Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:15]([C:11]1[CH:10]=[C:9]([C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][N:12]=1)=[C:16]=[S:17]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1ncccc1-c1ccnc(N)c1
Solvent: ClCCl
Product: COc1ncccc1-c1ccnc(N=C=S)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To 2-methoxy-3,4′-bipyridin-2′-amine (0.53 g, 2.63 mmol) in dichloromethane (20 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.62 g, 2.7 mmol) and the reaction mixture was stirred at 40° C. for 4 hours. The reaction was cooled to room temperature and chromatographed (Biotage: 10-100% ethyl acetate/hexanes) to yield 2′-isothiocyanato-2-methoxy-3,4′-bipyridine (0.46 g, 1.9 mmol, 71.8% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.67 (d, J=2.44 Hz, 1H), 8.26 (dd, J=4.88, 1.53 Hz, 1H), 8.15 (dd, J=8.24, 2.44 Hz, 1H), 7.89 (dd, J=7.32, 1.53 Hz, 1H), 7.48 (d, J=8.24 Hz, 1H), 7.15 (dd, J=7.32, 4.88 Hz, 1H), 3.91 (s, 3H). MS (LC/MS) R.T.=2.87; [M+H]+=244.9.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].O>CN(C)C=O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(=O)O[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1ccc([C@H]2CC[C@H](OC(C)=O)CC2)cc1
Temperature: 50 °C

Procedure:
A solution of 1 g (3.75 mmol) of trans-O-acetyl-4-(4-chloromethylphenyl)-cyclohexanol in 10 ml of dimethylformamide is mixed with 0.52 g (3.75 mmol) of potassium carbonate and 0.27 g (3.75 mmol) of diethylamine. This mixture is heated to 50° C. for 6 hours with stirring, then water is added and the mixture is extracted with methylene chloride. The organic phase is dried, evaporated down in vacuo and the residue remaining is purified by column chromatography (aluminium oxide basic, activity stage III, ICN; petroleum ether/ethyl acetate=15:1). Colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[NH3:10]>>[NH2:10][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8]
Reactant: Cc1noc(C)c1CCl
Reactant: N
Product: Cc1noc(C)c1CN

Procedure:
4-Chloromethyl-3,5-dimethylisoxazole (700 mg, 4.8 mmol) is suspended in concentrated aqueous ammonia at 20–25 degrees C., and vigorously stirred overnight. The reaction mixture is extracted with isopropyl alcohol/chloroform (10/90, 2×). The combined organic phases are concentrated under nitrogen flow. The residue is purified by flash chromatography methanol/methylene chloride (5–20%, 1% triethylamine) to give the title compound, MR (CDCl3, 300 MHz) delta 3.62, 2.37, 2.29, and 1.44.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[NH:36][N:35]=NN=3)[CH:14]=2)=[CH:4][N:3]=1.[C:37](Cl)(=[O:39])[CH3:38]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:23])=[O:24])=[C:15]([C:32]3[O:39][C:37]([CH3:38])=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(C)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
N-{2-Chloro-5-[1-[(4-methylphenyl)sulfonyl]-4-(1H-tetrazol-5-yl)-1H-indazol-6-yl]-3-pyridinyl}methanesulfonamide (50 mg, 0.092 mmol) and acetyl chloride (8.48 μl, 0.119 mmol) were placed in toluene (2 ml) and left to stand for 10 mins before heating under microwave irradiation at 120° C. for 40 mins. Additional acetyl chloride (8.48 μl, 0.119 mmol) was added and the reaction mixture heated for a further 40 mins at 120° C. The solvent was removed and the residue purified by column chromatography, on a silica cartridge (20 g) eluting with 0-100% ethyl acetate/cyclohexane followed by 0-20% methanol to give the title compound as a white solid (16 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH2:24]([O:31][C:32]([N:34]([CH2:36][C:37](O)=[O:38])[CH3:35])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.CC[N+](CCCN(C)C)=C=N.C(N(CC)CC)C>C(Cl)Cl>[CH2:24]([O:31][C:32](=[O:33])[N:34]([CH2:36][C:37](=[O:38])[NH:23][CH2:22][CH:18]1[C:19]2[C:14](=[CH:13][C:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=3)(=[O:11])=[O:10])=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17]1)[CH3:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CC[N+](=C=N)CCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21)C(=O)OCc1ccccc1
Yield: 51.1 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.2 gms, 0.56 mmole), (Benzyloxycarbonyl-methyl-amino)-acetic acid (0.15 gms, 0.67 mmole), 1-hydroxybenzotriazole (0.11 gms, 0.84 mmole), 0.16 gms N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (0.16 gms, 0.84 mmole) and triethylamine (0.50 ml, 3.36 mmole) in 30 mL methylene chloride was stirred at room temperature for 24 hours. The reaction was quenched with 0.2 ml water, and the entire mixture was absorbed on to silica gel and medium pressure chromatography, eluting with ethyl acetate, gave 0.15 gms of ({[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl)-methyl-carbamic acid benzyl ester as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>N1CCCCC1.C(O)C>[O:16]=[C:10]1[C:9](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1[nH]cc2c1CCOC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.6 %

