Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][C@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (S)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 124.1) and pyridin-3-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.97 min, m/z=459.1 [M+H]+, m/z=457.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.37 (m, 2H) 1.53-1.61 (m, 1H) 1.82 (d, J=8.56 Hz, 1H) 2.58 (dd, J=12.23, 9.05 Hz, 1H) 2.69-2.78 (m, 1H) 3.34-3.40 (m, 1H) 3.41-3.51 (m, 1H) 3.55-3.62 (m, 1H) 4.73 (d, J=4.40 Hz, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.52 (dd, J=7.95, 4.77 Hz, 1H) 7.83-7.89 (m, 2H) 8.02 (dt, J=7.82, 1.83 Hz, 1H) 8.10 (d, J=2.20 Hz, 1H) 8.59 (dd, J=4.65, 1.22 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 8.81 (d, J=1.71 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)COB([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])OC1.Br[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C@@:42]([CH3:57])([S:53]([CH3:56])(=[O:55])=[O:54])[C:43]([NH:45][O:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[O:44])=[CH:36][CH:35]=1.O>O1CCOCC1.[Pd+2]>[C:27]([NH:26][CH2:25][C@H:23]1[O:22][C:21](=[O:30])[N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:34]3[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][C@@:42]([CH3:57])([S:53]([CH3:56])(=[O:54])=[O:55])[C:43]([NH:45][O:46][CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][O:48]4)=[O:44])=[CH:38][CH:39]=3)=[C:15]([F:31])[CH:16]=2)[CH2:24]1)(=[O:29])[CH3:28]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OCC(C)(C)CO3)c(F)c2)C(=O)O1
Reactant: C[C@@](CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NC[C@@H]1CN(c2ccc(-c3ccc(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)cc3)c(F)c2)C(=O)O1
Temperature: 90 °C

Procedure:
Palladium (II) EnCat (230 mg, 0.07 mmol) was added to a mixture of potassium carbonate (207 mg, 1.5 mmol), N-({(5S)-3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (234 mg, 0.644 mmol), and 111a (2R)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which was prepared as in Preparation 7 (200 mg, 0.46 mmol) in dioxane:water (6 mL, 5:1) in a 20 mL sealed vial. The vial was heated overnight at 90° C. The reaction was cooled to ambient temperature, filtered through celite and the filtrate was washed with ethyl acetate (30 mL) and methanol (15 mL). The combined organics were concentrated in vacuo and purified by chromatography on silica gel (gradient: 80:20 heptanes:ethyl acetate to 0:100 heptanes:ethyl acetate, followed by ethyl acetate:methanol 90:10) to furnish the title compound as a light brown gum. Yield 50 mg, 18% theoretical yield. LCMS m/z 604.3 (M−1)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17].C1C(=O)N([Br:25])C(=O)C1.O>CN(C=O)C>[Br:25][C:5]1[O:4][C:3]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccoc1C=C1C(=O)Nc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)oc1C=C1C(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of 3-((3-methylfuran-2-yl)methylene)indolin-2-one (330 mg, 1.47 mmol) in DMF (7.0 mL) was added NBS (265 mg, 1.49 mmol) in DMF (1.0 mL) at 0° C. The reaction was stirred at 0° C. for 1 h and added H2O (13 mL). The resulting precipitate was collected by filtration to yield desired 3-((5-bromo-3-methylfuran-2-yl)methylene)indolin-2-one (320 mg). LCMS (ES): m/z 304 [M+1]+.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].O.[CH3:7][C:8]1[C:12]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:16]=[C:15]([CH2:25][CH2:26][CH3:27])[C:14]=2[C:28]#[N:29])=[C:11]([CH3:30])[O:10][N:9]=1>CS(C)=O>[CH3:7][C:8]1[C:12]([C:13]2[N:17]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([CH2:25][CH2:26][CH3:27])[C:14]=2[C:28](=[N:2][OH:3])[NH2:29])=[C:11]([CH3:30])[O:10][N:9]=1
Reactant: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C(N)=NO
Temperature: 65 °C
Yield: 24 %

