Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.S(C1C=CC(C)=CC=1)(O[CH2:14][C@@H:15]1[O:17][CH2:16]1)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[N:3]([CH2:14][C@@H:15]2[CH2:16][O:17]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn(C[C@@H]2CO2)c(Cl)n1
Yield: 105.1 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (1 g, 6.78 mmol) and (R)-(−)-glycidyl tosylate (1.7 g, 7.45 mmol) were dissolved in tetrahydrofuran (THF) (10 ml), sodium hydrogencarbonate (600 mg, 7.14 mmol) was added to the solution, and the resulting mixture was stirred under reflux for 11 hours. The reaction mixture was concentrated under reduced pressure, water was added to the solution, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated saline solution in this order, dried over sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to afford (R)-2-chloro-4-nitro-1-(oxiran-2-ylmethyl)imidazole (1.45 g, yield 57%) as a light yellow oil.
Reaction SMILES: CS([O:5][CH:6]1CN(C(C2OC(C3C=CC=CC=3)=NN=2)=O)C1)(=O)=O.C[C:24]1[CH:31]=[C:30]([O:32][CH:33]2[CH2:36][N:35]([C:37]([C:39]3[O:40][C:41]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[N:42][N:43]=3)=[O:38])[CH2:34]2)[CH:29]=[CH:28][C:25]=1[CH:26]=[O:27].[CH3:50]OC1C=CC(C2OC(C(OCC)=O)=NN=2)=CC=1>>[CH3:6][O:5][C:47]1[CH:46]=[CH:45][C:44]([C:41]2[O:40][C:39]([C:37]([N:35]3[CH2:36][CH:33]([O:32][C:30]4[CH:31]=[CH:24][C:25]([CH:26]=[O:27])=[CH:28][C:29]=4[CH3:50])[CH2:34]3)=[O:38])=[N:43][N:42]=2)=[CH:49][CH:48]=1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4C)C3)o2)cc1
Yield: 38 %

Procedure:
Using similar protocols as described in Example 53A, 53B and 53C employing ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate as starting material afforded 0.37 g (38%) of 54A as a solid. 1H NMR (500 MHz, CDCl3): δ 2.32 (s, 3H), 3.89 (s, 3H), 4.36 (d, 1H), 4.72 (dd, 1H), 4.80 (d, 1H), 5.17 (m, 2H), 6.62 (d, 1H), 7.02 (d, 2H), 7.71 (d, 1H), 7.74 (s, 1H), 8.10 (d, 2H), 9.89 (s, 1H), MS (APCI+) m/z 394 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[CH2:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:24][CH2:25][C:26]#[CH:27]>CCCCCCC>[C:28]1([CH2:23][CH2:24][CH2:25][C:26]#[C:27][C:6]2[CH:5]=[C:4]([O:3][C:2]([F:1])([F:21])[F:22])[CH:9]=[CH:8][CH:7]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OC(F)(F)F)cc2)cc1
Solvent: CCCCCCC
Product: FC(F)(F)Oc1cccc(C#CCCCc2ccccc2)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-trifluoromethoxy-phenyl ester and pent-4-ynyl-benzene. Chromatography eluent: heptane; yield (140 mg, 93%); 1H NMR δ (CDCl3): 7.41 (d, J=8.32 Hz, 2H), 7.38-7.28 (m, 2H), 7.27-7.18 (m, 3H), 7.21 (d, J=8.34 Hz, 2H), 2.77 (t, J=7.12 Hz, 2H), 2.45 (t, J=7.13 Hz, 2H), 1.93 (p, J=7.21 Hz, 2H); LCMS m/z: 300.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:24][CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: NC(=O)COc1ccc(C=O)cc1
Product: NC(=O)COc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-(4-formylphenoxy)acetamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 2-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenoxy]acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1)=[O:12].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11](=[O:12])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1.[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH2:11][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH:21]([CH3:22])[CH3:23])[CH:14]=1
Reactant: COc1cc(C)c(C(=O)c2ccc(OC)c(C(C)C)c2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(C)cc(O)cc2C)cc1C(C)C
Product: Cc1cc(O)cc(C)c1Cc1ccc(O)c(C(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49 %
Yield: 31 %

