Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:20]=[CH:19][C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[S:21]1[CH2:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[S:21]1[CH2:22][CH:23]=[C:24]([C:2]2[C:3]([O:8][C:9]3[CH:20]=[CH:19][C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Reactant: CON(C)C(=O)c1ccc(Oc2nccnc2Cl)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CON(C)C(=O)c1ccc(Oc2nccnc2C2=CCSCC2)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-(3-chloropyrazin-2-yloxy)-N-methoxy-N-methylbenzamide (1.4 g, 4.77 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.132 g, 5.01 mmol), potassium carbonate (1.976 g, 14.30 mmol), and bis(tri-tert-butylphosphine)palladium(0) (0.244 g, 0.477 mmol) in p-dioxane/H2O (10:1, 11 ml) was heated to 120° C. in 4 h, cooled, taken up in H2O, extracted with EtOAc (3×), dried over MgSO4, concentrated and purified by ISCO (50% EtOAc/hexanes) to give the titled compound. MS [M+1]: 358.1.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][C:18]#[C:19][CH2:20][CH3:21].C([CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32])=[O:27])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:10]1[CH:11]=[C:12](/[CH:13]=[CH:25]/[C:26]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])[CH:15]=[CH:16][C:9]=1[O:8][CH3:7])[CH2:19][C:20]#[CH:21]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCC#COc1cc(C=O)ccc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C#CCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 68.4 %

Procedure:
Piperidine (0.17 mL, 1.7 mmol) was added to a suspension of 4-methoxy-3-(but-1-ynyloxy)benzaldehyde (0.35 g, 1.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.35 g, 1.6 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(3-(but-3-ynyloxy)-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.40 g, 70%) as a colourless crystalline solid; mp 197-198° C.; δH (400 MHz, DMSO-d6) 2.65 (dt, J=6.8, 2.4 Hz, 2H, CH2CCH), 2.90 (t, J=2.4 Hz, 1H, CCH), 3.80 (s, 3H, OCH3), 4.13 (t, J=6.8 Hz, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 7.00 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.26 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.40 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.99 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 19.0, 55.6, 66.6, 72.5, 81.4, 111.9, 111.9, 116.6, 120.0, 120.3, 122.7, 123.0, 127.3, 131.1, 134.0, 141.0, 141.5, 147.8, 150.7, 164.2, 169.4; HRMS (ESI) calculated for C21H19NO6 [M+H]+ 366.1335. found 366.1337; vmax 753, 1263, 1512, 1581, 1671, 2833, 3250 cm−1.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:34][CH3:35])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:21].Cl>>[CH2:34]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:30][CH2:29]1)[CH3:35]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: CCN(CC)CCOCCC1CCNCC1
Agent: Cl
Product: CCN(CC)CCOCCC1CCN(C(=O)N2c3ccccc3NC(=O)c3cccnc32)CC1
Yield: 83 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 4-[2-[2-(diethylamino)ethoxy]ethyl]piperidine in a yield of 83% of theory. The colourless hydrochloride melted at 148°-150° C. (ethyl acetate).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2cccc(F)c2)C1
Agent: B
Solvent: C1CCOC1
Product: Fc1cccc([C@@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 60 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-fluorophenyl)piperidin-1-yl]methanone (19 mg, 0.056 mmol) was treated with BH3THF according to the above general procedure. Flash chromatography gave 11 mg of the title compound.
