Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[I:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[C:7]2[C:12]([C:13]=1[I:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1[nH]c2ccccc2c1I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(I)c2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a mixture of 3-iodoindol-2-carboxylic acid methyl ester (202) (0.604 g, 2 mmol) and NaH (60%, 0.192 g, 2.4 mmol) in DMF (20 mL) was added p-toluenesulfonylchloride (0.381 g, 2 mmol) at room temperature. After stirring for 1 hour, ethyl acetate (50 mL) was added to the reaction mixture. The mixture was washed with brine (3×30 mL). The organic layer was dried with MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (10% ethyl acetate/hexane V:V) to afford 203 (0.68 g, 76%). 1H NMR (CDCl3): 2.35 (s, 3H), 4.05 (s, 3H), 7.23 (d, 2H, J=8.4), 7.33 (t, 1H, J=7.2), 7.41, (m, 2H), 7.83 (d, 2H, J=8.4), 7.98 (d, 1H, J=8.4).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:2]1
Reactant: O=C1SC(Cc2ccc(OCCc3c[nH]c4ccccc34)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(OCCc3c[nH]c4ccccc34)cc2)S1
Yield: 62.9 %

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 1.77 g of 5-{4-[2-(indol-3-yl)ethoxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 11), 53 ml of methylene chloride and 0.3 ml of trifluoroacetic acid were used, to give 0.67 g of the title compound, melting at 42.6°-44.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C([O-])=O)=O)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[NH:17]1[CH2:32][C@H:30]([OH:31])[CH2:29][C@H:18]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C1COCC1.C(OCC)(=O)C>[N:17]1([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:8])[CH2:32][C@H:30]([OH:31])[CH2:29][C@H:18]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
t-Butyldicarbonate (1.1 g) and then sat. sodium bicarbonate (20 ml) were added to a suspension of trans-Hyp-OBn (1.1 g) in THF (25 ml) and the mixture stirred for 30 min. The mixture was diluted with ethyl acetate and washed with water, dried (MgSO4) and evaporated. Flash chromatography (SiO2 DCM then ether) gave Boc-Hyp-OBn 1.18 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:24][O:25][C:26](=[O:40])[C@H:27](OS(C)(=O)=O)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[CH3:24][O:25][C:26](=[O:40])[C@@H:27]([N:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[C:5]1=[O:8])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Nc1cc(Br)cnc1O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H](Cc1ccccc1)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)n1cc(Br)cc(NC(=O)c2ccc(C(F)(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a solution of N-(5-bromo-2-hydroxypyridin-3-yl)-4-trifluoromethyl-benzamide from Step D (760 mg, 2.1 mmol) in tetrahydrofuran (10 mL) was added 95% sodium hydride (80 mg, 3.15 mmol) at room temperature. After the reaction mixture was stirred at room temperature for 30 min, (R)-2-methanesulfonyloxy-3-phenylpropionic acid methyl ester from Step B (820 mg, 3.15 mmol) was added and the reaction was stirred and heated at 50° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with saturated ammonium chloride solution and brine. The organic layer was separated, dried with sodium sulfate, filtered and concentrated in vacuo. Purification by medium pressure liquid chromatography on silica gel (1:6 ethyl acetate/hexanes) gave 770 mg (70%) of the title compound as a semisolid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:35](O)(=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:35](=[O:37])[CH3:36])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (50 mg, 0.136 mmol) in DMF (0.8 ml) was added N,N-diisopropylethylamine (62 mg, 0.0833 ml, 0.477 mmol), acetic acid (9.82 mg, 9.35 μl, 0.164 mmol) and TBTU (52.4 mg, 0.164 mmol). The mixture was allowed to stir at room temperature for 4 h and poured into ice/water (0.5 ml) The crude reaction mixture was concentrated in vacuo. The reaction mixture was solved with sat NaHCO3 (1×10 mL). and extracted with dichloromethane (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 20% MeOH in dichloromethane) to yield the title compound as an white solid (31 mg, 61%), MS (ISP) m/z=373.5 [(M+H)+].
Reaction SMILES: [N:1](C(C1C(C2C=CC=CC=2C(C2C=CC(Cl)=CC=2)=O)=C(C)ON=1)C)=[N+:2]=[N-:3].CN(C=O)C.C(#N)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([C:44]2[C:45]([F:58])=[N:46][CH:47]=[CH:48][C:49]=2[C:50]2[C:51]([CH3:57])=[N:52][O:53][C:54]=2[CH2:55]O)=[O:43])=[CH:38][CH:37]=1>O>[N:1]([CH2:55][C:54]1[O:53][N:52]=[C:51]([CH3:57])[C:50]=1[C:49]1[CH:48]=[CH:47][N:46]=[C:45]([F:58])[C:44]=1[C:42]([C:39]1[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][CH:40]=1)=[O:43])=[N+:2]=[N-:3]
Reactant: Cc1noc(CO)c1-c1ccnc(F)c1C(=O)c1ccc(Cl)cc1
Reactant: Cc1onc(C(C)N=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1noc(CN=[N+]=[N-])c1-c1ccnc(F)c1C(=O)c1ccc(Cl)cc1

