Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([C@H:16]([CH3:35])[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])=[CH:24][CH:25]=1)=[O:18])C(=O)[O-])(C)C>ClCCl>[CH3:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:34])[C:27]=1[O:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C@@H:16]([CH3:35])[NH2:12])=[CH:25][CH:24]=1
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl[(1R)-2-({6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 43, 282 mg) was dissolved in dichloromethane (2 mL) to give a yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 min, the solvent was evaporated under vacuum affording a yellow oil that was charged on a 5 g SCX cartridge. It was then flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (173.8 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17]C)=O.[O-]CC.[Na+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:37][C:38]([NH2:40])=[NH:39])[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1>C(O)C>[OH:17][C:15]1[C:3]2[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7][C:2]=2[N:40]=[C:38]([NH:37][C:27]2[CH:28]=[CH:29][C:30]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)=[C:25]([O:24][CH3:23])[CH:26]=2)[N:39]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Nc2nc(O)c3c(n2)CCN(C(=O)OC(C)(C)C)C3)ccc1-n1cnc(C)c1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
In a microwave vial was 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (0.577 g, 2.24 mmol, Example 7c), Sodium ethoxide (0.153 g, 2.24 mmol), and 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (0.55 g, 2.24 mmol) added in ethanol (10 mL) to give a suspension. The reaction was heated in the microwave oven for 20 min at 100° C. Solvent was evaporated under reduced pressure. The crude was dissolved in minimal volume of EtOH and few drops of water added to allow the product to precipitate. The precipitated product was filtered and dried to give tert-butyl 4-hydroxy-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.400 g, 39.4%). MS (ESI+)/(ESI−) m/z 453/450
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[C:13]([C:16]23[CH2:23][CH2:22][C:19]([CH2:24][CH3:25])([CH2:20][CH2:21]2)[CH2:18][CH2:17]3)=[N:12][N:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[C:13]([C:16]23[CH2:23][CH2:22][C:19]([CH2:24][CH3:25])([CH2:20][CH2:21]2)[CH2:18][CH2:17]3)=[N:12][N:11]=1
Reactant: CCC12CCC(c3nnc(-c4ccc(OC)cc4Cl)n3C)(CC1)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC12CCC(c3nnc(-c4ccc(O)cc4Cl)n3C)(CC1)CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triazole 9-D (30 mg, 0.08 mmol) was dissolved in 0.5 mL of dry methylene chloride, placed under an inert atmosphere, and cooled to 0° C. To this solution was added BBr3 (1 M in CH2Cl2, 0.25 mL, 0.25 mmol) and the cooling bath was immediately removed. The reaction was stirred for 2 h then diluted with 20 mL of methylene chloride and washed with 1 N aqueous NaOH and brine. The residue was chromatographed by reverse-phase HPLC, eluting with a gradient of 0 to 100% acetonitrile in water. The product, 3-chloro-4-[5-(4-ethylbicyclo[2.2.2]oct-1-yl)-4-methyl-4H-1,2,4-triazol-3-yl]phenol (9-E), was isolated as a white powder. MS (ESI+)=346.2 (M+1); 1H NMR (500 MHz, CDCl3): δ 0.85 (3H, t, J=7.5 Hz), 1.25 (2H, q, J=7.5 Hz), 1.55 (6H, m), 2.13 (6H, m), 3.58 (3H,s), 6.68 (1H, dd, J=8.4 Hz, J=2.6 Hz), 6.91 (1H, d, J=2.6 Hz), 7.10 (1H, d, J=8.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([NH:17]C(=O)C)[CH:15]=[CH:16][C:10]=3[C:9]=2[C:21](=[O:37])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:10]2[C:9]([C:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:27]=3)=[O:37])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[S:12][C:11]=2[CH:13]=1
Reactant: CC(=O)Nc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(O)cc3)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(O)cc3)sc2c1

Procedure:
A solution of the product from Step 4, Example 12 (400 mg, 0.78 mmol) and 2.4 mL of 5N NaOH in 24 mL of ethanol was stirred at reflux for 48 hrs. The ethanol was evaporated off and the residue was diluted with water and acidified with 1N HCl to pH3. The aqueous solution was then made basic with saturated sodium bicarbonate solution. A solid precipitated and was filtered to yield the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C(C)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:27][CH2:26][O:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([O:17][CH3:16])=[O:29])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1

