc (2×150 mL) and dried over Na2SO4. The crude product obtained by removal of the solvent was purified by flash chromatography to give the product as a colorless solid (1.36 g , 63%). 1H NMR (CDCl3) 6.75 (m, 3H), 5.95 (s 2H), 3.67 (s, 3H), 3.66 (m, 1H), 1.46 (d, J=7.4, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([SH:10])[N:7]2[N:11]=[C:12]([CH2:14][OH:15])[N:13]=[C:6]2[N:5]=1)([OH:3])=[O:2].CC(O[CH2:20][C:21]1[CH2:30][S:29][C@@H:24]2[C@H:25]([NH2:28])[C:26](=[O:27])[N:23]2[C:22]=1[C:31]([OH:33])=[O:32])=O.O.N>C(#N)C>[NH2:28][CH:25]1[C:26](=[O:27])[N:23]2[C:22]([C:31]([OH:33])=[O:32])=[C:21]([CH2:20][S:10][C:8]3[N:7]4[N:11]=[C:12]([CH2:14][OH:15])[N:13]=[C:6]4[N:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=3)[CH2:30][S:29][C@H:24]12
Reactant: O=C(O)c1cc(S)n2nc(CO)nc2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Solvent: O
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3cc(C(=O)O)nc4nc(CO)nn34)CS[C@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.8 %

Procedure:
In 130 ml of acetonitrile were suspended 8 g of 5-carboxy2-hydroxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine and 9.53 g of 7-aminocephalosporanic acid and 17 ml of boron trifluoride - ethyl ether complex was added thereto, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added 300 ml of water and the mixture was adjusted to pH 2 with conc. aqueous ammonia. Precipitated crystals were collected by filtration, washed with water and with acetone, and dried to obtain 10.1 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[H-].[Na+].[C:13](=O)([O:16]C)[O:14][CH3:15].Cl>CN(C=O)C>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH2:1][C:13]([O:14][CH3:15])=[O:16])=[O:3])=[CH:5][CH:6]=1
Reactant: COC(=O)OC
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
A solution of 4-hydroxyacetophenone (500 g) in DMF (1.5 L) was slowly added to a suspension of sodium hydride (331 g) in DMF. The mixture was stirred for 15 min. till gas evolution had subsided. Dimethyl carbonate (1.55 L) was added and the reaction stirred overnight at room temperature. The reaction was worked up by pouring into ice (15 LB) followed by acidification to pH 2 with hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (3×5 L) and this was washed with water (3×1 L) and brine, then dried (Na2SO4), filtered, and concentrated. The crude product was purified by chromatography on silica gel (10 Kg) with 15 to 40% ethyl acetate-hexane. The chromatographed product was recrystallized twice from ethyl acetate-hexane to yield 313 gm first crop material as a white powder with mp 90-92° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=1)[O:10][C:9]([C:21]([OH:23])=O)=[CH:8][C:7]2=[O:24].[N:25]1([C:31]([C:33]2[CH:38]=[CH:37][C:36]([NH:39]C(C3OC4C(C(=O)C=3)=CC=CC=4N3CCN(C)CC3)=O)=[CH:35]C=2)=O)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([C:31]2[CH:35]=[C:36]([NH:39][C:21]([C:9]3[O:10][C:11]4[C:6]([C:7](=[O:24])[CH:8]=3)=[CH:5][C:4]([O:3][CH3:2])=[CH:13][C:12]=4[N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[O:23])[CH:37]=[CH:38][CH:33]=2)[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Reactant: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(C(=O)N5CCOCC5)cc4)oc23)CC1
Agent: Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3cccc(N4CCOCC4)c3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and 3-morpholin-4-yl-phenylamine (Reference Example 18) as prepared in Example 12, yielding a yellow solid. (80 mg=60%), LCMS-m/z=479.5.
Reaction SMILES: Cl.[CH2:2]1[O:16][C:15]2[C:4](=[CH:5][C:6]3[O:11][CH2:10][C@H:9]([CH2:12][NH2:13])[O:8][C:7]=3[CH:14]=2)[O:3]1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28](=[O:32])[O:29]2)=[CH:24][CH:23]=1.[I-].[Na+]>CN(C=O)C>[CH2:2]1[O:16][C:15]2[C:4](=[CH:5][C:6]3[O:11][CH2:10][C@H:9]([CH2:12][NH:13][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]5[CH:26]=[CH:27][C:28](=[O:32])[O:29][C:30]=5[CH:31]=4)[O:8][C:7]=3[CH:14]=2)[O:3]1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: NC[C@H]1COc2cc3c(cc2O1)OCO3
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNC[C@H]3COc4cc5c(cc4O3)OCO5)cc2o1
Temperature: 80 °C
Yield: 16.3 %