Procedure:
A procedure similar to the synthesis of (2-(3-(1-azidoethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone in Example 16 was followed, except that DMF was substituted by a mixture of acetonitrile and water; and that (4-Chlorophenyl)(2-fluoro-4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)pyridin-3-yl)methanone was used as starting material. LC/MS m/z 372 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20](F)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[K])(C)(C)C.[OH:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCN1CCCO
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCN4CCCC4=O)ccc23)CC1
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester 66.9 mg, 0.20 mmol), as prepared in Example 12b, and tert-BuOK (33.4 mg, 0.30 mmol) was added 1-(3-hydroxypropyl)-2-pyrrolidone (34.7 mg, 0.24 mmol) in anhydrous THF (3 mL). The mixture was stirred at 85° C. for 15 min and the solvent was evaporated under reduced pressure to give a light brown residue, which is used for the next step reaction without purification. 1H NMR (300 MHz, CDCl3) δ 9. 10 (s, 1H), 8.03 (d, J=9.13 Hz, 1H), 7.26 (m, 1H), 7.23 (dd, J=9.05 and 2.43 Hz, 1H), 4.14 (t, J=6.08 Hz, 2H), 3.58 (m, 1H), 3.50 (t, J=6.60 Hz, 4H), 3.42 (t, J=6.98 Hz, 4H), 2.37 (t, J=8.45 Hz, 2H), 1.80-2.15 (m, 8H), 1.46 (s, 9H). LC-MS (ESI) calcd for C25H35N4O4 (MH+) 455.3, found 455.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.C([Li])CCC.[B:23](OC)([O:26]C)[O:24]C.C(OC1C=CC(B(O)O)=CC=1)CCCCCCC>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:23]([OH:26])[OH:24])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COB(OC)OC
Reactant: CCCCCCCCCOc1ccc(Br)cc1
Agent: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCOc1ccc(B(O)O)cc1

Procedure:
Quantities: compound 27 (14.70 g, 0.066 mol) in anhydrous THF (140 ml), n-butyllithium (30 ml, 2.5M in hexane, 0.075 mol), trimethyl borate (13.72 g, 0.132 mol) in anhydrous THF (50 ml). The experimental procedure was as described for the preparation of compound 33.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[C:3]=1[C:13]#[N:14].[OH-:15].[K+].O>CC(O)(C)C>[NH2:14][C:13]([C:3]1[C:4]2[O:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]=2[CH:11]=[CH:12][C:2]=1[Cl:1])=[O:15]
Reactant: [OH-]
Reactant: CC1(C)Cc2ccc(Cl)c(C#N)c2O1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1(C)Cc2ccc(Cl)c(C(N)=O)c2O1
Yield: 75.7 %

Procedure:
A stirred solution of 10.0 grams (0.048 mole) of 6-chloro-7-cyano-2,3-dihydro-2,2-dimethylbenzofuran in 200 mL of 2-methyl-2-propanol is warmed to reflux, and 9.5 grams (0.17 mole) of 85% potassium hydroxide is added in one portion. Upon completion of addition, the reaction mixture is heated at reflux for about 75 minutes. The reaction mixture is then cooled and poured into 400 mL of water that is cooled in an ice bath. The resultant solid is collected by filtration and dried under vacuum, yielding 8.2 grams of 7-aminocarbonyl-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I:23]I>O>[Cl:11][C:10]1[C:2]([I:23])=[CH:3][C:4]([O:12][CH3:13])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: II
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(I)c(Cl)cc1C(=O)O
Temperature: 5 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To a stirred solution of 4-amino-5-chloro-2-methoxybenzoic acid (5 g, 24.8 mmol) in water (10 mL) at 0° C., concentrated sulfuric acid (50 mL) was added. Then a solution of NaNO2 (1.9 g, 27.3 mmol) in water (10 mL) was added dropwise while keeping the internal temperature around 0° C. KI (4.5 g, 27.3 mmol) and I2 (3.5 g, 13.64 mmol) were dissolved in water and added dropwise to the stirred reaction mixture. The reaction was stirred at 5° C. for 2 h and then extracted with ethyl acetate. The organic layer was washed with water, Na2SO3 (aq, 10%) and brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford desired product (1.55 g, 19% yield). ESI-MS m/z: 311.1[M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][C:10]=1[O:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.S(=O)(=O)(O)O.[N+:35]([O-])([OH:37])=[O:36]>C(O)(=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[C:23]([N+:35]([O-:37])=[O:36])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 23 h

