Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:18]=2[C:27]([F:30])([F:29])[F:28])[C:7]=1[CH3:31])C.[Li+].[OH-]>C1COCC1>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][C:18]=1[C:27]([F:28])([F:29])[F:30])[C:7]([CH3:31])=[C:6]2[CH2:5][C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ccc(F)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cc(F)ccc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of [5-fluoro-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-indol-3-yl]-acetic acid ethyl ester (28 mg, 0.06 mmol) dissolved in THF (1 ml) at room temperature, is added 2N LiOH aq (1 ml). The reaction mixture is stirred at room temperature for 2 h and partitioned between water/EtOAc (20 ml). The aqueous phase is separated and acidified with 1N HCl aq to pH 4. The product is extracted into EtOAc (20 ml), dried (MgSO4) and evaporated in vacuo; [M+H]+ 444.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2([CH3:28])[C:20](=[O:21])[NH:19][C:18]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:17]2)[CH2:11][CH2:10]1.[CH2:29](Br)[CH:30]=[CH2:31].[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[CH2:31]([N:19]1[C:20](=[O:21])[C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)([CH3:28])[N:17]=[C:18]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: COc1ccccc1N1CCN(CC2(C)N=C(c3cccnc3)NC2=O)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCN1C(=O)C(C)(CN2CCN(c3ccccc3OC)CC2)N=C1c1cccnc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-methyl-2-(3-pyridyl)-2-imidazolin-5-one (3.7 g; prepared in a similar manner to that described in Example 36), allyl bromide (1.05 ml), finely-powdered potassium hydroxide (0.79 g), 18-Crown-6 (0.26 g) and tetrahydrofuran (50 ml) was stirred at ambient temperature under nitrogen for 120 hours, then poured onto ice-water (30 ml). The product was extracted into ethyl acetate, the extracts were dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 9:1 mixture of ethyl acetate and ethanol as eluant. Appropriate fractions were combined, and the solvents removed in vacuo to leave 1-allyl-4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-methyl-2-(3-pyridyl)-2-imidazolin-5-one as an off-white solid (0.25 g), m.p. 66-69° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18](OC)=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[OH:23][C:24]1C=CC(NC(N)=S)=CC=1.C(=O)C>C(Cl)Cl.CO>[CH3:24][O:23][C:19]1[CH:20]=[C:15]([C:12]2[S:11][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)=[N:14][CH:13]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: NC(=S)Nc1ccc(O)cc1
Reactant: COc1ccc(Nc2ncc(-c3ccc(OC)cc3)s2)cc1
Agent: CC=O
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(-c2cnc(Nc3ccc(O)cc3)s2)c1

