Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1.[NH2:15][C@@H:16]1[C@@H:21]([OH:22])[CH2:20][CH2:19][O:18][CH2:17]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1.[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:15][C@@H:16]2[C@@H:21]([OH:22])[CH2:20][CH2:19][O:18][CH2:17]2)=[O:14])[CH:3]=1
Reactant: N[C@H]1COCC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cc(Br)c2ccccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1COCC[C@@H]1O)c1cc(Br)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Bromoquinoline-2-carboxylic acid (A3) was prepared as described in Example 1. To a solution of A3 (0.35 g, 1.4 mmol) in 6.0 mL CH2Cl2 was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.20 g, 1.7 mmol), BOP reagent (0.74 g, 1.7 mmol), and triethylamine (0.58 mL, 4.2 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with CH2Cl2, washed with water, dried over sodium sulfate, filtered, and concentrated. The resultant residue was subjected to silica gel chromatography eluting with 25-100% ethyl acetate in hexanes to afford 4-bromo-N-[(3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]quinoline-2-carboxamide that gave a mass ion (ES+) of 353.1 (81Br) for M+H+.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:27]([NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:28])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: S=C=Nc1ccccc1
Reactant: CC(=O)NNc1ccc(NCc2ccccc2)cc1
Solvent: CCO
Solvent: O
Product: CC(=O)NNc1ccc(N(Cc2ccccc2)C(=S)Nc2ccccc2)cc1

Procedure:
1-Acetyl-2-(4-benzylaminophenyl)hydrazine (2.80 g, 0.011 mole) and phenylisothiocyanate (1.35 g, 0.01mole) were mixed in ethanol (25 ml) and the resulting mixture was refluxed for 5 minutes. The mixture was chilled in ice and water was added to precipitate the product. The product oiled out of solution, but became crystalline upon standing and scratching. The solid was filtered off and washed with water, then ether. After drying the product was a pale yellow crystalline powder. Yield 3.0 g (77%), m.p. 114°-117° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](Cl)(=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:12]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)(=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Reactant: O=C(Cl)C=Cc1ccccc1
Product: O=C(C=Cc1ccccc1)NC1=NC(=O)C2=CC=NC2=N1

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and cinnamoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9]>C(Cl)Cl>[CH3:7][S:8]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:10])=[O:9]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N1CCOCC1
Temperature: -20 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
To a solution of morpholine (2.00 mL, 22.96 mmol) in DCM (40 mL) was added TEA (3.20 mL, 22.96 mmol) at about −20° C., then methanesulfonyl chloride (2.68 mL, 34.4 mmol) was added dropwise at about −20° C. The reaction mixture was stirred at about −20° C. for about 2 h, then warmed to rt. The mixture was partitioned with saturated aqueous NH4Cl (100 mL) and DCM (3×50 mL). The combined organic layers were concentrated and purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc/heptane to give 4-(methylsulfonyl)morpholine (3.95 g, 100%) as a white solid: 1H NMR (DMSO-d6) δ 3.70-3.60 (m, 4H), 3.12-3.04 (m, 4H), 2.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27]>>[Cl:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCc1cccs1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cc2Cl)cn1
Yield: 72.9 %