Procedure:
Benzyl 4-(benzyloxy)-3-methoxybenzoate (78 g) was mixed with dichloromethane (580 ml), water (72 ml) and glacial acetic acid (288 ml). The mixture was cooled to 10° C. Concentrated sulfuric acid (108 ml) was added in a controlled manner maintaining the is temperature of the reaction mixture below 25° C. Concentrated nitric acid (17.5 ml) was then added keeping the temperature of the reaction mixture below 20° C. The reaction mixture was then stirred at 20° C. for 23 hours. The lower aqueous layer was removed and the organic layer was washed with water (290 ml). The organic layer was separated and distilled to 270 ml at atmospheric pressure. Isopropanol (750 ml) was added to the reaction mixture at 45° C. The reaction mixture was then heated to 40° C. and stirred at this temperature for 15 minutes. The resulting suspension was then cooled to 20° C., then to 5° C. and held at this temperature for one hour. The product (benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate) was isolated by filtration, washed with isopropanol (200 ml) and dried at less than 25° C. Yield: 78.4 g, 89.6%;
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=C(C(O)=O)[CH:2]=1.C[O:14][C:15]([O:18][CH3:19])([CH3:17])C.[ClH:20].[CH3:21]O>>[ClH:20].[CH3:21][O:9][C:7]([C:5]1[CH:6]=[N:1][CH:2]=[C:17]([C:15]([O:18][CH3:19])=[O:14])[CH:4]=1)=[O:8]
Reactant: CO
Reactant: O=C(O)c1cncc(C(=O)O)c1
Reactant: COC(C)(C)OC
Agent: Cl
Product: COC(=O)c1cncc(C(=O)OC)c1
Temperature: 23 °C
Yield: 86 %

Procedure:
To pyridine-3,5-dicarboxylic acid (19.9 g, 119.1 mmol) in methanol (400 mL) was added of 2,2-dimethoxypropane (160 mL, 1.3 mol) and concentrated HCl (15 mL). The reaction mixture was refluxed for 18 h under an atmosphere of Ar. The solvent was evaporated then ether (100 mL) was added to the crude material and the resulting mixture heated to reflux. The mixture was allowed to remain at reflux for 2 hours then s allowed to cool to 23° C. and the precipitate filtered. The precipitate was dried to afford 27.5 g (86% yield) of the title compound as described in J. Org. Chem. Vol. 16, No 10, 1996. LCMS (+ESI, M+H+) m/z: 196.
Reaction SMILES: [C:1](Cl)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O1CCCC1.[NH:16]=[C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[SH:19](=[O:27])([CH3:26])[NH:18]1.C(N(CC)CC)C>O>[C:1]([N:16]=[C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[SH:19](=[O:27])([CH3:26])[NH:18]1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(Cl)c1ccccc1O
Reactant: C[SH]1(=O)NC(=N)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C[SH]1(=O)NC(=NC(=O)c2ccccc2O)c2ccccc21

Procedure:
A solution of 1.6 g. salicylic acid chloride in 5 cc. tetrahydrofuran is added dropwise, while stirring, to a solution of 1.8 g. 3-imino-1-methyl-3H-1,2-benzisothiazole-1-oxide and 1.2 g. triethylamine in 50 cc. tetrahydrofuran. The reaction mixture is stirred overnight at ambient temperature, thereafter poured into water and the precipitate obtained is filtered off with suction. There is thus obtained 3-(salicyloylimino)-1-methyl-3H-1,2-benzisothiazole-1-oxide which, after recrystallisation from ethanol, melts at 168° - 169°C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[N:12]1([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(O)CO>[N:4]1[C:3]([CH2:2][N:15]2[CH2:14][CH2:13][N:12]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH2:24])=[O:23])=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: NC(=O)c1ccc(N2CCN(Cc3cn4ccccc4n3)CC2)cc1
Yield: 63.5 %