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:19][O:20]CCN>>[CH3:19][O:20][CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: COCCN
Reactant: CN(C)CCNc1nc2ccc([N+](=O)[O-])cc2s1
Product: COCCNc1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
The title compound was prepared following the procedure for N,N-dimethyl-N′-(6-nitrobenzothiazol-2-yl)-ethane-1,2-diamine, using 6.78 eq of 2-methoxyethylamine. 1H NMR (400 MHz, CDCl3): δ=3.42 (s, 3H), 3.65 (td, J=4.4, 0.8 Hz, 2H), 3.70 (t, br, J=4.4 Hz, 2H), 5.92 (s, br, —NH), 7.53 (d, J=8.8 Hz, 1H), 8.21 (dd, J=9.2, 2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H). MS (ES+): m/z 254.10 (100) [MH+]. HPLC: tR=2.89 min (ZQ2000, polar—5 min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[NH2:38])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[NH:38][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Cc1c(-c2cccc(F)c2)nc2ccccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2cccc(F)c2)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-2-(3-fluorophenyl)-3-methylquinoline (127 mg, 467 μmol), 2,5-dimorpholinobenzenamine (123 mg, 467 μmol) and 4N hydrochloric acid solution in dioxane (0.12 mL, 467 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel, eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=8.2 Hz), 7.90 (1H, dd, J=8.0, 1.0 Hz), 7.66-7.75 (1H, m), 7.43-7.56 (2H, m), 7.32-7.43 (2H, m), 7.25 (1H, s), 7.07-7.22 (2H, m), 6.45 (1H, dd, J=8.6, 2.7 Hz), 6.03 (1H, d, J=2.7 Hz), 3.88-3.99 (4H, m), 3.67-3.80 (4H, m), 3.01-3.14 (4H, m), 2.88-2.99 (4H, m), 2.32 (3H, s). Mass Spectrum (ESI) m/e=499.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[OH-].[Na+].[ClH:15]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][C:7]=1[Cl:15]
Reactant: Cl
Reactant: COC(=O)c1cc(Cl)c(Br)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-bromo-4-chloropicolinate (1.08 g) in THF (25 mL) and methanol (12.5 mL) was added 1N aqueous sodium hydroxide solution (25 mL), and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (944 mg) as a pale-yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:37])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][OH:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:37])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][OH:36])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCO)c1
Yield: 51 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10.0 mmol, 18 eq) of sodium hydroxide and 270 mg (0.55 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-(3-hydroxypropoxy)biphenyl-4-yl]propanoate in 3 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from ethyl acetate/heptane, 135 mg of 3-[3′-(3-heptyl-1-methylureido)-2-(3-hydroxypropoxy)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=107° C.). Yield=51%
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.O.C(=O)([O-])O.[Na+].[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>O1CCCC1>[Cl:16][C:17]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1)=[O:20]
Reactant: Cc1ccc(N)cc1O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2Cl)cc1O
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoic acid (5.26 g, 23.4 mmol) in tetrahydrofuran (50 mL) were added N,N-dimethylformamide (40 μL) and oxalyl chloride (2.8 mL, 31.9 mmol), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give 2-chloro-3-(trifluoromethyl)benzoyl chloride. To a solution of 5-amino-2-methylphenol (2.62 g, 21.2 mmol) in tetrahydrofuran (20 mL) was added water (30 mL) in which sodium hydrogen carbonate (2.68 g, 31.9 mmol) has been suspended, and the mixture was vigorously stirred at room temperature. To the mixture was added dropwise a solution of 2-chloro-3-(trifluoromethyl)benzoyl chloride produced above in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, and filtered through a pad filled with silica gel. The solvent was concentrated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (6.37 g, 91%) as a pale-brown powder. The obtained compound was used for the next reaction without further purification operation.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:5][CH:4]=1)=O.[NH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][O:28][C:29]2=[O:34].[O-]S([O-])(=O)=O.[Mg+2]>CC#N>[O:34]=[C:29]1[C:30]2[C:26](=[C:25](/[N:24]=[CH:1]/[C:3]3[CH:4]=[CH:5][C:6]([CH:9]4[CH2:13][CH2:12][CH2:11][N:10]4[C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:15])=[CH:7][CH:8]=3)[CH:33]=[CH:32][CH:31]=2)[CH2:27][O:28]1
