Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[OH:24])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:28][C:29]3[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=3)=[CH:19][C:18]=2[O:24][CH2:28][C:29]2[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=2)[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(O)cc2O)CC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(OCc3cccc(C#N)c3)cc2OCc2cccc(C#N)c2)CC1
Yield: 67.1 %

Procedure:
{2-[1-(2,4-Dihydroxy benzoyl)piperidin-4-yl]ethyl}carbamic acid tert-butyl ester (1.05 g, 2.88 mmol) and 3-bromomethyl-benzonitrile (2.25 g, 11.5 mmol) and other reagents as described in Example 75(a) were used to afford 1.15 g of the required product. 1H NMR (DMSO-d6): δ 1.4 (9H, s), 2.1 (2H, d), 2.6 (1H, m), 2.95 (4H, m), 3.45 (1H, m), 4.5 (2H, m), 5.2 (4H, s), 6.7 (2H, d), 6.84 (1H, d), 7.14 (1H, dd), 7.52 (1H, m), 7.62 (3H, d), 7.7 (2H, d), 7.8 (5H, m), 7.95 (1H, s).
Reaction SMILES: C([O:5][C:6](=[O:37])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:36])[CH:13]([CH3:35])[CH2:14][S:15]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[SH:15][CH2:14][CH:13]([CH3:35])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:37])=[O:5])=[O:36]
Reactant: CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-[3-(triphenylmethylthio)-2-methylpropanoyl]-L-proline tert.butyl ester (5 g.) is dissolved in a mixture of anisole (55 ml.) and trifluoroacetic acid (110 ml.). After one hour storage at room temperature, the solvents are removed in vacuo and the residue is applied to a column of silica gel equilibrated with benzene:acetic acid (75:25) and eluted with the same solvent. The fractions corresponding to the component with Rf 0.40 (TLC silica gel with same system) are pooled and concentrated to dryness to yield 1-[3-mercapto-2-methylpropanoyl]-L-proline. Rf 0.62 (silica gel, chloroform/methanol:acetic acid:water 50:40:10), identical to the compound of Example 34.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH3:22][NH:21][C:19](=[O:20])[C:18]([CH3:24])([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:3][C:2]([C:35]4[CH:34]=[N:33][C:32]([CH3:31])=[CH:37][CH:36]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)[CH3:23]
Reactant: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(-c4ccc(C)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N-methyl-isobutyramide (Example 88) was reacted with 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine via General Procedure A. Purification on silica yielded 177. NMR (400 MHz CDCl3): 1.27 (6H, s, CH3), 2.58 (8H, b, CH2), 2.65 (3H, s, CH3), 2.82 (3H, d (J=4.97), CH3), 3.86 (2H, s, CH2), 3.90-3.92 (4H, m, CH2), 4.06-4.09 (4H, m, CH2), 7.21 (1H, b, NH), 7.26 (1H, d (J=8.23), ar), 7.33 (1H, s, ar), 8.58 (1H, dd (J=8.07, 2.17), ar), 9.53 (1H, d (J=1.80), ar). MH+ 510.24
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][C:10]1=[O:16]>C(O)C.O>[C:1]1([NH:7][NH:8][C:12]2[CH2:13][CH2:14][NH:9][C:10](=[O:16])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCNC(=O)C1
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C1C=C(NNc2ccccc2)CCN1