Procedure:
Using a method similar to Example 405, using 5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140 mmol) and 2-(2-thienyl)ethylamine (0.018 g, 0.140 mmol) gives the title compound (0.0396 g, 72.8%): TOF MS ES+ 388.1 (M+H)+. HRMS calcd for C19H19N2O2ClS 388.0887 (M+H)+, found 388.0866, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.6 min, 100% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(#N)C>[C:10]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: CC#N
Product: CC(=O)Nc1ccc(Cl)c(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension containing 80 g (0.56 mole) of 5-amino-2-chlorophenol, 70 ml (0.74 mole) of acetic anhydride, and 200 ml of acetonitrile was refluxed with stirring for 2 hours. This suspension was cooled to room temperature and the resulting crystalline precipitate was collected by filtration and washed with 200 ml of acetonitrile.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.[B-](F)(F)(F)[CH:26]=[CH2:27].[K+].C(N(CC)CC)C>C(O)CCC>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:9]3[N:10]=[CH:11][C:2]([CH:26]=[CH2:27])=[CH:3][C:4]=3[C:5]3=[N:24][CH:23]=[N:22][N:6]3[C:7]2=[O:21])=[CH:14][CH:15]=1
Reactant: C=C[B-](F)(F)F
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: C=Cc1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (2.00 g, 5.18 mmol), potassium trifluoro(vinyl)borate (1.51 g, 11.3 mmol), butan-1-ol (20 ml), triethylamine (1.05 ml, 7.53 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (0.31 g, 0.38 mmol) were combined and heated at 100° C. for 20 hours. The mixture was cooled, concentrated under vacuum and taken up in dichloromethane (120 mL). It was washed with water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated under vacuum. The residue was triturated with ethyl acetate (15 mL) for 20 hours, filtered, washed with cold ethyl acetate and suction dried to afford 1.09 g (63%) of the title compound as a yellow powder. 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 5.52 (d, J=10.92 Hz, 1H), 5.75 (s, 2H), 5.98 (d, J=17.57 Hz, 1H), 6.75-6.88 (m, 3H), 7.60 (d, J=8.66 Hz, 2H), 8.36 (s, 1H), 8.66 (d, J=2.13 Hz, 1H), 8.79 (d, J=2.26 Hz, 1H). LCMS (MH+, 334.1).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Cl:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.Cl.CCCCCC>C(Cl)Cl>[ClH:16].[N+:23]([C:22]1[C:17]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 0.75 h
Yield: 8.2 %

Procedure:
A mixture of 56.0 g (0.28 mole) of 2-aminobenzophenone and 49.6 g (0.31 mole) of 2-chloro-3-nitropyridine was heated in an oil bath with stirring at 150° C. for 45 minutes. After cooling, an 8.7 g portion of the product was dissolved in 45 ml of methylene chloride, hydrogen chloride gas was added for 15 min and 100 ml of hexane was added. After stirring for 20 min, solid was collected and washed twice with 1:3 mixture of methylene chloride to hexanes. After drying in air, 8.2 g (81.6%) product was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([OH:32])=[O:31].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=4)[C:30]([OH:32])=[O:31])[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(c4cccc(C(=O)O)c4)CC3)cc2)c1

Procedure:
3-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 3-bromo-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C29H32N2O3 (m/e) 456, obsd 457 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:11])=[N:6][C:5]=1[C:12]1[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=1.[H-].[Na+].[CH3:25][S:26]([CH3:28])=O>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:25][S:26][CH3:28])[C:7]([CH3:11])=[N:6][C:5]=1[C:12]1[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=1
Reactant: CS(C)=O
Reactant: COC(=O)c1cc(O)c(C)nc1C1=NC(C)(C(C)C)C(=O)N1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(OCSC)c(C)nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 0 °C

Procedure:
A solution of 2.5 g (8.19 mmol) 5-hydroxy-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-6-methyl-nicotinic acid methyl ester in 25 ml dimethyl sulfoxide is reacted with 0.26 g (8.19 mmol) sodium hydride (80%) and after 10 minutes' stirring, 0.87 g (9.01 mmol) chlorodimethylsulfide is added. It is stirred overnight, then added to 500 ml ice water. The product is extracted with ethyl acetate, the extract is dried over magnesium sulfate, and compressed. The residue is chromatographed over silica gel with ethyl acetate/hexane 1:1.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1Br
Yield: 46 %

Procedure:
2,4-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,4-dichlorobenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 138-141° C., yield 46%.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)=[CH:55][C:54]=1[CH3:66])[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:60]=2)=[CH:55][C:54]=1[CH3:66])[CH3:51]
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1C
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 62.6 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.37 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 65% yield: LCMS (ESI) m/z 430 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:9]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccccc1-c1nc(-c2ccccc2)[nH]c1-c1ccccc1Cl
Reactant: CCOC(=O)CCCCCCCBr
Product: CCOC(=O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2Cl)c1-c1ccccc1Cl
Yield: 77.6 %