Procedure:
The title compound is prepared as described in Example 4 for (4-methoxy-phenyl)-[5-(4-methoxy-phenyl)-thiazol-2-yl]-amine but using (4-hydroxy-phenyl)-thiourea and 3-methoxy-phenyl)-acetaldehyde. Title compound: ES-MS: 312.9 [M−H]−; single peak at tR=6.81 min (System 1); Rf=0.28 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]([NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][S:25]([C:28]1[C:33]2=[N:34][S:35][N:36]=[C:32]2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)=[O:6].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[OH-].[Na+].OO>C1COCC1.CCO.O>[CH3:1][O:2][C:3](=[O:38])[CH:4]([NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][S:25]([C:28]1[C:33]2=[N:34][S:35][N:36]=[C:32]2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[OH:6]
Reactant: COC(=O)C(NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)C(=O)c1ccc(Cl)c(Cl)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)C(NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)C(O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-oxo-propionic acid methyl ester (35 mg, 0.057 mmol) in THF (2 mL) was cooled to −78° C. and lithium tri-sec-butylborohydride (L-Selectride; 1 M in THF, 86 μL, 0.086 mmol) was added. The mixture was stirred at −78° C. for 1 h and water (0.1 mL), EtOH (0.1 mL), 15% NaOH (0.1 mL), and 30% H2O2 (0.1 mL) were added and the solution was warmed to rt. The mixture was diluted with satd. aq. Na2S2O3 and water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by reverse phase HPLC to provide 2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionic acid methyl ester as a single diastereomer (20 mg, 57%). The methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to provide the title compound (73%). HPLC: RT=9.51 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 601.87; m/z found, 599/601 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.31 (s, 1H), 8.34 (dd, J=7.0, 0.6, 1H), 8.19 (dd, J=8.8, 0.6, 1H), 7.71 (dd, J=8.8, 7.1, 1H), 7.64 (d, J=1.9, 1H), 7.43 (d, J=1.7, 1H), 7.36 (d, J=8.3, 1H), 7.23 (d, J=8.5, 1H), 7.18 (dd, J=8.3, 1.8, 1H), 7.01 (d, J=7.3, 1H), 6.86 (dd, J=8.4, 1.9, 1H), 5.37 (d, J=3.7, 1H), 5.10 (dd, J=7.3, 3.9, 1H).
Reaction SMILES: C(O[C:6](=[O:35])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@@H:16]([N:19]=[N+]=[N-])[CH2:15][C@H:14]2[CH2:22][S:23]([C:26]2[CH:31]=[CH:30][C:29](SC)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:9]1=[O:34])(C)(C)C.[C:36](O)([C:38]([F:41])([F:40])[F:39])=O>C(Cl)Cl>[C:26]1([S:23]([CH2:22][C@@H:14]2[CH2:15][C@H:16]([NH:19][CH:8]([CH3:12])[CH3:9])[CH2:17][CH2:18][C@@H:13]2[N:10]2[CH2:11][CH2:12][C@H:8]([NH:7][C:6](=[O:35])[C:14]3[CH:13]=[CH:18][CH:17]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:15]=3)[C:9]2=[O:34])(=[O:24])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2N2CC[C@H](NC(=O)OC(C)(C)C)C2=O)cc1
Solvent: ClCCl
Product: CC(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
{(3S)-1-[(1S,2R,4R)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (240 mg), see example 18, was dissolved in CH2Cl2 (5 mL) prior to the addition of TFA (2.5 mL). After 30 min, it was concentrated and dried. The resulting residue was dissolved in DMF prior to the addition of 4-methylmorpholine (0.25 mL) and 3-trifluoromethyl-benzoic acid (104.5 mg). BOP Reagent (64 mg) was added and the mixture was stirred for 40 min. After concentration, EtOAc was added along with 1N HCl solution. The EtOAc layer was washed with NaHCO3 solution (aq) and brine, dried (MgSO4), filtered, and concentrated. This material was passed through a plug of silica and concentrated. The resulting material (178 mg) was dissolved in MeOH (5 mL) prior to the addition of 20% Pd(OH)2 (100 mg). A hydrogen balloon was added and the mixture was stirred. After stirring overnight, the palladium was filtered off and the solvent was concentrated. A portion of this material (68 mg) was dissolved in dichloroethane (2.5 mL) prior to the adddition of acetone (0.04 mL) and NaBH(OAc)3 (64 mg). After 40 min, the solution was concentrated. The resulting residue was dissolved in EtOAc and washed with saturated NaHCO3. The organic layer was dried, filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (66 mg). MS found: (M+H)+=566.4.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[CH:11]=[C:12](Br)Br)[CH2:3][CH2:2]1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[CH2:11][C:12]2[NH:17][CH2:16][CH2:15][N:18]=2)[CH2:3][CH2:2]1
Reactant: Cc1cccc(C2CC2)c1C=C(Br)Br
Reactant: NCCN
Product: Cc1cccc(C2CC2)c1CC1=NCCN1

Procedure:
2-(2-cyclopropyl-6-methyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from 1-cyclopropyl-2-(2,2-dibromo-vinyl)-3-methyl-benzene and ethylenediamine in analogy to Example 1e): yellow crystals; MS (ISP): 215.3 ([M+H]+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cnccn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 3.4 %

Procedure:
To a solution of aminopyrazine (2.00 g, 21.0 mmol) and pyridine (5.10 ml, 63.1 mmol) in tetrahydrofuran was added 2,2,2-trichloroethyl chloroformate (4.34 ml, 31.5 mmol) with ice-cooling, the mixture was stirred for 2 hours with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (193 mg, 3.4%) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.Cl.[F:19][C:20]1[CH:21]=[N:22][C:23]([C@@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)=[N:7][C:2]([NH:28][C@H:26]([C:23]2[N:24]=[CH:25][C:20]([F:19])=[CH:21][N:22]=2)[CH3:27])=[N:3][CH:4]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CN(C)c1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(N(C)C)[nH]n2)n1)c1ncc(F)cn1
Temperature: 160 °C