Procedure:
A neutral 2 M solution of hydroxylamine hydrochloride and NaOH in water (0.5 mL, 1.0 mmol) was added to 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carbonitrile (5.4 mg, 0.017 mmol) in DMSO (0.5 mL) and stirred at 65° C. over night. Crude LCMS on the reaction mixture show 41% product, 38% amide and 21% starting material. Purification using preparative HPLC gave E5 5-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-1-(4-hydroxyphenyl)-3-propyl-1H-pyrazole-4-carboximidamide (1.42 mg, 24%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 356.2 (M+H), 354.21 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.11 m 2H, 6.85 m 2H, 2.77 m 2H, 2.11 s 3H, 1.88 s 3H, 1.75 m 2H, 0.98 t (7.5 Hz) 3H.
Reaction SMILES: [S:1]([O:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Na+].[NH2:23]Cl.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:23][N:14]1[CH:15]=[CH:16][C:12]([O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])=[C:13]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1[nH]ccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: NCl
Agent: O=S([O-])S(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(OS(=O)(=O)c2ccc(C)cc2)ccn1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Solid methyl 3-(tosyloxy)-1H-pyrrole-2-carboxylate (1.33 μm, 4.50 mmole) was added in portions to an ice-cooled suspension of NaH (60% in mineral oil, 234 mg, 5.85 mmole) in dry DMF (15 mL) under a dry N2 atmosphere. Upon completion of the addition, the reaction was removed from the bath and left stirring at RT. After 1 hr, a solution of NH2Cl (59 mL; 0.1 M in Et2O prepared according to J. Chem. Soc. C, 1971, 824; 5.85 mmole) was added and the reaction was left stirring for 1.3 hr. It was then cooled to −5° C. and an aqueous solution of Na2S2O4 (20 mL, 1.0 M) was slowly added over 5 min. Water (60 mL) was added and the bath was removed. After 10 min, this was extracted with EtOAc (2×200 mL) and the organic extracts were washed with brine and dried (Na2SO4). Removal of the solvents followed by flash chromatography on silica gel using step gradient elution (hexane:EtOAc from 100:0 to 70:30) afforded the title compound (1.22 gm, 88% yield) as a solid. 1H NMR (CDCl3): 2.39 (s, 2H), 3.62 (s, 3H), 5.44 (s, 2H), 5.76 (m, 1H), 6.73 (m, 1H), 7.26 (m, 2H), 7.66 (m, 2H); MS: 311 (M+H)+; HPLC Ret Time: 1.28 min (YMC Xterra S7 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:11]2[N:10]=[N:9][C:8]([C:6](=[O:7])[NH:5][CH2:4][CH2:3][CH:2]([CH3:15])[CH3:1])=[CH:13][CH:12]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazine-1-carboxylic acid t-butyl ester, the title compound was obtained as a white solid (83% yield). 1H NMR (500 MHz, CDCl3) δ 8.03, 7.86, 6.97, 3.75, 3.56-3.63, 3.49, 1.65-1.76, 1.52, 0.94. MS (ES+) m/z 378 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:35][N:36]([CH3:56])[CH2:37][CH2:38][O:39][CH:40]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:45](=[O:46])[C:44]2[CH:43]=[CH:42][C:41]([CH:40]([O:39][CH2:38][CH2:37][N:36]([CH3:35])[CH3:56])[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:49][CH:48]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CCOC(c1ccccc1)c1ccc(C(=O)Cl)cc1
Reactant: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Reaction time: 16 h
Yield: 47.2 %

Procedure:
Under a nitrogen atmosphere, 4-(2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butan-1-amine (122 mg, 0.33 mmol) was dissolved in dichloromethane and triethylamine (0.093 mL, 0.67 mmol). The solution was cooled in an ice-water bath and 4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzoyl chloride (106 mg, 0.33 mmol) was dissolved/slurried in dichloromethane and added dropwise. The ice bath was removed and the reaction was stirred for an additional 16 hours. The reaction was quenched with 10% aqueous sodium carbonate. The phases were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed with water followed by brine, dried (Na2SO4), decanted and evaporated to yield a yellow oil. Purification by flash column chromatography (silica gel, 92:8 dichloromethane/methanol gradient to 95:5 dichloromethane/methanol) provided 101 mg of N-[4-(2-butyl-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-4-[[2-(dimethylamino)ethoxy](phenyl)methyl]benzamide as a pale yellow solid. The product was determined to be 97+% pure by HPLC.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Nc1ccccn1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccccn3)ncc12
Temperature: 110 °C
Yield: 30 %