Procedure:
4,5-Bis(2-chlorophenyl)-2-phenylimidazole (1.7 g) (J. Org. Chem., 1971, 36, 2262) was reacted with ethyl 8-bromooctanoate in a method similar to Example 9. Column chromatography on silica gel eluted with a dichloro-methane:ethanol gradient gave 4,5-bis(2-chloro-phenyl)-1-(7-ethoxycarbonylheptyl)-2-phenylimidazole (1.94 g, 77.6%) as an oil.
Reaction SMILES: CCN(CC)CC.[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:14]([O-:16])[CH:15]=1)[CH3:9].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:15]1[N:14]=[C:13]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=1[CH2:8][CH3:9].[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:14]([O-:16])[CH:15]=1)[CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Agent: CCc1ccc(NC(=O)C(C)(C)C)[n+]([O-])c1
Solvent: CCN(CC)CC
Product: CCc1ccc(NC(=O)C(C)(C)C)nc1Cl
Yield: 5 %

Procedure:
Et3N (123 mL, 93.6 mmol) was added to a solution of 5-ethyl-2-pivalamidopyridine 1-oxide (16.0 g, 72.0 mmol) in POCl3 (250 mL) and the reaction mixture was heated at reflux for 3 days. Excess POCl3 was distilled off and the residue was poured into water. The mixture was neutralized with aqueous NaOH to pH 9. The aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to afford N-(6-chloro-5-ethylpyridin-2-yl)pivalamide (900 mg, 5%) and unreacted 5-ethyl-2-pivalamidopyridine 1-oxide (4.8 g). 1H NMR (CDCl3, 300 MHz) δ 8.12 (d, J=8.7, 1H), 7.94 (br s, 1H), 7.56 (d, J=8.7, 1H), 2.70 (q, J=7.5, 2H), 1.30 (s, 9H), 1.23 (t, J=7.5, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:40]=[CH:39][C:28]2[N:29]([CH2:37][CH3:38])[C:30](=[O:36])[CH2:31][CH2:32][C:33]([CH3:35])([CH3:34])[C:27]=2[CH:26]=1.Cl>O1CCOCC1.COCCO>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:24][C:25]2[CH:40]=[CH:39][C:28]3[N:29]([CH2:37][CH3:38])[C:30](=[O:36])[CH2:31][CH2:32][C:33]([CH3:34])([CH3:35])[C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)ccc21
Yield: 92.3 %

Procedure:
Combined (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (113 mg, 0.3185 mmol), 7-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (74 mg, 0.3185 mmol), 4 N HCl in dioxane (100 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 3 hours. Evaporated off solvent and purified with normal phase chromatography to yield a yellow solid, 7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (162 mg, 92%). LCMS: m/z=551.00 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.21 (d, 1H, J=9.4 Hz), 8.04 (s, 1H), 7.69 (d, 1H, J=9.4 Hz), 7.60 (s, 1H), 7.34 (s, 1H), 7.19 (d, 1H, J=8.1 Hz), 6.92 (s, 1H), 6.56 (s, 1H), 6.49 (d, 1H, J=8.6 Hz), 3.94 (s, 3H), 3.90 (m, 4H), 3.82 (m, 2H), 3.16 (m, 4H), 2.32 (m, 2H), 2.06 (m, 2H), 1.33 (m, 9H).
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][C@@H:6]([C:11]([OH:13])=[O:12])[C:7]([SH:10])([CH3:9])[CH3:8].[CH3:14][N:15]([CH3:22])[C:16](=[O:21])[CH2:17][C:18]([CH3:20])=O>C(O)C>[CH3:8][C:7]1([CH3:9])[S:10][C:18]([CH2:17][C:16]([N:15]([CH3:22])[CH3:14])=[O:21])([CH3:20])[NH:5][CH:6]1[C:11]([OH:13])=[O:12]
Reactant: CC(=O)CC(=O)N(C)C
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN(C)C(=O)CC1(C)NC(C(=O)O)C(C)(C)S1
Yield: 76.1 %

