Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[NH:19]1[C:23]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)=[N:22][N:21]=[N:20]1.[BH3-]C#N.[Na+].Cl>CN1C(=O)N(C)CC1.CO.C(O)(=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:28][C:27]4[CH:26]=[CH:25][C:24]([C:23]5[NH:19][N:20]=[N:21][N:22]=5)=[CH:31][CH:30]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(-c2nnn[nH]2)cc1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(NCc4ccc(-c5nnn[nH]5)cc4)c23)c1

Procedure:
Under a nitrogen atmosphere, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1 H-pyrazolo[3,4-d]pyrimidine (see Step 1.6), 261 mg (1.5 mmol) of 4-(tetrazol-5-yl)-benzaldehyde and 180 mg of acetic acid are stirred in 39 ml of DMEU/methanol (1:2) at RT for 1 hour. Then 440 mg (7 mmol) of NaCNBH3 are added and the reaction mixture is heated to boiling. After 15 hours a further 440 mg of NaCNBH3 are added and the reaction mixture is again stirred at boiling temperature for 15 hours, then poured into 0.6 liter of a 1 aqueous K2B4O7.4H2O solution and stirred overnight to complete the reaction. The mixture is acidified to pH 3.9 with 2N HCl and the product that precipitates is filtered off and washed with water. Heating in 20 ml of ethanol and filtration yield 4-(3chloro-phenylamino)-3-[4-(tetrazol-5-yl)-benzylamino]-1H-pyrazolo-[3,4-d]pyrimidine; HPLC:tRet(grad20-100/20)=9.8; MS: (M)+=418.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.Cl.[NH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=O.[OH2:34]>>[NH2:17][C:18]1[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[N:8][C:9]2[C:5]([C:6]=1[C:7]([OH:34])=[O:12])=[CH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:11][CH:10]=2
Reactant: O=C1Nc2ccc(C(F)(F)F)cc2C1=O
Reactant: O
Reactant: NCC(=O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: Nc1c(-c2ccc(Oc3ccccc3)cc2)nc2ccc(C(F)(F)F)cc2c1C(=O)O

Procedure:
A solution of 6.45 g of 5-trifluoromethylisatin in water was reacted with 7.91 g of 2-amino-4'-phenoxyacetophenone hydrochloride (example 5) by the procedure described in example 6, giving 7.7 g of the desired compound as a yellow solid, mp 220°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:37]([NH:36][C:34](=[O:35])[C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[S:38])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 99%).
Reaction SMILES: C1(N(C2CCCCC2)C(=O)NC2SC(S(NC[C:20](O)=[O:21])(=O)=O)=CN=2)CCCCC1.[CH:30]1([NH:36][C@H:37]2[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C[O:45][C:46](=[O:60])[C:47]([NH:50][S:51]([C:54]1[S:58][C:57]([NH2:59])=[N:56][CH:55]=1)(=[O:53])=[O:52])([CH3:49])[CH3:48]>>[CH:30]1([N:36]([C@H:37]2[CH2:38][CH2:39][C@H:40]([CH3:43])[CH2:41][CH2:42]2)[C:20](=[O:21])[NH:59][C:57]2[S:58][C:54]([S:51]([NH:50][C:47]([CH3:49])([CH3:48])[C:46]([OH:45])=[O:60])(=[O:53])=[O:52])=[CH:55][N:56]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COC(=O)C(C)(C)NS(=O)(=O)c1cnc(N)s1
Reactant: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Product: CC(C)(NS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and 2-(2-amino-thiazole-5-sulfonylamino)-2-methyl-propionic acid methyl ester to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=3[F:21])=[N:7][C:6]=2[CH:5]=[C:4]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)[CH:3]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[H][H].[Pd]>[F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=3[F:21])=[N:7][C:6]=2[CH:5]=[C:4]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(F)c3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(F)c3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Yield: 67.7 %