Procedure:
A microwave reaction vessel was charged with N3-(2,5-dichloropyrimidin-4-yl)-N5,N5-dimethyl-1H-pyrazole-3,5-diamine (Method 36, 50 mg, 0.2 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 50 mg, 0.23 mmol), and DIPEA (0.15 ml, 0.86 mmol) in n-BuOH (1 ml) was heated in a microwave reactor at 160° C. for 2 hours. Solvent was removed. The residue was purified by silica gel chromatography (by ISCO Combiflash with gradient 0-5% methanol in DCM with 1% NH4OH) to afford the title compound as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.77 (s, 2H), 8.26 (br, 1H), 5.35 (br, 1H), 3.49 (q, 1H), 3.11 (s, 6H), 1.72 (d, 3H); m/z 378.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH2:21][CH2:22][O:23][CH2:24][CH:25]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:20]2[CH2:25][CH2:24][O:23][CH2:22][CH:21]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1cc(Br)cnc1C1=CCOCC1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
A stirred mixture of 2,5-dibromo-3-nitropyridine (0.31 g, 1.11 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.26 g, 1.23 mmol), tetrakis(triphenylphosphine)palladium (64.7 mg, 0.056 mmol), and 2.0M sodium carbonate (3.0 mL, 6.00 mmol) in toluene (3.0 mL) and EtOH (1.0 mL) was heated to 70° C. After 19 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-20% EtOAc in hexanes) to afford a light yellow solid as 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-nitropyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.81 (1H, d, J=2.0 Hz), 8.20 (1H, d, J=2.0 Hz), 6.09 (1H, m), 4.30 (2H, q, J=2.8 Hz), 3.94 (2H, t, J=5.4 Hz), 2.61 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:37]1([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:9](=[O:10])[NH:47][CH2:46][CH2:45][CH2:44][CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCCCCc1ccccc1
Product: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCCCc1ccccc1

Procedure:
This compound was prepared by reacting the compound of Example 63 with 4-phenyl butylamine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>C1(C)C=CC=CC=1>[C:7]([C:6]1[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][S:3][C:2]=1[NH:1][C:22]([NH:21][CH2:20][CH2:19][Cl:18])=[O:23])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)csc1NC(=O)NCCCl
Reaction time: 1 h

Procedure:
A solution of 2-amino-3-carboethoxy-4-phenylthiophene, prepared by the method of Gewald Chem. Ber. (1966), 99, 94, (2.47 g, 0.010 mol) in toluene (30 mL) was heated to reflux, treated with 2-chloroethylisocyanate (1.0 mL, 0.012 mol), stirred for 1 hour, treated with a second portion of 2-chloroethylisocyanate (1.0 mL, 0.012 mol), stirred for 1 hour, cooled, and concentrated. The product was crystallized from ethyl acetate/hexane to provide 2.93 g (83%) yield of the title compound.
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:11]([C:23]1[S:24][C:25]([CH:3]=[O:4])=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCc1cccs1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCc1ccc(C=O)s1
Temperature: 5 °C
Yield: 75.9 %

Procedure:
In a 1 liter-four-necked flask, 93.7 (1.28 mol) of N,N-dimethylformamide was placed and cooled to 5° C., followed by addition of 107.4 g (7.00×10-1 mol) of POCl3 in 15 min. below 10° C. under stirring. After stirring for 30 min. below 10° C., 160 g (6.35×10-1 mol) of 2-dodecylthiophene was added dropwise to the mixture in 10 min. at room temperature, followed by stirring for 1.5 hours and further stirring for 2.5 hours at 60° C. After the reaction, the reaction mixture was poured into 2 liters of iced water, subjected to 3 times of extraction with 500 ml of chloroform and washed 6 times with 500 ml of water. The organic layer was dried on CaCl2, followed by distilling-off of the solvent to obtain 237 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 135 g of a product (yield: 75.9%). b.p.: 160° C./0.6 mmHg
Reaction SMILES: [CH2:1]([C:5]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](S(C)=O)[N:15]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)[CH:2]([CH3:4])[CH3:3].[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:28][C:16]2[N:15]=[C:14]([C:13]3[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[N:6][N:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=34)[CH:19]=[CH:18][N:17]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCC1
Reactant: CC(C)Cc1nn2ccccc2c1-c1ccnc(S(C)=O)n1
Product: CC(C)Cc1nn2ccccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 2-isobutyl-3-[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (930 mg, 2.98 mmol) in cyclopentylamine (5 mL) was heated at 130° C. for 4 h. The mixture was cooled to room temperature and concentrated in vacuo and the residue was purified by flash chromatography on silica gel (2:1 to 1:1 hexane-ethyl acetate) to give N-cyclopentyl-4-(2-isobutylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (890 mg, 89%) as a White solid. 1H NMR (CDCl3) δ 8.44 (d, 1H), 8.28–8.25 (m, 2H), 7.26 (m, 1H), 6.85–6.76 (m, 2H), 5.08 (m, 1H), 4.40 (m, 1H), 3.00 (d, 2H), 2.26–2.05 (m, 3H), 1.83–1.51 (m, 6H), 1.00 (d, 6H); MS m/z 336 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:30]([C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)=[O:31])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cccs1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1cccs1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 66 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 2-thiophenecarbonyl chloride, the title compound was synthesized according to Example 1b. Yield: 66%. Melting point: 222-224° C. (Ethyl acetate-hexane)
Reaction SMILES: [C:1]1(=[O:31])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])C(=O)C2=CC=CC=C12.O.NN.[CH2:35]([O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([N:46]=C=O)=[CH:42][CH:41]=1)=[O:39])[CH3:36]>CCO>[CH2:35]([O:37][C:38]([C:40]1[CH:41]=[CH:42][C:43]([NH:46][C:1](=[O:31])[NH:5][CH2:6][CH2:7][CH2:8][N:9]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:44][CH:45]=1)=[O:39])[CH3:36]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: O=C(O)CCCN(CCCN1C(=O)c2ccccc2C1=O)C1CCCc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)NCCCN(CCCC(=O)O)C2CCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.2 %