Procedure:
(S)-2,3-Dihydro-6,7-methylenedioxy-1,4-benzodioxin-2-methanamine hydrochloride (5.50 g, 22.4 mmole), 7-(3-chloropropoxy)coumarin (5.49 g, 23.0 mmole) diisopropylethylamine (39.0 ml, 224 mmol) and sodium iodide (3.45 g, 23.0 mmole) were combined in 200 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with chloroform. The mixture was treated with an equal volume of saturated aqueous sodium bicarbonate and the aqueous phase was then back-extracted with 3:1 chloroform-isopropanol. The combined organic extracts were washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on a silica gel column using dichloromethane as eluant. The product-containing fractions (Rf=0.59 on silica gel tlc with 1:5:95 ammonium hydroxide-methanol-chloroform) were combined and concentrated in vacuum, and the residue redissolved in methanol and acidified with 4N HCl/isopropanol to pH<3 in an ice bath to precipitate a white solid. This was recrystallized from methanol and triturated with a small amount of isopropanol to give 1.50 g of the title compound as an off-white crystalline, solid, monohydrochloride, m.p. 244°-245° C.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[N:9]1([CH2:15][C:16]([N:18](C)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O1CCOC[CH2:27]1>>[CH3:27][CH:15]([C:16](=[O:17])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:9]1[CH2:14][CH2:13][N:12]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:11][CH2:10]1
Reactant: CN(C(=O)CN1CCNCC1)c1ccccc1
Reactant: O=C1CCCC(=O)O1
Reactant: C1COCCO1
Product: CC(C(=O)Nc1ccccc1)N1CCN(C(=O)CCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1.517 g of glutaric anhydride and then 1.715 g of N-[2-(piperazin-1-yl)acetyl]-N-methylaniline are added to 15 cm3 of dioxane. After stirring for 19 hours at 25° C., the white precipitate formed is filtered on No. 4 sintered glass, rinsed with dioxane and then with diethyl ether and then dried at 20° C. (90 Pa) to give 2 g of 5-[4-(methylphenylcarbamoylmethyl)piperazin-1-yl]-5-oxopentanoic acid in the form of a white solid which is used as it is.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([OH:12])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][O:22][CH3:23].O>CC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:20][CH2:21][O:22][CH3:23])[N:3]=1
Reactant: Oc1cccc2nc(Cl)ccc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COCCOc1cccc2nc(Cl)ccc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 32.4 %

Procedure:
2-Chloro-quinolin-5-ol (CAS 124467-35-2) (0.3 g, 1.56 mmol) was dissolved in acetone (10 mL) and potassium carbonate (0.368 g, 2.75 mmol) was added. After addition of 2-bromethylmethylether (0.25 ml, 2.7 mmol) the reaction mixture was stirred for 18 h at 50° C. Then water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phases were dried, filtered and concentrated. The residue was subjected to column chromatography (silica gel, heptane/ethyl acetate 9:1/4:1) to yield 2-chloro-5-(2-methoxy-ethoxy)-quinoline as a colourless oil (0.12 g, 30%). MS: m/e=238.8 (M+H+)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C@@:14]3([C:27]4([CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28]4)[N:26]4[C@@H:21]([C:22](=[O:47])[O:23][C@@H:24]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C@H:25]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:20]3[C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=3[F:55])[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]3([C@@H:20]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=4[F:55])[C@H:21]([C:22]([NH:1][C@H:2]4[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]4)=[O:47])[N:26]([C@H:25]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@@H:24]([OH:23])[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:27]43[CH2:28][CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][CH2:32]4)[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1cccc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)N[C@H]1CC[C@H](O)CC1)[C@H](c1cccc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21