Procedure:
A mixture of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (370 mg, 1 mmol, prepared as in Example 6 of WO 01/707041 which is incorporated here by reference) and 2-aminopyridine(140 mg, 1.5 mmol) in toluene (5 mL) was heated at 110° C. for 18 hours then cooled to room temperature. The solid formed was collected by filtration and washed with toluene, then acetone, and dried in vacuo to give 6-bromo-8-cyclopentyl-5-methyl-2-(pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a beige solid (22 mg, 30%). mp 267–268° C. Anal. Calc'd. for C18H18BrN5O.0.33H2O: C, 53.22; H, 4.63; N, 17.24. Found: C, 52.88; H, 4.38; N, 17.04.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:31]2[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[CH2:35][CH2:36]2)=[CH:42][CH:41]=1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cc(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
113 mg (69%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (78 mg, 0.272 mmol), DIPEA (0.071 mL, 0.408 mmol) and NaBH(OAc)3 (173 mg, 0.816 mmol).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6]1(=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>O.C(O)C>[C:6]1(=[N:2][OH:3])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: O=C1CCc2ccccc21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=C1CCc2ccccc21
Temperature: 25 °C

Procedure:
In a 12 l four-necked flask fitted with a mechanical stirrer, a reflux condenser and a thermometer was placed 3.6 l of deionized water. Hydroxylamine hydrochloride was added. A clear, colorless solution formed (pH 2.5) to which was added 475 ml of 50% sodium hydroxide which had been diluted to 2.4 l with deionized water (pH 6.2). 1-Indanone was dissolved in 2.4 l of 3A anhydrous ethanol and added to the flask. The slightly turbid solution was heated at reflux for 15 minutes. A white solid started to precipitate at 39° C. The mixture was cooled to room temperature and then in an ice-water bath. The product was filtered off and washed with three 2 l portions of chilled water. The product was dried in a vacuum oven at 46° C. A white fluffy solid was obtained.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33]Br)=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([NH:13][C:14]([C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[C:17]([Br:35])[CH:16]=1)=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCN2CCOCC2)c(-c2cccc(C(F)(F)F)c2)c1
Yield: 100.3 %

Procedure:
To a solution of N-dodecyl-3-bromo-4-(2-bromoethoxy)-5-(m-trifluoromethylphenyl)-benzamide (0.294 g, 0.46 mmol, 1 eq) in CH3CN (4 mL) was added morpholine (0.50 mL, 0.57 mmol 1.24 eq) and K2CO3 (0.509 g, 3.68 mmol, 8 eq). The reaction was heated at reflux overnight. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (50% EtOAc:hexane) to afford the title compound (0.296 g, 100%) as a colorless oil. 1H NMR (DMSO-d6) δ 8.53 (bt, 1H); 8.11 (d, 1H); 7.88-7.83 (m, 3H); 7.78 (d, 1H); 7.72 (dd, 1H); 3.63 (dd, 2H); 3.40 (dd, 4H); 3.21 (dd, 2H); 2.38 (dd, 2H); 2.15 (dd, 4H); 1.48 (dd, 2H); 1.22 (m, 18H); 0.82 (t, 3H); IR (KBr) 3400, 2900, 2800, 1630, 1540, 1450, 1330, 1310, 1170, 1120, 700 cm−1; mass spectrum [(+)APCI], m/z 641/643 (M+H)+; Anal. Calcd. for C31H34BrF3N2O4: C, 59.90; H, 6.91; N, 4.37, Found: C, 58.58; H, 7.01; N, 4.18.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:13]#[N:14].C1(=O)C=CC(=O)C=C1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:18][C:17]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[N:9]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=Cc1ccccn1
Agent: O=C1C=CC(=O)C=C1
Solvent: CCO
Product: N#Cc1ccc2[nH]c(-c3ccccn3)nc2c1
Yield: 79.8 %

Procedure:
A mixture comprising 2-pyridinecarboxaldehyde (212 mg, 1.98 mmol, 1 eq), 3,4-diaminobenzonitrile (263 mg, 1.98 mmol, 1 eq) and ethanol (20 mL) was stirred at ambient temperature under nitrogen for 5 to 10 minutes and then 1,4-benzoquinone (233 mg, 2.16 mmol, 1.2 eq) was added. The mixture was heated at reflux for 3 hours and then concentrated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, dried (MgSO4), filtered and concentrating to dryness to provide 2-pyridin-2-yl-1H-benzimidazole-5-carbonitrile (348 mg, 1.58 mmol) as an off white solid; ESI LC/MS: 261.9=(MH+ +CH3CN); 1H-NMR (300 Mhz, DMSO-d6): 7.65-7.755 (m, 2H), 7.769 (d, 1H), 8.060 (t, 1H), 8.163 (s, 1H), 8.395 (d, 1H), 8.772 (d, 1H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].CC1C=CN=C(N)C=1C.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)=[O:26]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: c1ccc2c(c1)NCc1c(-c3noc(C4CC4)n3)ncn1-2
Agent: Cc1ccnc(N)c1C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1Cl)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2ccccc21
Reaction time: 1.5 h