Procedure:
To (2,6-dimethyl-4-methoxyphenyl)-(3-isopropyl-4-methoxyphenyl) methanone (10) (1 g, 3.20 mmol) in 60 ml of methylene chloride at -78° C. was added 32 mL of boron tribromide (1.0M in methylene chloride). The reaction mixture was stirred at -78° C. for 30 minutes, and then for 12 hours at room temperature. The reaction mixture was washed with water (2×125 mL), dried (MgSO4), and evaporated to give crude product (900 mg). Purification using flash column chromatography (silica gel, 90:10 hexane/ethylacetate) gave 3,5-dimethyl-4-(4'-methoxy-3'-isopropylbenzoyl) phenol (13) (300 mg, 31%) and 3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl) phenol (14) (450 mg, 49%).
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[O:8]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:27](=[O:28])[NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNC(=O)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Triethylamine (15 ml, 0.11 mol) was added dropwise under a nitrogen atmosphere to a solution of 4-phenoxyphenol (25.1 g, 0.14 mol) and butyl isocyanate (18 ml, 0.16 mol) in 400 ml of methylene chloride. After the addition, the solution was stirred overnight at room temperature. The solution was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 39.59 g of a tan solid. Recrystallization from diisopropyl ether gave the title compound as a white crystalline solid (21.01 g, 55%), mp 75°-77° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[C:13][CH:14]([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[OH:15].[H-].[Na+].Br[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26]>CN(C)C=O>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[C:13][CH:14]([O:15][CH2:24][C:25]([OH:27])=[O:26])[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1nc2ncnn2c(N)c1C#CC(O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2ncnn2c(N)c1C#CC(OCC(=O)O)C1CCCC1
Reaction time: 2 h
Yield: 20.5 %

Procedure:
To a stirring solution of Example 35B (20 mg, 0.074 mmol) in 0.5 mL of anhydrous N,N-dimethylformamide was added NaH (60%, 4.0 mg, 0.096 mmol). The resulting mixture was stirred for 20 min before tert-butyl bromoacetate (11 μL, 0.074 mmol) was added, and stirring continued for 2 h. The reaction mixture was then partitioned between ethyl acetate (10 mL) and brine (10 mL), the organic layer was dried over MgSO4, filtered, evaporated to dryness in vacuuo. The residue was treated with 1.0 mL of 4N HCl in 1,4-dioxane for 3 h. Organic solvent was then removed on a rotavap, and the residue was purified using reverse phase HPLC (C-18 column, eluting with a 5-100% CH3CN gradient in 10 mM ammonium acetate(aq.)) to give the title compound (5 mg, 21% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.15 (brs, 2H), 4.79-4.60 (m, 2H), 4.34 (d, J=7.1 Hz, 1H), 2.54 (s, 3H), 2.25-2.15 (m, 1H); 1.81-1.38 (m, 8H). MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([O:1][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:3]([CH3:20])([CH3:19])[CH2:4]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Yield: 70 %

Procedure:
Using 1-hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine (prepared as described by: Kurumada T. et. al., loc. cit.) and pivaloyl chloride in a procedure otherwise similar to the preparation of the compound 101 gives a 70% yield of the compound 107 which is obtained in the form of colourless crystals; melting point: 107-110° C. (hexane).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C:7](=O)C)[CH2:4][O:3]1.C1COCC1.Cl.[NH2:17][OH:18].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH:7]=[N:17][OH:18])[CH2:4][O:3]1
Reactant: CC(=O)[C@@H]1COC(C)(C)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](C=NO)O1
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a solution of (S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanone (10.5 g, 72.8 mmol) in 150 (mL) THF: 60 mL water was added hydroxylamine hydrochloride (5.06 g, 72.8 mmol), and the reaction was stirred for 20 minutes. Na2CO3 (3.78 g, 35.7 mmol) was added and the reaction was stirred overnight. The reaction was extracted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated to afford (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde oxime (10.3 g, 71.0 mmol, 97.4% yield).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH2:2][CH2:3]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(SC)nn12
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CCOCC3)CC3CC3)c(SC)nn12
Reaction time: 1 h
Yield: 55.2 %

Procedure:
After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (100 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde (78 mg) [CAS No. 50675-18-8] and sodium triacetoxyborohydride (87 mg) were added, and the mixture was stirred for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (70 mg) was obtained from the n-hexane:ethyl acetate (7:1) fraction as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:10][C:11](=O)[NH:12][CH:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[N:10]=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccncc2)c(-c2ccc(F)cc2)c[nH]1
Product: Fc1ccc(-c2cnc(Cl)nc2-c2ccncc2)cc1