Procedure:
Following the general procedure of Example 2, Step 3, and making noncritical variations, 2-(chloromethyl)imidazo[1,2-a]pyridine (Example 2, Step 1; 0.245 g), 4-(piperazin-1-yl)benzamide (0.302 g), diisopropylethylamine (Aldrich; 0.256 mL), and ethylene glycol (2 mL) gives 0.313 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 8/92, as eluent) and crystallization from methanol/dichloromethane; mp 249-250° C.; IR (mineral oil) 1608, 1398, 1253, 1739, 3133, 756 cm-1. 1H NMR (CDCl3) δ2.74, 3.36, 3.78, 5.7, 6.78, 6.88, 7.16, 7.55, 7.58, 7.71, 8.09.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH2:19][NH:18][CH2:17][CH2:16]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[CH2:19][N:18]([CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1)[CH2:17][CH2:16]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Reactant: CCCN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCCN1CCC(N2CCc3cc(OC)c([N+](=O)[O-])cc3C2)CC1
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A mixture of 1-propyl-4-piperidinone (01.25 mL, 8.3 mmol), 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (1.0 g, 4.8 mmol), acetic acid (0.55 mL) and triethylamine (1.3 mL) in 1,2-dichloroethane (5 mL) was stirred for 30 minutes. Sodium triacetoxyborohydride (1.8 g, 2.8 mmol) was added. After stirring for 12 hours the reaction was quenched by the addition of saturated NaHCO3 (aq). The reaction was diluted with dichloromethane and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by flash column chromatography to give 6-(methyloxy)-7-nitro-2-(1-propyl-4-piperidinyl)-1,2,3,4-tetrahydroisoquinoline (1.43 g, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 7.60 (s, 1 H), 6.78 (s, 1 H), 3.91 (s, 3 H), 3.73 (s, 2 H), 3.07 (d, J=9.17 Hz, 2 H), 2.91 (t, J=5.87 Hz, 2 H), 2.83 (t, J=5.68 Hz 2 H), 2.47-2.60 (m, 1 H), 2.29-2.42 (m, 2 H), 2.04 (d, J=10.63 Hz, 2 H), 1.68-1.94 (m, 4 H), 1.49-1.66 (m, 2 H), 0.91 (t, J=7.33 Hz, 3 H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(CC)=C.[OH:29]P([O-])(O)=O.[Na+].Cl([O-])=O.[Na+]>CC(O)(C)C.C1COCC1>[C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([C:20]([OH:29])=[O:21])=[CH:22][CH:23]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C=C(C)CC
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reaction time: 1 h

Procedure:
A solution of 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde (1-5, 250 mg, 0.835 mmol, 1 equiv) in a 4:1 mixture of THF and t-BuOH (20 mL) was treated with 2-methyl butene (5 mL), an aqueous solution of sodium phosphate monobasic (0.14 M, 230 mg, 1.67 mmol, 2 equiv) and sodium chlorite (194 mg, 2.15 mmol, 2.57 equiv). After 1 hour at 23° C., additional solid sodium phosphate monobasic (230 mg, 1.67 mmol, 2 equiv) and sodium chlorite (194 mg, 2.15 mmol, 2.57 equiv) were added. The reaction mixture was stirred for an additional 4 hours, concentrated, and the residue dissolved in EtOAc (100 mL) then washed with a 25:1 mixture of aqueous 10% sodium bisulfite solution and 10% potassium hydrogen sulfate solution (2×100 mL). The organic layer was dried over sodium sulfate and concentrated to afford 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzoic acid (3-1) as a yellow solid. LRMS m/z: Calc'd for C19H14N3O2 (M+H) 316.35, found 316.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Br:12][CH2:13][C:14](=O)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>CN(C=O)C>[BrH:12].[C:17]1([C:15]([C:14]2[N:1]=[C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]3[CH:13]=2)=[O:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(CBr)C(=O)c1ccccc1
Solvent: CN(C)C=O
Product: Br
Product: O=C(c1ccccc1)c1cn2cc(C(F)(F)F)ccc2n1
Temperature: 4 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
To a solution of 0.324 g of 2-amino-5-trifluoromethylpyridine in 4 mL of DMF cooled to 4° C. is added dropwise a solution of 0.65 g of 3-bromo-1-phenylpropane-1,2-dione in 11 mL of DMF. The reaction mixture is stirred for 16 hours at 4° C. The precipitate is filtered off and washed with diethyl ether, and then dried. 0.32 g of phenyl[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methanone hydrobromide (1:1) is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]2[CH:34]=[C:35]([NH2:38])[NH:36][N:37]=2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C[Al](C)C.C(Cl)Cl.CCOCC>C1(C)C=CC=CC=1>[CH3:30][O:29][C:27]1[CH:26]=[C:25]([CH2:31][CH2:32][C:33]2[CH:34]=[C:35]([NH:38][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([N:6]4[CH2:7][CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]4)=[CH:20][CH:19]=3)[NH:36][N:37]=2)[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=1
Reactant: CCOC(=O)c1ccc(N2CCCN(CC)CC2)cc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCN1CCCN(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Yield: 25.6 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-ethyl-1,4-diazepan-1 was prepared using the same procedure as for Example 159, but starting from ethyl 4-(4-ethyl-1,4-diazepan-1-yl)benzoate (0.502 g, 1.4 mmol), 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.346 g, 1.40 mmol) and A 2M solution of trimethylaluminium (1.750 mL, 3.50 mmol) in toluene. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford a gum which solidified on trituration with DCM/Ether to afford the title compound (0.171 g, 25.6%) as a white solid.