Procedure:
To a solution of 4-[[(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (137 mg, 0.32 mmol) in EtOH (5 ml) was added hydrazine monohydrate (63 μl, 1.3 mmol), and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated under vacuum, and then water was added. The mixture was extracted with chloroform, washed with water and brine, dried over sodium sulfate, and filtered. To the filtrate was added 4-(ethoxycarbonyl)phenyl isocyanate (62 mg, 0.32 mmol), and the mixture was stirred at RT for 30 min. The reaction mixture was concentrated under vacuum to dryness, and the residue was adsorbed on a plate of silica gel and then developed with 17% methanol/chloroform to afford 4-[[3-[4-(ethoxycarbonyl)phenylureido]propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (25 mg, 16%): MS(ES+) m/e 482 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 8.80 (br, 1H), 7.91 (m, 3H), 7.61 (m, 3H), 7.21 (m, 1H), 7.12 (m, 2H), 4.70 (t, J=7.6 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 3.32 (m, 2H), 3.23 (m, 1H), 3.03-2.84 (m, 3H), 2.74 (m, 2H), 2.55 (m, 1H), 2.21 (m, 2H), 2.02-1.78 (m, 5H), 1.70 (m, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[NH2:15])[CH3:2].[Cl:16][C:17]1[C:18]([C:27]([F:30])([F:29])[F:28])=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:16][C:17]1[C:18]([C:27]([F:29])([F:28])[F:30])=[N:19][N:20]([CH2:23][C:24]([NH:15][C:4]2[CH:5]=[N:6][N:7]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:3]=2[CH2:1][CH3:2])=[O:25])[C:21]=1[CH3:22]
Reactant: CCc1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(NC(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 5-ethyl-1-(4-fluorophenyl)pyrazol-4-amine (0.02 g, 0.1 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid (0.024 g, 0.10 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.045 g, 0.12 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water, and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.035 mmol, 35%). 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.92 (s, 1H), 7.40-7.31 (m, 2H), 7.17 (dd, J=8.9, 8.1 Hz, 2H), 4.93 (s, 2H), 2.56 (q, J=7.6 Hz, 2H), 2.39 (s, 3H), 1.01 (t, J=7.6 Hz, 3H); MS: (ES) m/z calculated for C18H16ClF4N5O [M+H]+ 430.1, found 430.0.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])=[O:24]
Reactant: Nc1ccccc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Nc1ccccc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -10 °C
Yield: 62.4 %

Procedure:
The title product of Example 2 (830 mg, 3.25 mMol) was dissolved in about 200 ml of boiling chloroform and then cooled to about -10° C. A solution of 662 mg (ca. 3.25 mmol) of ca. 85% m-chloroperoxybenzoic acid in 10 ml of chloroform was then added with stirring over about ten minutes. After another thirty minutes, the reaction was quenched with 4 drops of dimethylsulfide and a white solid was collected by filtration. The solid was washed sequentially with chloroform and diethyl ether, then air dried, giving 550 mg of the title compound: m.p. 164-165° C. Anal. Calc'd. for C14H13N3OS*1/2 H2O: C,59.98; H,5.03; N, 15.00; S, 11.44. Found: C, 60.11; H, 4.82; N, 14.93; S, 11.44.
Reaction SMILES: [Br:1]C1N=C(CBr)C=CN=1.[Cl:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[N:12]=1>>[Br:1][CH2:17][C:13]1[N:12]=[C:11]([Cl:10])[CH:16]=[CH:15][N:14]=1
Reactant: BrCc1ccnc(Br)n1
Reactant: Cc1nccc(Cl)n1
Product: Clc1ccnc(CBr)n1

Procedure:
Prepared according to the same procedure as 2-bromo-4-(bromomethyl)pyrimidine, starting with 4-chloro-2-methylpyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 8.83 (d, J=5.5 Hz, 1H), 7.69 (d, J=5.5 Hz, 1H), 4.68 (s, 2H), Mass spec.: 208.9 (MH)+.