Procedure:
10 g (0.05 mol) of 4-(3-indolyl)-piperidine, 16.1 g (0.075 mol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester both prepared in Example 1 (parts A and B), 31.1 g (0.225 mol) of potassium carbonate and 1.33 g (0.008 mol) of potassium iodide were suspended in 90 ml of methyl isobutyl ketone. This mixture was refluxed for 24 h. Once the reaction was completed, the inorganic salts were filtered and the liquid phase evaporated to dryness. The remaining material was redissolved in dichloromethane and water and worked-up as usual. The crude mixture was purified by flash-chromatography over silica gel affording 9.58 g (51% of yield) of methyl 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])O1.Br[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:37])[C@H:31]([OH:36])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>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.O.CC#N.CC#N.O>[OH:36][C@H:31]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:30]([N:27]1[CH2:26][CH2:25][N:24]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])[N:23]=2)[CH2:29][CH2:28]1)=[O:37]
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: CC(C)C[C@@H](O)C(=O)N1CCN(c2cccc(Br)n2)CC1
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: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2cccc(-c3ccccc3O)n2)CC1
Temperature: 120 °C

Procedure:
2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (25 μL, 120/μmol), 1a (36 mg, 100 μmol), Pd(Ph3P)4 (12 mg, 10 μmol), K2CO3 (28 mg, 200 μmol), CH3CN (900 μL), and H2O(100 μL) were sealed in a microwave vessel and heated by microwave irradiation at 120° C. for 15 minutes. The reaction was filtered and purified by reverse phase HPLC to give 4. (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O(0.05% TFA). LCMS: m/z 370.1 (M+H)+ at 2.89 minutes (10%-99% CH3CN/H2O), (10%-99% CH3CN (0.035% TFA)/H2O(0.05% TFA).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:9][C:8](=[O:10])[CH2:7][C:5]1[N:4]=[CH:3][NH:2][CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c[nH]cn1
Temperature: 80 °C
Yield: 66 %

Procedure:
To a solution of 4-imidazoleacetic acid hydrochloride (499 mg, 3.07 mmol) in MeOH (10 mL) was added concentrated sulfuric acid (1 mL) and the mixture was heated to 80° C. overnight. Then the mixture was cooled and concentrated. The residue was dissolved in CH2Cl2 (30 mL) and washed with saturated NaHCO3 (30 mL). The aqueous layer was saturated with NaCl (s) and extracted with EtOAc (3×30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford (1H-imidazol-4-yl)-acetic acid methyl ester as a yellow oil (330 mg, 66%). 1H NMR (CDCl3) δ 3.70 (s, 2H), 3.72 (s, 3H), 6.97 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C(OC1C2N(C=CN=2)C=CC=1)C1C=CC=CC=1.ClC1N2C=CN=C2C=CC=1.ClC1C=CN2C=CN=C2C=1.CC1N2C=CN=C2C=CC=1.CC1C=CC2N(C=CN=2)C=1.CC1C2N(C=CN=2)C=CC=1.C(OC1C=CC2N(C=CN=2)C=1)C1C=CC=CC=1>>[N:10]1[CH:9]=[CH:8][N:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=12
Reactant: Clc1ccc2nccn2c1
Agent: Cc1ccc2nccn2c1
Agent: Cc1cccc2nccn12
Agent: Cc1cccn2ccnc12
Product: c1ccn2ccnc2c1

Procedure:
6-chloroimidazo[1,2-a]pyridine, 8-benzyloxyimidazo[1,2-a]pyridine, 5-chloroimidazo[1,2-a]pyridine, 7-chloroimidazo[1,2-a]pyridine, 5-methylimidazo[1,2-a]pyridine, 6-methylimidazo[1,2-a]pyridine, 8-methylimidazo[1,2-a]pyridine and 6-benzyloxyimidazo[1,2-a]pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C)cc2)cc1
Yield: 69.4 %

Procedure:
To a stirred mixture of (4-methylphenyl)boronic acid (0.818 g, 0.00602 mol) and 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.3556 g, 0.00500 mol) in toluene (10 mL) was added tetrakis(triphenylphosphine)-palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol), and the mixture was heated at reflux under nitrogen for 12 hours and allowed to cool. The mixture was diluted with toluene and dichloromethane (10 mL/10 mL), and filtered through a pad of Celite. The Celite was washed with additional toluene and dichloromethane. Filtrate and washings were combined and washed with 2.0 M aqueous sodium carbonate, brine, 3% aqueous ammonium hydroxide, water, and brine. The organics were dried (Na2SO4) and rotary evaporated. The residue was dissolved in chloroform and purified by column chromatography on silica gel (144 g, 230-400 mesh), eluting with hexanes-acetone (6:1, 17×125 mL) to give 0.98 g of 4-(4′-methyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 121-122° C.
Reaction SMILES: [C:1]([CH:5]1[NH:10][NH:9][C:8](=[S:11])[N:7]([CH3:12])[C:6]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:16]I.CBr>O>[C:1]([C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8]([S:11][CH3:16])=[N:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)C(C(C)(C)C)NNC1=S
Reactant: CI
Agent: CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nnc(C(C)(C)C)c(=O)n1C