Procedure:
Phenylhydrazine (17.4 ml) was added over 15 min to a stirred suspension of 2,4-piperidinedione (20 g) in ethanol (200 ml) at ca. 20°. The resulting suspension was diluted with ethanol (80 ml) and water (300 ml) and the solid was filtered off to give the title compound (23.31 g), m.p. 165°-168°.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH:12]2[CH2:14][CH2:13]2)[C:9]2[CH:15]=[C:16]([Br:21])[C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Br:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH:12]3[CH2:14][CH2:13]3)[C:9]=2[CH:15]=1
Reactant: COc1cc2c(cc1Br)C(C1CC1)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1Br)C(C1CC1)CNCC2
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-cyclopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.014 g, 0.037 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred for 2 hours at 50 C. The product mixture was diluted with brine (10 mL), extracted twice with EtOAc (10 mL), dried with MgSO4, and concentrated to give 0.008 g of a clear oil. 1H NMR (400 MHz, CD3OD) d 7.26 (s, 1H), 6.78 (s, 1H), 3.83 (s, 3H), 3.02 (m, 2H), 2.92 (m, 2H), 2.67 (s, 2H), 0.91 (m, 2H), 0.85 (m, 2H). MS calculated for C13H16BrNO+H: 282, observed: 282.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH2:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][N:27]2[CH2:26][CH2:25][N:24]1[C:33]1[N:38]=[CH:37][C:36]([C:39](OC)=[O:40])=[CH:35][N:34]=1>C1(C)C=CC=CC=1>[CH2:23]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][N:27]2[CH2:26][CH2:25][N:24]1[C:33]1[N:38]=[CH:37][C:36]([C:39]([NH:22][C:19]2[NH:20][N:21]=[C:17]([CH2:16][CH2:15][C:9]3[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)[CH:18]=2)=[O:40])=[CH:35][N:34]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN3CCCCC3C2)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN5CCCCC5C4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
Trimethylaluminium (2M in toluene, 1.45 mL, 2.90 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (286 mg, 1.16 mmol) and methyl 2-(1,3,4,6,7,8,9,9a-octahydropyrido[2,1-c]pyrazin-2-yl)pyrimidine-5-carboxylate (320 mg, 1.16 mmol) in toluene (5.8 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h and then at 60° C. for 2 h. The reaction mixture was quenched with methanol (20 mL) and treated with HCl (2N aqueous solution, until a freely stirred solution was obtained). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (238 mg, 42%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C)C=O.O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[N:8]2[CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one prepared in example 4a (2.3 g, 7.9 mmol) in N,N-dimethyl-formamide (20 mL) at 0° C. was added NaH (60% in mineral oil) (0.32 g, 7.9 mmol) (Aldrich), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.32 g, 7.9 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na2SO4. The solvent was removed and the residue was purified by chromatography (EtOAc:hexanes=1:5) to give E/Z-6-chloro-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as yellow oil (Yield 3.0 g, 90%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C:9]1[C:10]([CH3:31])=[N:11][C:12]2[N:13]([CH:23]=[C:24]([C:26]([O:28]CC)=[O:27])[N:25]=2)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([CH2:8][C:9]1[C:10]([CH3:31])=[N:11][C:12]2[N:13]([CH:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=2)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CC(=O)OC(C)(C)C)c(C)nc2n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2nc(C(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1CC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 101.1 %

Procedure:
To a stirred solution of ethyl 6-((tert-butoxycarbonyl)methyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (100 mg, 021 mmol) in THF (2 mL) and H2O (0.5 mL) at room temperature was added LiOH.H2O (18 mg, 0.42 mmol). After 16 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure gave 6-((tert-butoxycarbonyl)methyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid (95 mg, 100%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:17]([F:20])([F:19])[F:18])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:7][C:6]1[N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:4]=[C:3]([C:17]([F:20])([F:19])[F:18])[C:2]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(Br)c(C(F)(F)F)nn1-c1ccc(CCO)cc1
Reactant: OB(O)c1ccccc1
Product: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-{4-[4-bromo-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethanol (step 2) and phenylboronic acid: MS (ESI) m/z 346 [M+H]+, 1H-NMR (CDCl3) δ 7.44-7.32 (9H, m), 3.89-3.83 (2H, m), 2.94-2.89 (2H, m), 2.33 (3H, s), 2:32 (3H, s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[N:7]=1.Br[CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(C#Cc2ccc(C(=O)OC)cc2)ccc1O
Reactant: CC(C)=CCCC(C)CCBr
Product: COC(=O)CCc1nc(C#Cc2ccc(C(=O)OC)cc2)ccc1OCCC(C)CCC=C(C)C
Yield: 74.2 %