Procedure:
A mixture of 5-(4-fluorophenyl)-4-(4-pyridyl)-2-(1H)-pyrimidinone (2.41 mmol) and phosphorus oxychloride (3 ml) was heated at reflux for 45 min. It was evaporated to dryness at a bath temperature of >500° C. The flask was cooled in an ice-bath and ice-water was added. If the pH value was found still acidic, then the mixture was neutralized with aqueous 5% ammonium hydroxide. It was extracted with dichloromethane, followed by washing of the organic solution with aqueous sodium chloride, drying and evaporation to yield the title compound as a yellowish foam which was used without further purification.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[OH:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.O>CS(C)=O>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: COc1cc(C(O)C2CC2)ccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C(=O)C2CC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of cyclopropyl(2-methoxypyridin-4-yl)methanol (5.30 g) and triethylamine (41.2 mL) in DMSO (120 mL) was added sulfur trioxide pyridine complex (18.8 g), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (4.42 g) as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: C1(S([C:10]2[N:11]=[N:12][C:13]([C:16]3[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[CH:14][CH:15]=2)(=O)=O)C=CC=CC=1.[OH-:31].[Na+].Cl>O1CCOCC1>[O:31]=[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:12][NH:11]1
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.5 %

Procedure:
A mixture of 3-(3-phenylsulfonylpyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (20.0 g), sodium hydroxide solution (80 ml; containing 7.8 g of sodium hydroxide), and 1,4-dioxane (40 ml) was stirred for 2 hours under reflux. After being cooled to room temperature, the reaction mixture was acidified with 36% hydrochloric acid (15 ml). The precipitate formed was collected, washed with three 25 ml portions of water, and dried to give 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (16.0 g). An analytical sample was prepared by recrystallization from ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.Cl.[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>C(#N)C.O>[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:3]=2)[CH2:22][CH2:21]1
Reactant: NC1CCC(F)(F)CC1
Reactant: Cc1nc(NCc2ccccn2)nc(Cl)c1C
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cc1nc(NCc2ccccn2)nc(NC2CCC(F)(F)CC2)c1C
Yield: 41 %

Procedure:
A solution of 4-chloro-5,6-dimethyl-N-(pyridin-2-ylmethyl)pyrimidin-2-amine (200 mg, 0.8 mmol, Example 29, Step C) and (4,4-difluorocyclohexyl)amine hydrochloride (172 mg, 1 mmol) in acetonitrile (5 mL) was refluxed overnight. The reaction mixture was diluted with water (50 mL) and a formed precipitate was collected by filtration. The crude material was purified by HPLC (column: YMC-PACK ODS-AQ C18, 250 mm×20 mm, 10 μm; gradient: 20-50% acetonitrile in 0.02% trifluoroacetic acid/water over fifteen minutes; 50-100% acetonitrile in 0.02% trifluoroacetic acid/water over five minutes; flow rate: 25 mL/min; temperature: 25° C.) to afford 114 mg, 25% of the titled compound as the trifluoroacetic acid salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.45-1.55 (m, 4H), 1.70-1.82 (m, 2H), 1.88 (s, 3H), 1.90-2.00 (m, 2H), 2.25 (s, 3H), 3.90 (bs, 1H), 4.70 (d, J=5.37 Hz, 2H), 7.38 (t, J=6.25 Hz, 1H), 7.47 (d, J=7.52 Hz, 1H), 7.64 (d, J=7.52 Hz, 1H), 7.90 (t, J=7.52 Hz, 1H), 8.46-8.52 (m, 1H), 8.57 (d, J=4.57 Hz, 1H), 12.78 (bs, 1H); MS (ESI) m/z 348.8 (M+1)+. N4-(4,4-Difluorocyclohexyl)-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine trifluoroacetate was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1) to afford 58 mg (68%) of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40-1.51 (m, 2H), 1.60-1.71 (m, 3H), 1.81 (bs, 4H), 1.90-1.98 (m, 2H), 2.07 (s, 3H), 3.76-3.84 (m, 1H), 4.46 (d, J=5.91 Hz, 2H), 5.84 (d, J=7.25 Hz, 1H), 6.70-6.75 (m, 1H), 7.10-7.22 (m, 1H), 7.24 (d, J=7.79 Hz, 1H), 7.67 (t, J=7.52 Hz, 1H), 8.45 (d, J=4.30 Hz, 1H); MS (ESI) m/z 348.8 (M+1)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[CH:18]=[C:19](CO)[CH:20]=[CH:21][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:24]1(C)C=CC=CC=1.[OH2:31]>[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]2[C:18]([CH:24]=[O:31])=[CH:19][CH:20]=[CH:21][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCCc1nc2ccc(CO)cc2n1Cc1ccccc1Cl
Reactant: Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Product: CCCCc1nc2cccc(C=O)c2n1Cc1ccccc1Cl
Reaction time: 4 h
Yield: 66 %