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (117 mg, 0.54 mmol), 4-oxo-2,4,6,7-tetrahydropyrano[3,4-c]pyrrole-1-carbaldehyde (89.3 mg, 0.54 mmol) and piperidine (1 drop) in ethanol (3 mL) was stirred at room temperature for 2 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 54.1 mg (28%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[CH:9]=2)=[CH:4][CH:3]=1.C([NH:31][CH2:32][CH:33]([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])C1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:35]([O:34][CH:33]([O:37][CH2:38][CH3:39])[CH2:32][NH:31][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)=[O:23])[CH3:36]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reactant: CCOC(CNCc1ccccc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1)OCC
Reaction time: 23 h
Yield: 46 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid (prepared according to the methods described by Barth, et al. in U.S. Pat. No. 5,624,941); 740 mg, 2.01 mmol) and N-benzyl-N-(2,2-diethoxyethyl)amine (450 mg, 2.01 mmol) in methylene chloride (6.5 ml) at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (464 mg, 2.42 mmol) and then diisopropylethylamine (0.42 ml, 2.2 mmol), dropwise. After stirring for 23 hours, the reaction mixture was concentrated, in vacuo, and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and concentrated, in vacuo. The crude material (1.05 g) was purified on a Biotage™ Flash 40S column using 0-20% ethyl acetate in hexanes as eluant to afford I-1A-1a as a foam (534 mg, 46%): +ESI MS (M+1) 572.1; 1H NMR (500 MHz, CD2Cl2) 1:1 mixture of rotamers, δ 7.51 (br s, 0.5H), 7.47 (d, J=2.1 Hz, 0.5H), 7.38-7.34 (m, 2H), 7.38-7.23 (m, 9H), 7.18-7.11 (m, 2H), 7.03 (s, 0.5H), 6.95 (s, 0.5H), 5.22 (s, 1H), 4.91 (s, 1H), 4.83-4.79 (m, 1H), 3.56-3.07 (m, 6H), 1.20 (t, J=7.0 Hz, 3H), 1.07 (t, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25]C)[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:35](=O)([O-])[O-].[K+].[K+].IC.Cl>C(#N)C>[OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]([CH3:35])[C:21](=[O:25])[CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Yield: 51.3 %

Procedure:
(S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (28 mg, 0.061 mmol), potassium carbonate (17 mg, 2 equiv), and Iodomethane (404, 10 equiv) were mixed with acetonitrile (2.5 mL) and heated at reflux for 4 h. After being cooled to rt, the mixture was acidified with 5% aq HCl and purified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (14.4 mg. 52%). LC-MS and 1H NMR (CD3OD) were the same as those of product made by Method 1.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(Cl)Cl>[CH2:19]([O:18][C:16]([NH:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a stirred solution of valinol (13.96 g, 0.14 mol) and triethylamine (18.87 mL, 0.14 mol) in 250 mL of dry methylene chloride cooled to 0° C. under a nitrogen atmosphere was added 19.3 mL (0.14 mol) of benzyl chloroformate dropwise over 20 min. After warming to RT overnight, the mixture was diluted with methylene chloride (100 mL) and washed with 1 N HCl (2×), brine and dried with anhydrous magnesium sulfate. The resulting mixture was filtered and evaporated to give 30.70 g (95.6%) of N-benzyloxycarbonyl-valinol as a white solid: Rf =0.27 (silica gel; 1:1 hexane:ethyl acetate). Used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:9]([CH3:21])[O:8][N:7]=1)=O)C.O.[NH2:23][NH2:24]>C(O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:10]3[C:6](=[N:7][O:8][C:9]=3[CH3:21])[C:4](=[O:3])[NH:23][N:24]=2)=[CH:13][CH:14]=1
Reactant: NN
Reactant: CCOC(=O)c1noc(C)c1C(=O)c1ccc(OC)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2n[nH]c(=O)c3noc(C)c23)cc1
Yield: 93.8 %