Procedure:
Under the conditions of example 1 D, 500 mg of 3-{3-hydroxy-6-[2-(4-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is reacted with 354 mg of 1-bromo-(3RS)-3,7-dimethyl-6-octene, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 522 mg of 3-{6-[2-(4-methoxycarbonylphenyl)-ethinyl]-3-[(3RS)-3,7-dimethyl-6-octenyloxy]-2-pyridyl}-propionic acid methyl ester is obtained as yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([C:10]2[N:14]3[CH:15]=[C:16]([C:19]4[C:20]([C:43](O)=[O:44])=[N:21][N:22]([C:24]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:23]=4)[CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.C([N:49]=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(CC)CC)C>CN(C)C=O>[CH3:1][S:2]([C:5]1[S:9][C:8]([C:10]2[N:14]3[CH:15]=[C:16]([C:19]4[C:20]([C:43]([NH2:49])=[O:44])=[N:21][N:22]([C:24]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:23]=4)[CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(=O)O)cn23)s1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(N)=O)cn23)s1
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A mixture of 40 mg 4-{3-[5-(methylsulfonyl)-2-thienyl]imidazo[1,2-a]pyridin-6-yl}-1-trityl-1H-3-pyrazole carboxylic acid, 37 mg 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 26 mg 1-oxybenzotriazole, 17 mg ammonium chloride, 0.077 mL triethylamine and 3 mL N,N-dimethylformamide was left overnight at room temperature. The solvent was evaporated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) to give 22 mg 4-{3-[5-(methylsulfonyl)-2-thienyl]imidazo[1,2-a]-pyridin-6-yl}-1-trityl-1H-3-pyrazole carboxamide as colorless crystals. This product was subjected to deprotection of the trityl group in the same manner as in Example 79, to give 14 mg of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[NH2:18][C:19]1[C:26]([OH:27])=[C:25]([F:28])[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH3:35])[C:20]=1[C:21]#[N:22].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:18][C:19]1[C:26]([OH:27])=[C:25]([F:28])[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH3:35])[C:20]=1[C:21]#[N:22])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(Cl)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C#N)c(NC(=O)COCc2ccccc2)c(O)c(F)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
Under nitrogen atmosphere, benzyloxyacetyl chloride (489 μl, 3.10 mmol) was dropwise added to a tetrahydrofuran solution (10 ml) of 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (500 mg, 2.06 mmol) and sodium hydrogencarbonate (520 mg, 6.19 mmol) cooled with ice, followed by stirring at room temperature for 18 hours. Ethyl acetate was added to the reaction liquid, followed by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (621 mg, 1.59 mmol, 77%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC#N>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH:18]2[CH2:19][CH2:20][O:16][CH2:17]2)[CH2:12][CH2:11]1)([O-:3])=[O:2]
Reactant: O=C1CCOC1
Reactant: O=[N+]([O-])c1cnccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnccc1N1CCN(C2CCOC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round-bottomed flask was charged with 1-(3-nitro-4-pyridyl)piperazine (prepared according to methods similar to the one depicted in Step 1 of Preparation N-1), dihydrofuran-3(2H)-one (98 mg, 1.13 mmol) and acetic acid (129 uL, 2.27 mmol) in MeCN (4 mL). Na(OAc)3BH (482.4 mg, 2.27 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was partitioned between EtOAC and an aqueous saturated solution of Na2CO3. The organic extracts were dried over MgSO4, and concentrated under reduced pressure to give 1-(3-nitropyridin-4-yl)-4-(tetrahydrofuran-3-yl)piperazine as a yellow solid. MS (ES+) 279.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:12]1[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1ccccn1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccn2)CC1

Procedure:
Prepared from 2-(bromomethyl)pyridine and tert-butyl 1-piperazine-carboxylate using the procedure described in Step A of Intermediate 113. LC/MS: m/z (ES) 278.1 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=O)=[C:15]3[N:14]=2)=[CH:8][CH:7]=1.[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([CH:22]=[C:31]4[NH:25][C:26](=[O:27])[NH:28][C:29]4=[O:30])=[C:15]3[N:14]=2)=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc(Nc2ccn3ncc(C=O)c3n2)cc1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCOc1ccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)cc1
Temperature: 70 °C