Procedure:
A suspension of 2-n-butyl-1-(2-chlorophenyl)methyl-6-hydroxymethyl-1H-benzimidazole (1 g, 3.04 mmol, prepared in Example 9(i)), toluene (500 mL) and activated manganese dioxide (4 g) was refluxed with a Dean-Stark water separator for 4 hours. The mixture was filtered hot, concentrated and the crude product was treated with celite in methylene chloride to afford, after concentration, a residue that crystallized. Recrystallization from hexane gave 0.65 g (66%) of 2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-benzimidazole-7-carboxaldehyde; mp 113.5°-115° C.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH:11](OC)OC)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)([O-:18])=[O:17].FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH:10]=[CH:11][N:25]([C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=3)[C:26]2=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(CNCCCC1CCCC1)OC
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1n(CCCC2CCCC2)ccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The product from Example 48 (2.6 g, 12.1 mmol) was dissolved in CH2Cl2 (30 mL) and cooled to 0° C. 4-Nitrophenylisocyanate (1.98 g, 12.1 mmol) was added, and the mixture was allowed to warm to 23° C. The reaction was diluted with additional CH2Cl2 (30 mL) and cooled to 0° C. before a 1:1 solution of trifluoroacetic acid and water was added. The biphasic solution was vigorously stirred for 18 hours at ambient temperature. The layers were separated, and the aqueous layer was extracted with CHCl3. The combined organic layers were washed with saturated NaHCO3, brine, dried (MgSO4), and concentrated to a yellow solid. Mp 105-107° C. Rf=0.4 (2:1 hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.30 (d, 2H), 8.11 (d, 2H), 7.26 (d, 1H), 6.91 (d, 1H), 3.57 (t, 2H), 1.71 (m, 3H), 1.63 (m, 2H), 1.47 (m, 4H), 1.24 (m, 2H), 1.03 (m, 2H); MS (CI) m/z 316 (MH+).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:12]([O-])=O>CO.[Pd]>[NH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[SH:1])[NH:6][C:7](=[O:9])[CH3:8]
Reactant: CC(=O)Nc1ccc(S)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(S)c(N)c1
Yield: 92.9 %

Procedure:
A suspension of 4′-mercapto-3′-nitroacetanilide (3.0 g, 14 mmol) and 10% Pd/C (0.6 g) in MeOH (200 mL) was hydrogenated at 60 psi overnight. The catalyst was removed by filtration, and the filtrate was concentrated to give 3′-amino-4′-mercaptoacetanilide (2.5 g, 13 mmol), which was used in the next reaction immediately.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2)C1
Yield: 99.1 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.21 mmol), a solution of phenylboronic acid (222 mg, 1.82 mmol) in ethanol (1.4 ml), 2N aqueous sodium carbonate solution (5 ml) and tetrakis(triphenylphosphine)palladium(0) (168 mg, 0.146 mmol) in toluene (10 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (390 mg, 99.0%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6](=[CH:9]N(C)C)[CH:7]=O.[C:17]([NH2:23])(=[O:22])[CH2:18][C:19]([NH2:21])=[O:20].CC([O-])(C)C.[K+].Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:9]=[C:18]([C:17]([NH2:23])=[O:22])[C:19]([OH:20])=[N:21][CH:7]=1
Reactant: CN(C)C=C(C=O)Oc1ccc(Cl)c(Cl)c1
Reactant: NC(=O)CC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2ccc(Cl)c(Cl)c2)cnc1O
Temperature: 45 °C
Reaction time: 24 h
Yield: 43.5 %

Procedure:
2-(3,4-Dichlorophenoxy)-3-dimethylaminopropenal (13 g), malonamide (5.6 g), and t-BuOK (6.2 g) were mixed in 50 ml of DMSO and heated at 45° C. for 30 minutes. This mixture was then stirred at room temperature for an additional 24 hours after which it was poured into 200 g of an ice-water mixture and acidified with concentrated HCl. A solid formed which was collected by centrifugation, vacuum dried, and recrystallized from 2-propanol to give 6.5 g of the desired 5-(3,4-dichlorophenoxy)-2-hydroxy-3-pyridinecarboxamide, m.p. 246°-249° C.