Procedure:
A slurry consisting of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXlII, EXAMPLE 88, 0.492 g), 2-chlorobenzoyl chloride (0.268 ml), dimethyl-aminopyridine (0.0538 g), diisopropylethylamine (0.368 g), and THF (9 ml) is stirred at 20°-25° for 1.5 hr. The mixture is then partitioned between ethyl acetate, aqueous sodium bicarbonate, and saline. The product is poorly soluble in both the organic and aqueous phases, filtration of the extraction solvents gives additional material. The crude product is then triturated with ethyl ether and dried to give the title compound, mp 254°-256°; MS (m/z) at 417, 419; IR (mineral oil) 1659, 1576, 1508, 765 and 1394; NMR (CDCl3) 8.16 δ.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>O>[CH2:9]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCBr
Reactant: Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCNc1ccc(C)cc1

Procedure:
A stirred mixture of p-toluidine (1100 parts) and nonyl bromide (478 parts) was heated on a steam bath for 20 hours, cooled and diluted with water (200 parts). The mixture was then made alkaline with caustic soda and after separation of the aqueous phase the residual oil was distilled under reduced pressure to obtain N-nonyl-p-toluidine (452 parts) as a pale yellow oil boiling at 136°-140° C. at 0.8 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:13]1[CH2:12][C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=4)=[O:35])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[C:14]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: Cc1ccc(N=C=O)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C)cc4)cc3)cc2C1=O

Procedure:
The compound of example 23 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 4-methyl phenyl isocyanate. The compound of example 23 was used directly without isolation for the preparation of compound of example 24.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[S:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1.C(#N)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(OCC)C>[CH3:21][O:20][C:18]1[N:17]=[C:16]([O:22][CH3:23])[N:15]=[C:14]([NH:13][C:11](=[S:12])[NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[N:19]=1
Reactant: O=S(=O)(N=C=S)c1ccccc1
Reactant: COc1nc(N)nc(OC)n1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOCC
Solvent: CC#N
Product: COc1nc(NC(=S)NS(=O)(=O)c2ccccc2)nc(OC)n1

Procedure:
A mixture containing 20 g of benzenesulfonyl isothiocyanate, 15.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine, 250 ml of acetonitrile and a catalytic amount of dibutyltin dilaurate was stirred for 24 hours. After filtration to remove unreacted triazine, the evaporation of the acetonitrile yielded a gummy residue. Trituration of this material with ethyl ether resulted in the precipitation of the desired compound, which was isolated by filtration and melted at 148°-150° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([N+]([O-])=O)[CH:10]=[CH:9][N:8]=1.CCOCC>C(OC(=O)C)(=O)C>[C:1]([O:4][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:6])[C:12]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: Cc1nccc([N+](=O)[O-])c1C
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)Oc1ccnc(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
Anhydrous potassium acetate (49 g, 0.5 mol) was added to a solution of 2,3-dimethyl-4-nitropyridine (45.6 g, 0.3 mol) prepared in Step 2 in 300 ml of acetic anhydride and then refluxed under stirring for 16 hours. The reaction mixture was cooled to room temperature and then 400 ml of anhydrous ether was added thereto. The reaction mixture was stirred for 1 hour, filtered with Celite, and then concentrated under reduced pressure to give 4-acetoxy-2,3-dimethylpyridine (45 g, 91%). The resulting residue was added to 250 ml of water, refluxed under stirring for 4 hours, and then left overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give 32.6 g of 2,3-dimethyl-4-hydroxypyridine as a liquid form. The liquid product was dissolved in 120 ml of concentrated sulfuric acid and heated to 60° C. A mixture of 90% nitric acid (40 ml) and sulfuric acid (30 ml) was slowly added to the reaction mixture for 45 minutes, while maintaining the temperature at 60-65° C. The reaction mixture was heated for 2 hours at 65° C. and then for 30 minutes at 75° C. The reaction mixture was cooled to room temperature and then added to ice water. The resulting solution was brought to pH 5˜6 with ammonium hydroxide to give a pale yellow solid. The resulting solid was filtered, washed with cold water, and then dried at 80˜90° C. to give 34.5 g of the titled compound.