Procedure:
To 5-(4-(2-(dimethylamino)ethoxy)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (90 mg, 0.276 mmol) in EtOH was added hydantoin (28 mg, 0.276 mmol) and piperidine (28 μL, 0.276 mmol). The mixture was heated at 70° C. overnight three times. Solvent was removed under reduced pressure and MeOH was added. Insolubilities were filtered off, and the filtrate was purified by HPLC to yield 5-((5-(4-(2-(dimethylamino)ethoxy)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=408)
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)[C:18]([OH:20])=[O:19]>>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)([OH:20])=[O:19]
Reactant: N[C@@H](Cc1cccs1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1cccs1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-thiophen-2-yl-propionic acid to provide the title compound in good yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C(O)(=O)C.[N+:25]([CH3:28])([O-:27])=[O:26]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]=[CH:28][N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccccc2C=C[N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
4'-Methylbiphenyl-2-carboxaldehyde (13.21 g, 67.3 mmol (1.0 eq), nitromethane (4.74 mL, 87.5 mmol, 1.3 eq), ammonium acetate (2.07 g, 26.0 mmol, 0.4 eq) and glacial acetic acid (30 mL) were mixed and refluxed for 2 days, at which time more nitromethane (4.74 mL) and ammonium acetate (2.07 g) were added and the reaction was refluxed for an additional 5 hours. The reaction mixture was poured into ice water (300 mL) and extracted with ethyl acetate (300 mL). The ethyl acetate layer was washed with water (3×200 mL), the organic layer dried (MgSO4), the solvent removed in vacuo and the residue chromatographed in 1:1 hexane/toluene to yield 11.22 g of a light yellow oil which crystallized. The product was recrystallized from methylcyclohexane to yield 8.47 g of yellow crystals; m.p. 64.0°-65.0°. NMR (200 MHz, CDCl3)δ8.04 (d, 1H, J= 13 Hz); 7.69 (d, 1H, J=9 Hz) 7.59-7.37 (m, 4H); 7.50 (d, 1H, J=13 Hz); 7.27 (d, 2H, J=7 Hz); 7.19 (d, 2H, J=7 Hz); 2.41 (s, 3H). Anal. Calcd. for C15H13NO2 : C, 75.30; H, 5.48; N, 5.85. Found: C, 75.32; H, 5.56; N, 5.58.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[O:7])=[O:4].CC(C)([O-])C.[K+]>C(COC)OC>[F:17][C:16]([F:19])([F:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[O:7][CH2:2][C:3](=[O:4])[N:5]=2)=[CH:10][CH:11]=1)([OH:24])[C:20]([F:23])([F:22])[F:21]
Reactant: O=C(CCl)NC(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C1COC(Nc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)=N1
Reaction time: 16 h

Procedure:
To 1-(2-chloroacetyl)-3-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl] urea (9.7 gm., 0.026 mole) in dimethoxyethane (500 ml) add potassium t-butoxide (5.7 gm., 0.051 mole). Stir 16 hr., concentrate, add water, acidify with conc. HCl, neutralize with sodium bicarbonate and extract with ether. Dry, concentrate, and recrystallize the residue from ether, to obtain the product, m.p. 272°-274° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1.[C:10]([NH:14][C:15]1[C:24]([CH3:25])=[N:23][C:22]2[C:17](=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][CH:21]=2)[N:16]=1)([CH3:13])([CH3:12])[CH3:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O>[C:10]([NH:14][C:15]1[C:24]([CH3:25])=[N:23][C:22]2[C:17]([N:16]=1)=[C:18]([C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[NH:5][CH:6]=1)[CH:19]=[CH:20][CH:21]=2)([CH3:13])([CH3:12])[CH3:11]
Reactant: NC(=O)c1cc(Br)c[nH]1
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3c[nH]c(C(N)=O)c3)c2nc1NC(C)(C)C
Temperature: 100 °C
Reaction time: 16.5 h
Yield: 50.7 %

Procedure:
A mixture of 4-bromo-1H-pyrrole-2-carboxamide (100 mg, 0.529 mmol), N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (174b; 311 mg, 0.529 mmol), K3PO4 (337 mg, 1.587 mmol), XPhos (Strem Chemicals, Inc.; 25.2 mg, 0.053 mmol), and (Aldrich; 24.22 mg, 0.026 mmol) in a mixture of dioxane (4.0 mL) and water (1.0 mL) was stirred under argon at 100° C. for 16.5 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes) to provide 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-2-carboxamide (86.7 mg, 0.268 mmol, 51% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.), 7.78 (1H, dd, J=2.6, 1.5 Hz), 7.61 (1H, dd, J=7.3, 1.3 Hz), 7.54 (1H, dd, J=8.1, 1.5 Hz), 7.44 (1H, br. s.), 7.31 (1H, t, J=7.7 Hz), 7.22-7.26 (1H, m), 6.94 (1H, br. s.), 5.78 (1H, s), 2.53 (3H, s), 1.53 (9H, s). m/z (ESI, +ve) 324.0 (M+H)+.