Reactant: Nc1cccc2c1COC2=O
Reactant: O=Cc1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3ccc(C4CCCN4C(=O)OCc4ccccc4)cc3)cccc21
Temperature: 120 °C
Yield: 39.7 %

Procedure:
A mixture of benzyl 2-(4-formylphenyl)pyrrolidine-1-carboxylate (0.62 g, 2 mmol), 4-aminoisobenzofuran-1(3H)-one (0.298 g, 2 mmol), MgSO4(2.4 g, 20 mmol) in CH3CN (20 mL) was refluxed at 120° C. for 4 days. After a hot filtration, the filtrate was concentrated in vacuo and the residue was purified by column chromatography (EtOAc:DCM:hexane=1:1:6) to give the title compound (0.35 g, yield 30%) as a white solid. LC-MS (ESI) m/z: 440 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cu][C:11]#[N:12]>N1C=CC=CC=1>[OH:8][C:4]1[C:3]([CH3:9])=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:11]#[N:12]
Reactant: Cc1c(O)cccc1Cl
Reactant: N#C[Cu]
Solvent: c1ccncc1
Product: Cc1c(O)cccc1C#N

Procedure:
A further process starts from 3-chloro-2-methylphenol (Cresp et al., J. Chem. Soc. Perkin Trans.1, 2435(1974)). This is reacted with copper(I) cyanide in pyridine at boiling heat to give 3-hydroxy-2-methylbenzonitrile. In the second stage, the nitrile is hydrolyzed to 3-hydroxy-2-methylbenzoic acid (2) in 18 hours in a boiling mixture of water, glacial acetic acid and concentrated sulfuric acid. The first stage of this process has the significant disadvantage that very toxic copper(I) cyanide is employed--under the reaction conditions toxic hydrogen cyanide gas can escape from the reaction mixture. Harmful pyridine is employed as a solvent. The reaction is distinguished by difficult working up and a high yield of toxic salts. In the second stage (amide hydrolysis), a very long reaction time is necessary. At the very high reaction temperatures, the acidic reaction medium is very corrosive to the materials customarily employed in chemical plants.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:5])[CH3:2].C(OC([C@@H]1CCC[C@H]1NCCC(C)(C)C)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][CH2:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)(C)C
Agent: CCOC(=O)[C@@H]1CCC[C@H]1NCCC(C)(C)C
Product: CCOC(=O)C1CCCC1NCCC(C)(C)C

Procedure:
To a solution of 2-(3,3-dimethylbutylamino)-cyclopent-1-enecarboxylic acid ethyl ester (5.59 g, 23.4 mmol) in acetic acid (70 mL) was added a 8.0 M solution of borane in pyridine (3.2 mL, 25.6 mmol) at 25° C. After stirring for 15 min, the reaction mixture was concentrated in vacuo. The crude material was triturated with 1.0 M aqueous hydrochloric acid solution (25 mL) and stirred for 0.5 h (until the gas evolution ceased). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-10% methanol in dichloromethane) to afford cis-2-(3,3-dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester as a yellowish oil (0.40 g, 1.7 mmol, 7%) and trans-2-(3,3-dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester and an off-white solid (2.37 g, 9.8 mmol, 42%). cis-2-(3,3-Dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 0.91 (9H, s), 1.28 (3H, t, J=7.0 Hz), 1.35-1.50 (2H, m), 1.56-1.73 (2H, m), 1.80-2.03 (4H, m), 2.60-2.75 (2H, m), 2.98-3.02 (1H, m), 3.35 (1H, q, J=7.4 Hz), 4.15 (2H, q, J=6.9 Hz), 6.38 (1H, s). trans-2-(3,3-Dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester: 1H NMR (400 MHz, CDCl3) δ 0.94 (9H, s), 1.29 (3H, t, J=7.0 Hz), 1.66-2.01 (6H, m), 2.11-2.27 (2H, m), 2.86 (2H, t, J=8.6 Hz), 3.10 (1H, q, J=7.8 Hz), 3.68 (1H, q, J=7.0 Hz), 4.18 (2H, q, J=7.0 Hz). LC-MS (ESI) calcd for C14H27NO2 241.20, found 242.4 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.CC(OC)(C)C.Cl[Pd]Cl>[ClH:12].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COC(C)(C)C
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(Cl)cc2)c1
Temperature: 100 °C
Yield: 128.6 %

Procedure:
Methyl 2-bromoisonicotinate (3.39 g, 15.69 mmol), 4-chlorophenylboronic acid (3.68 g, 23.54 mmol), potassium carbonate (3.25 g, 23.54 mmol) and PdCl2 (dppf) (0.341 g, 0.47 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield an orange solid. The solid was dissolved in MTBE, then HCl (4 M in dioxane) was added to give crude methyl 2-(4-chlorophenyl)isonicotinate hydrochloride (4.3 g). MS m/z 248 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.CS(O[CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[O:8][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1OC1CCOCC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 89.9 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (100 g), tetrahydro-2H-pyran-4-yl methanesulfonate (172 g) and potassium carbonate (176 g) in N,N-dimethylformamide (1000 mL) was stirred at 50° C. for 3 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 25:75, volume ratio) to give the title compound (138 g, yield 90%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:8]=1)#[N:2].Cl.[OH-:26].[Na+]>CCOCC>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]2[C:11]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[C:6]3[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:26])=[CH:8][N:7]3[N:9]=2)=[CH:19][CH:20]=1
Reactant: N#Cc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: NC(=O)c1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of 6-cyano-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 52. 100 mg, 0.318 mmol) and concentrated hydrochloric acid (2 mL) were stirred at room temperature overnight. The mixture was diluted with ether, basified with 5N sodium hydroxide solution and extracted thoroughly with ethyl acetate several times. The combined organic layers were dried (MgSO4), filtered and evaporated to dryness. The title compound was isolated in 85% yield (90 mg). 1H NMR (d6-DMSO) δ 9.36 (s, 1H), 8.60 (d, 2H, J=5.2 Hz), 8.22 (bs, 1H), 7.81 (bs, 2H), 7.67 (bs, 1H), 7.58 (m, 2H), 7.28–7.37 (m, 4H). MS (ES+ve): 334 (25, M+2), 333 (100, M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[S:19])[NH:9][N:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]([O-])([O-])=O.[Cs+].[Cs+].IC>CC#N>[CH3:20][S:19][C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1
Reactant: O=[N+]([O-])c1ccc2c(=S)[nH]n(-c3ccccc3)c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: CSc1nn(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 6-nitro-1-phenyl-1,2-dihydroindazole-3-thione (3.1 g, 11.44 mmol, 1.00 equiv) in CH3CN (20 mL), Cs2CO3 (21 g, 64.42 mmol, 5.63 equiv). To the resulting mixture was then added a solution of iodomethane (11.3 g, 79.58 mmol, 6.96 equiv) in CH3CN (15 mL) dropwise with stirring at 10° C. in 30 min. The resulting solution was stirred for 30 min at 10° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100) to yield 3-(methylthio)-6-nitro-1-phenyl-1H-indazole as a yellow solid. MS: 285 (MH+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([CH2:15][CH2:16][O:17][CH3:18])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:20]1([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:18][O:17][CH2:16][CH2:15][N:4]1[C:3](=[O:19])[C:2]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:32][CH:31]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COCCN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-morpholin-4-ylaniline in a similar manner as described for Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 2.92-2.97 (m, 4H), 3.38 (s, 3H), 3.70-3.75 (m, 6H), 3.90 (t, 2H), 6.51-6.56 (m, 2H), 6.68-6.72 (m, 2H), 7.08-7.16 (m, 4H), 7.22-7.27 (m, 1H), 7.67 (bs, 1H); Mass Spectrum: M+H+ 444.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([CH:10]([C:17]([O:19][CH3:20])=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:7](=[O:21])[N:8]([CH:10]([C:17]([O:19][CH3:20])=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(C(C(=O)OC)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCCc1nn(C(C(=O)OC)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 65 °C
Yield: 96 %

Procedure:
Deprotection of 5-n-butyl-2-[α-(carbomethoxy)benzyl]-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one in 67% aqueous acetic acid was accomplished by the procedure of Example 3, Step B, except the mixture was heated overnight at 65° C. After work-up, the residue was flash chromatographed over silica gel (30 mL for 0.14 mmole, elution with 4-10% MeOH/CH2Cl2) to give the title compound in 96% yield as an off-white foam, homogeneous by TLC in 9:1 CH2Cl2 /MeOH, mass spectrum (FAB) m/e 524 (M+1)+.