Procedure:
A solution of 2.47 g of 4-(4-methoxybenzoyl)-5-methylisoxazole-3-carboxylic acid ethyl ester (8.54 mmol) and 0.598 mL of hydrazine monohydrate (12.0 mmol) in 18.4 mL ethanol was stirred at room temperature for 19 hours. The heterogeneous reaction was cooled in an ice bath then filtered off the white solid, washing with cold ethanol then diethyl ether. Dried on under high vacuum to give 2.06 g (92%) of 4-(4-methoxyphenyl)-3-methyl-6h-isoxazolo[3,4-d]pyridazin-7-one.
Reaction SMILES: C([S:5][C:6]1[C:11]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:10][C:9]([CH2:24][CH3:25])=[C:8]([CH3:26])[N:7]=1)(C)(C)C.Cl.N1C=CC=CC=1>O>[CH2:24]([C:9]1[CH:10]=[C:11]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:6](=[S:5])[NH:7][C:8]=1[CH3:26])[CH3:25]
Reactant: CCc1cc(NCc2ccc3ccccc3c2)c(SC(C)(C)C)nc1C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1cc(NCc2ccc3ccccc3c2)c(=S)[nH]c1C
Temperature: 140 °C
Yield: 38.4 %

Procedure:
A mixture of 2-tert-butylthio-5-ethyl-6-methyl-3-(2-napthylmethylamino)pyridine (98 mg, 0.27 mmol) and pyridine hydrochloride (0.45 g, 3.8 mmol) was heated under an atmosphere of nitrogen at 140° C. until evolution of gas ceased (about 45 minutes). Water was added and the resultant mixture was extracted three times with chloroform. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (15 torr). The residue was then subjected to column chromatography on silica gel (eluted with 2% methanol in ethyl acetate). Collection and concentration of appropriate fraction yielded 32 mg (36%) of the pyridinethione. Anal. Calcd for C19H20N2S·0.25 EtOAc: C, 72.68; H, 6.71; N, 8.48. Found: C, 72.41; H, 6.59; N, 8.86.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1
Reactant: NCCCO
Reactant: CCOC(=O)c1ccnc(C=O)c1
Product: CCOC(=O)c1ccnc(CNCCCO)c1

Procedure:
By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and 3-aminopropan-1-ol. Purification by column chromatography (0-5% MeOH in DCM) gave the title compound. 1H NMR (300 MHz, CDCl3), δ ppm: 8.72 (d, 1H), 7.98 (s, 1H), 7.75 (d, 1H), 4.45 (q, 2H), 3.95 (s, 2H), 3.70 (t, 2H), 2.80 (t, 2H), 1.75 (m, 2H), 1.40 (t, 3H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([SH:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CI.[CH2:16](N(CC)CC)C>ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13][CH3:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(S)ccc21
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CI
Product: CSc1ccc2c(c1)CCN2C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
A mixture of 1-acetyl-5-mercaptoindoline (D3) (0.98 g, 5.07 mmol), methyl iodide (0.35 ml, 5.6 mmol) and triethylamine (0.78 ml, 5.6 mmol) in dichloromethane (25 ml) was stirred for 18 h at room temperature. The mixture was evaporated, and the residue was redissolved in dichloromethane and washed with dilute hydrochloric acid. The organic solution was dried and evaporated to give the title compound (0.98 g, 93%).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]=[C:9]=[CH:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[C:14]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8]/[CH:9]=[CH:10]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C=C=C=C(c1ccccc1)c1ccccc1
Reactant: NCCCCc1cccnc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/C=C(c1ccccc1)c1ccccc1)NCCCCc1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.4 %