Procedure:
30 ml of 3-benzyl-4-hydroxy-biphenyl polyglycol ether, as an emulsifier, and 5,690 g (28.6 mol) of 6-tert.-butyl-4-methyl-5-oxo-3-thioxo-tetrahydro-1,2,4-(2H,4H)-triazine were added to a solution of 1,145 g of NaOH in 57 liters of water. 4,302 g (30.3 mol) of methyl iodide were added dropwise (or 2,900 g of methyl bromide were passed in) and the mixture was subsequently stirred until the slightly exothermic reaction had ended and the pH value had reached 7-8. After filtering off the product, washing it with water and drying it at 50° C., 5,810 g (95% of theory) of the compound (IIa) of melting point 90°-100° C. were obtained. The crude product was sufficiently pure for further reaction. A sample recrystallised from methanol or petroleum ether melted at 104°-105° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:25])[NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[N:19][NH:20]3)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[NH:20]1[C:21]2[C:17](=[C:16]([CH2:15][NH:14][C:13]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH:10]([CH3:12])[CH3:11])[CH:8]=3)=[O:25])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)O
Reaction time: 15 h

Procedure:
A mixture of 5-[(1H-Indazol-4-ylmethyl)-carbamoyl]-3-isopropyl-thiophene-2-carboxylic acid methyl ester (126 mg, 0.35 mmol), lithium hydroxide monohydrate (150 mg, 3.53 mmol), THF (4 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 115.6 mg (96%). MS m/e 344.3 (M+H+).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[K+].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21](Cl)[CH3:22])=[CH:17][CH:16]=1.C1(C)C=CC=CC=1>CO.O>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:21]([S:1][CH2:2][C:3]([OH:5])=[O:4])[CH3:22])=[CH:19][CH:20]=1
Reactant: O=C(O)CS
Reactant: CC(Cl)c1ccc(-c2ccccc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(SCC(=O)O)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
6.35 gm (0.055 mol) of 80% mercaptoacetic acid were admixed in 70 ml of methanol with a solution of 6.2 gm (0.11 mol) of potassium hydroxide in 6.2 ml of water. To the solution of the dipotassium salt, 11.7 gm (0.05 mol) of 1-(2'-fluoro-4-biphenylyl)-1-chloro-ethane were added, the reaction mixture was rinsed with 20 ml of methanol and stirred for 18 hours at room temperature. Subsequently, the mixture was evaporated, the residue was digested with acetone, and the precipitated potassium salt was suction-filtered off. The free acid was obtained by dissolving the salt in water and acidifying the solution. M.p. 128°-130° C (from toluene). Yield: 55% of theory.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12]C(=O)OC(C)(C)C)=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1.[ClH:20].O1CCOCC1>C(Cl)Cl>[ClH:20].[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cnnn2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ccc(-n2cnnn2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 5-(1H-tetrazol-1-yl)pyridin-2-ylcarbamate (300 mg, 1.14 mmol) was dissolved in DCM (2 mL), followed by addition of 4 M HCl in dioxane (2.86 mL, 11.4 mmol). The mixture was stirred at RT for 4 hours, then concentrated to give title compound. LC/MS: [(M+1)]+=163.20.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH3:10].[OH-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.ClCCl>[CH3:10][C:4]1[CH:5]=[C:6]([O:9][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][OH:1]
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)ccc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(OCc2ccccc2)ccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a solution of 4-(hydroxymethyl)-3-methylphenol (4.25 g, 30.8 mmol) in ethanol (90 ml) was added 2M aqueous sodium hydroxide (17 ml, 34 mmol) and then benzyl bromide (3.65 ml, 30.8 mmol, Aldrich). The pale yellow mixture was stirred at ambient temperature under nitrogen overnight. The solvent was removed in vacuo to leave an aqueous suspension. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The phases were separated and the aqueous phase extracted with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an orange oil. The residue was loaded in dichloromethane and purified on silica (100 g×3) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and the solvent evaporated in vacuo to give {2-methyl-4-[(phenylmethyl)oxy]phenyl}methanol (2.59 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]1[O:11][C:5]2([CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:8][CH2:9]1
Reactant: OCCO
Reactant: O=C1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: OC1CCC2(CC1)OCCO2