Procedure:
Trans-4-aminocyclohexanol (167 mg, 1.45 mmol) was added to a tetrahydrofuran (10 ml) solution of the compound (194 mg, 0.29 mmol) obtained in Step 1 above and the resulting mixture was heated to reflux for 6 days. After cooling, saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [chloroform:methanol=100:0→30:1 (v/v)] to give 230 mg (100%) of the title compound as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:28](Cl)(Cl)=[S:29]>C(Cl)(Cl)Cl>[N:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:20][CH:19]=1)=[C:28]=[S:29]
Reactant: Cc1cc(-c2cccnc2Oc2ccc(N)cc2)ccn1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2cccnc2Oc2ccc(N=C=S)cc2)ccn1
Reaction time: 8 h

Procedure:
To a 15 mL round bottomed flask was added 4-(3-(2-methylpyridin-4-yl)pyridin-2-yloxy)benzenamine (0.0978 g, 0.35 mmol) and sodium carbonate (0.0823 g, 0.78 mmol) in chloroform. Thiophosgene (0.030 mL, 0.39 mmol) was slowly added and allowed to stir overnight. The solution was filtered and concentrated to give 2-(4-isothiocyanatophenoxy)-3-(2-methylpyridin-4-yl)pyridine. To the flask was then added 1,2-phenylenediamine (0.0470 g, 0.410 mmol), and N,N′-dicyclohexylcarbodiimide (0.1032 g, 0.5200 mmol) in tetrahydrofuran at 75° C. to stir overnight. Upon completion, the solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (25M), eluting with a gradient of 1% to 5% methanol in DCM, to provide N-(4-(3-(2-methylpyridin-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 394.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1][C:2]1([C:30]([NH2:32])=[O:31])[CH2:5][N:4]([C:6]2[N:11]3[N:12]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:14]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)=[C:10]3[N:9]=[C:8]([CH3:29])[N:7]=2)[CH2:3]1.CO[C:35](OC)([CH3:37])[CH3:36]>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:13]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[C:10]2[N:9]=[C:8]([CH3:29])[N:7]=[C:6]([N:4]3[CH2:3][C:2]4([C:30](=[O:31])[NH:32][C:35]([CH3:37])([CH3:36])[NH:1]4)[CH2:5]3)[N:11]2[N:12]=1
Reactant: COC(C)(C)OC
Reactant: Cc1nc(N2CC(N)(C(N)=O)C2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nc(N2CC3(C2)NC(C)(C)NC3=O)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1

Procedure:
To a mixture of 3-amino-1-[7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]-azetidine-3-carboxylic acid amide (3A-6; 27 mg, 0.057 mmol) and 2,2-dimethoxypropane (0.75 ml, 6.1 mmol) in toluene (1.3 ml) was added acetic acid (5 drops). After stirring at reflux for 18 hours, the reaction was cooled and extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined extracts were dried (MgSO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 12S column using 0-5% methanol in methylene chloride as eluant to afford after drying, in vacuo, 4A-1 (16 mg, 55%) as an off-white solid: +ESI MS (M+1) 508.1; 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.56-7.42 (m, 4H), 7.34-7.30 (m, 4H), 4.92 (d, J=10.4 Hz, 1H), 4.73 (d, J=10.4 Hz, 1H), 4.43 (d, J=10.4 Hz, 1H), 4.19 (d, J=10.4 Hz, 1H), 2.40 (s, 3H), 1.23 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[NH:21][C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1.[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[N:21]([CH3:31])[C:20]4=[O:30])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 3-[3-(6-methoxy-m-tolyl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (160 g, 0.369 mol), potassium carbonate (76.6 g, 0.554 mol) and iodomethane (34.5 mL, 0.554 mol) in N,N-dimethylformamide is stirred at room temperature for 4 hours, and poured onto ice. The resultant aqueous mixture is extracted with methylene chloride. The organic extract is diluted with hexanes, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as an orange foam (163 g, 98.8%) which is identified by NMR spectral analyses.