Procedure:
To a stirred solution of 5,5-diphenyl-2,4-pentadienenoic acid (6.00 g) and triethylamine (3.7 mL) in dry tetrahydrofurane (40 mL) at 0°- C. was added a solution of ethyl chloroformate (2.37 mL) in tetrahydrofurane (15 mL) dropwise such that the reaction temperature was maintained at 0° C. After the addition was complete, the reaction was stirred at 0° C. for 15 minutes, then a solution of 3-pyridinebutanamine (3.78 g) in tetrahydrofurane (20 mL) was added dropwise while keeping the reaction at 0° C. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours before the precipitated triethylamine hydrochloride was removed by filtration. The evaporated filtrate was partitioned between 1N hydrochloric acid solution (80 mL) and ether (80 mL). After the ethereal extract was discarded, the aqueous layer was basified with 4N sodium hydroxide (30 mL) and extracted with ether (4×100 mL). Evaporation of the dried (K2CO3) organic extracts afforded the crude amide which was purified by HPLC (hexane-ethyl acetate-triethylamine; 25:75:2) to provide 3.55 g of (E)-5,5-diphenyl-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide 0.2 molar hydrate as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:35])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[CH:36](=O)[CH:37]([CH3:39])[CH3:38]>>[NH2:1][C:2]1[C:3](=[O:35])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([N:29]3[CH2:34][CH2:33][N:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:31][CH2:30]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(N4CCNCC4)n3)cccc2[nH]c1=O
Reactant: CC(C)C=O
Product: CC(C)CN1CCN(c2nc(Oc3cccc4[nH]c(=O)c(N)nc34)cc(-c3ccc(C(F)(F)F)cc3)n2)CC1

Procedure:
The reaction of 3-amino-5-(2-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (97 mg, 0.2 mmol, Example 135) with isobutyraldehyde (43 mg, 0.6 mmol, Aldrich) under the conditions of Example 36 provided the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 540 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one (26.0 g, 69.9 mmol) and (R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (×3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen. The suspension was cooled to −20° C. (external temperature) and borane dimethyl sulfide complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours. After complete addition the reaction mixture was stirred for one hour before quenching with methanol (25 mL). The reaction was warmed to RT over 20 minutes. The mixture was concentrated under reduced pressure and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for 18 hours. After this time the solid was collected by filtration and washed with water (3×100 mL). The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours. The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product. This process was repeated four more times. The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76%).
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)C.C1(C)C=CC=CC=1>[C:11]1([C:2]2[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CCc1ncccc1Br
Reactant: OB(O)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#CCc1ncccc1-c1ccccc1
Temperature: 110 °C
Yield: 94.4 %

Procedure:
To a stirred solution of (3-bromo-pyridin-2-yl)-acetonitrile (158) (1 g, 5.07 mmol) and phenyl boronic acid (928 mg g, 7.16 mmol) in a solvent mixture of toluene (25 mL) and ethanol (25 mL) was added K2CO3 (2.1 g, 15.23 mmol). The mixture was degassed by argon, X-Phos (484 mg, 1.01 mmol) and Pd(triphenyl phosphine)4 (586 mg g, 0.51 mmol) were added and the mixture was again degassed. The reaction mixture was refluxed (110° C.) for 4 h. Silica thin layer chromatography was performed (30% ethyl acetate in hexane, Rf=0.45). The catalyst was filtered off through a celite bed, washing with ethyl acetate (3×50 mL) was conducted, the mixture was concentrated, the crude product was purified by a CombiFlash column (eluted at 15% ethyl acetate in hexane) to get (3-phenyl-pyridin-2-yl)-acetonitrile (159) (930 mg, 94.34%) as a light yellow solid.
Reaction SMILES: [BrH:1].C1(O[CH2:9][C:10]2[CH:17]=[C:16]([C:18]3([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]3[O:21][C:22](=[O:24])[CH3:23])[OH:19])[CH:15]=[CH:14][C:11]=2[C:12]#[N:13])C=CC=CC=1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:1][CH2:9][C:10]1[CH:17]=[C:16]([C:18]2([O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]2[O:21][C:22](=[O:24])[CH3:23])[OH:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: Br
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(C#N)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(O)(c2ccc(C#N)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A 33% solution of hydrobromic acid in acetic acid (15 mL) is added to a solution of 2-phenyloxymethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile (0.71 g) and acetic anhydride (0.12 mL) in acetic acid (10 ml). The resulting solution is stirred at 55° C. for 6 h and then cooled in an ice-bath. The reaction mixture is neutralized with chilled aqueous potassium carbonate solution, and the resultant mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate/cyclohexane (1:5), and the precipitate is separated by filtration and dried at 50° C. to give the pure product.