Procedure:
A reaction mixture consisting of 10 gm. (0.085 mole) 4-hydroxycyclohexanone, 4.75 ml. ethylene glycol, 0.20 gm. p-toluenesulfonic acid, and 100 ml. benzene is heated at the reflux temperature in a reaction vessel fitted with a Dean and Stark trap for 2 hours. After the reaction mixture has cooled, it is washed first with water and then with brine. The benzene is then removed by evaporation under reduced pressure giving the intermediate 4-hydroxycyclohexanone ethylene monoketal as a viscous oil weighing 14.12 gm. The 4-hydroxycyclohexanone ethylene monoketal is dissolved in 100 ml. methylene chloride and added with stirring to a suspension consisting of 55.0 gm. chromium trioxide (predried for 24 hours under reduced pressure over phosphorous pentoxide), one liter dry methylene chloride, and 52.8 gm. 3.5-dimethylpyrazole. After continued stirring for ten (10) min. this dark reaction mixture is poured onto a two liter column of silica gel. When the reaction mixture has been completely adsorbed, the chromatogram is developed with a 1:1 mixture of ethyl acetate and technical hexane (Skellysolve B - a mixture of isomeric hexanes having a boiling range between 60° and 70° C.) The appropriate fractions as determined by TLC are collected and combined, after which the solvents are removed by evaporation under reduced pressure. The crystals thus obtained are recrystallized from technical hexane, and there is thus obtained 10.82 gm. (91% yield) of the desired cyclohexane - 1,4-dione, ethylene monoketal hving a melting point at 68° to 69° C. [The literature value is 71.5° to 72.5° C.]
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:13][OH:14])[N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=12>CN(C=O)C.C1(C)C=CC=CC=1.O=[Mn]=O>[N:1]1[CH:2]=[C:3]([CH:13]=[O:14])[N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=12
Reactant: OCc1cnc2sc3ccccc3n12
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1cnc2sc3ccccc3n12
Yield: 101 %

Procedure:
A solution of imidazo[2,1-b]benzothiazole-3-methanol (Formula J-2) (2.0 g) in DMF (30 mL) and toluene (200 mL) was treated with MnO2 (4.5 g) and the mixture was azeotropically distilled for 4.5 hours. A second change of MnO2 (2.0 g) and distillation for 1 hour completed the conversion. The suspension was filtered, the combined filtrate and ethyl acetate washes of the cake were concentrated, the residue was diluted with water, and filtered to yield imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula J-3) (2.0 g). Crude imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula J-3) was used without further purification.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH2:24])[CH3:23])[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][N:16]=[CH:17]2.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:23])[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][N:16]=[CH:17]2
Reactant: CC(N)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (74 mg, 0.37 mmol), 1-[5-chloro-8-(3-fluorophenyl)isoquinolin-7-yl]ethanamine (0.075 g, 0.25 mmol), and N,N-diisopropylethylamine (0.087 mL, 0.50 mmol) in isopropyl alcohol (2 mL) was heated at 90° C., under nitrogen, overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H17ClFN6 (M+H)+: m/z=419.1; Found: 419.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.58 (2H, m), 8.30 (2H, m), 8.06 (1H, s), 8.00 (1H, d, J=5.2 Hz), 7.92 (1H, d, J=6.0 Hz), 7.58 (2H, m), 7.37˜7.20 (2H, m), 5.19 (1H, m), 3.29 (1H, br s), 1.39 (3H, m) ppm. 19F NMR (DMSO-d6, 376 MHz) δ −113.5 ppm.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>C1COCC1.CCOC(C)=O>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.5 %

Procedure:
To a suspension of N-acetylisonipecotoyl chloride (3.70 g, 19.50 mmol) in THF (60 mL) were added phenol (2.70 g, 27 mmol) and Et3N (5.0 mL, 36 mmol). The resulting heterogeneous mixture was stirred at 25° C. for 20 h, diluted with EtOAc (50 mL) and was washed with a saturated solution of NH4Cl (50 mL). The crude compound was purified by filtration on silica gel using EtOAc/n-hexane as eluant to afford the title compound as a colorless solid (3.45 g, 80%): mp 96-98 C; 1H NMR (CDCl3) d 1.60-1.95 (m, 2H), 2.00-2.2 (m, 5H), 2.70-3.00 (m, 2H), 3.10-3.30 (m, 1H), 3.75-3.90 (m, 1H), 4.40-4.60 (m, 1H), 7.06 (d, J=7.5 Hz, 2H), 7.22 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.5 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].Cl[S:15]([C:18]1[CH:19]=[CH:20][C:21]([OH:28])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:17])=[O:16]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([N:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[S:15]([C:18]2[CH:19]=[CH:20][C:21]([OH:28])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])(=[O:17])=[O:16])=[CH:5][CH:4]=1)[CH3:2]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: CCc1ccc(NCC(C)C)cc1
Solvent: c1ccncc1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(O)c(C(=O)OC)c2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 4-ethyl-N-isobutylaniline (598 mg, 3.37 mmol) in pyridine (10 mL) stirred in air at 20° C., was added methyl 5-(chlorosulfonyl)-2-hydroxybenzoate (845 mg, 3.37 mmol) portionwise, over 1 hour. The reaction mixture was then stirred at 20° C. for 30 minutes. The solvent was evaporated in vacuo to give the crude product as a yellow sticky solid. This was triturated with methanol then filtered and dried to give the title product as a white solid, 907 mg. LCMS [LCMS1] Rt 1.38 min, m/z (ES+) 392 (M+H).