Procedure:
In 40 ml of a mixture of chloroform and ethyl alcohol (1:1) were suspended 1.49 g (10 mmoles) of D-penicillamine and 1.89 g (15 mmoles) of N,N-dimethylacetoacetamide. The suspension was heated at 80°-90° C. with stirring under a stream of argon to concentrate to a half its volume. 20 ml of a mixture of chloroform and ethyl alcohol (1:1) was added. The concentration and addition of the solvent were repeated until the reaction mixture turned completely clear and a small amount of insolubles was removed by filtration. The solvent was distilled off, and the resulting residue was treated according to the same procedure as in Example 1 to give 1.98 g of 4-carboxy-2,5,5-trimethylthiazolidine-2-N,N-dimethylacetamide as colorless prisms.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[O:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][C:24]=1[C:21]1[O:22][CH:23]=[C:19]([CH2:18][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)=[CH:4][CH:3]=2)[N:20]=1
Reactant: ClCc1coc(C2=Cc3ccccc3CC2)n1
Reactant: Oc1ccc(CCCCn2cncn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C1=C(c2nc(COc3ccc(CCCCn4cncn4)cc3)co2)CCc2ccccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 49 %

Procedure:
A mixture of 1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole (450 mg), 4-chloromethyl-2-(3,4-dihydro-2-naphthyl) oxazole (565 mg), potassium carbonate (290 mg) and N,N-dimethylformamide (10 ml) was stirred for 6 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. A crystalline product obtained from the fraction eluted with chloroform-methanol (50:1, v/v) was recrystallized from ethyl acetate-hexane to give 1-[4-[4-[2-(3,4-dihydro-2-naphthyl)-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole as colorless prisms, mp 96-97° C. The yield was 49%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[CH:35]=[CH:34][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[N:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:40][C:39]2[CH:41]=[CH:42][C:36]([N:33]3[CH:34]=[CH:35][C:31]([CH3:30])=[N:32]3)=[CH:37][CH:38]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Cc1ccn(-c2ccc(N)cc2)n1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: Cc1ccn(-c2ccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)cc2)n1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(3-methyl-1H-pyrazol-1-yl)aniline in step 1. MS: 407.5 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl.O>[Br:23][C:6]1[C:5]([OH:11])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=[C:2]([Br:1])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC(C)(C)c1cc(Br)c(C(=O)O)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)c(C(=O)O)c(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
step 3—To a solution of 120 (1.0 eq, 2.27 mmol, 621 mg) in DCM (10 mL) at RT was added in three portions NBS (2.0 eq, 4.55, 809 mg). The mixture was stirred RT for 30 min. The reaction was diluted with water, the organic layer was separated, dried (MgSO4) and concentrated to afford 767 mg of 2,6-dibromo-4-tert-butyl-3-hydroxybenzoic acid (122) as a light brownish solid.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[N:2]1.[CH:12]1([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22](Cl)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]2)[CH2:14][CH2:13]1>C(#N)C.N1C=CC=CC=1>[CH:12]1([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22]([N:8]4[CH2:9][CH2:10][CH2:11][CH:6]([N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)[CH2:7]4)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cn(C2CCCNC2)nn1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CCCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 100 °C

Procedure:
3-(1,2,3-triazol-1-yl)piperidine (150 mg, 0.96 mmol) was added to a solution of ethyl 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (150 mg, 0.48 mmol) in a mixture of acetonitrile (10 ml) and pyridine (3 ml). The reaction mixture was heated at 100° C. for 6 hrs and then concentrated to dryness. The residue was diluted with water and thus solid separated was filtered, washed thoroughly with water and dried. Yield 90 mg, m.p. 205°-206° C.; 1H NMR (CDCl3) δ: 8.58 (s, 1H), 8.15 (d, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 4.90 (m, 2H), 4.40 (m, 3H), 3.45 (m, 3H), 1.75-2.50 (m, 4H), 1.40 (t, 3H), 0.95-1.35 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[CH:13]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH3:9][N:10]([CH3:14])[CH2:11][C:12]#[C:13][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CC#Cc1cncc(N)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 54.3 %

Procedure:
To a degassed solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol) and N,N-dimethylprop-2-yn-1-amine (1.57 mL, 14.6 mmol) in TEA (26 mL) were added bis(triphenylphosphine)palladium(II)chloride (0.203 g, 0.29 mmol) and copper iodide (0.110 g, 0.58 mmol). The reaction mixture was allowed to stir under an atmosphere of argon at 80° C. for 14 h. The reaction mixture was allowed to cool to rt and then filtered through Celite. The filter pad was washed with EtOAc and the filtrate was concentrated. The residue was purified by column chromatography to give 5-[3-(dimethylamino)prop-1-yn-1-yl]pyridin-3-amine (0.55 g, 54%).