Procedure:
Following the general procedure-1 Tert-butyl 4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate (180 mg) obtained from intermediate 31 (600 mg, 1.38 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (456 mg, 1.38 mmol). Tert-butyl 4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.30 mmol) dissolved in MeOH and added Pd/C (71 mg). This mixture was stirred in an auto clave in hydrogen atmosphere at 55 Psi for 12 h. Reaction mixture filtered through celite and washed the cetile with MeOH. Methanol was removed on rotavapour to obtain the titled compound (100 mg) as a brown solid. M.P.: 188-192.4° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.47 (t, J 7.12, 1H), 7.89 (t, J 7.6, 2H), 7.49 (s, 1H), 7.07 (d, J 11.2, 1H), 4.28 (bs, 2H), 3.13 (s, 3H), 2.90-2.72 (m, 3H), 1.95-1.85 (m, 2H), 1.72-1.56 (m, 2H). 1.49 (s, 9H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[C:25]([CH2:26]Br)=[C:24]([F:28])[C:23]([F:29])=[C:22]([F:30])[C:21]=1[F:31]>C(COC)OC.CS(C)=O>[F:19][C:20]1[C:25]([CH2:26][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[C:24]([F:28])[C:23]([F:29])=[C:22]([F:30])[C:21]=1[F:31]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-hydroxyphthalimide (8.15 g, 0.05 mol) was dissolved in a mixture of dry dimethoxyethane (40 ml) and dry dimethyl sulphoxide (10 ml). To this solution was added, in one portion, potassium carbonate (3.46 g, 0.05 mol). An orange suspension resulted. The pentafluorobenzyl bromide (10.8 g, 0.05 mol) in dry dimethoxyethane (10 ml) was added dropwise over 1 h at room temperature. The reaction mixture was stirred at room temperature for 64 h and then quenched by pouring into water (1 l). The resulting slurry was filtered, the crystals washed with water and dried in vacuo to give N-(pentafluorobenzyloxy)phthalimide as white crystals (15.9)g.
Reaction SMILES: [NH:1]([C:3]1N(CC(C)C)[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH:25]=O)=[CH:17]1.[CH3:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH:33]=O>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([CH2:25][N:2]2[C:33]([C:29]3[N:28]([CH3:27])[CH:32]=[CH:31][CH:30]=3)=[C:4]3[C:3]([CH:20]([CH2:19][CH:18]([CH3:25])[CH3:17])[C:7](=[O:13])[N:6]([CH3:14])[C:5]3=[O:15])=[N:1]2)=[CH:17]1
Reactant: Cn1cccc1C=O
Reactant: O=Cc1csc2ccccc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CC(C)CC1C(=O)N(C)C(=O)c2c1nn(Cc1csc3ccccc13)c2-c1cccn1C

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 1-benzothiophene-3-carbaldehyde, followed by 1-methyl-1H-pyrrole-2-carbaldehyde. 447 (M+H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>ClCCl>[C:1]1(/[CH:7]=[CH:7]/[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: C(=C/c1ccccc1)\c1ccccc1
Product: c1ccc(CCc2ccccc2)cc1
Temperature: 0 °C
Yield: 35 %
Yield: 15 %

Procedure:
In this example the substrate was toluene. Helium was fed into the bottom chamber of the reactor at 3.6 mL/min, and toluene and water were added to the carrier gas at a rate of 1.0 mmol/h and 2.0 mmol/h, respectively, by syringe pump. Air was passed through the top chamber of the reactor at the rate of 3.6 mL per min. The reaction was run at 600° C., and a scrubber containing 5.0 mL of dichloromethane cooled to 0° C. was used to collect the reaction products. Nonane and tetradecane were used as g.c. internal standards. At 2.0% conversion, a 50% selectivity to toluene dimers (15% trans-stilbene and 35% bibenzyl) was obtained.
Reaction SMILES: [K].Br[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[P:13](=[O:18])([OH:17])[O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=1.[F-:19].[K+].[Br-].[K+]>O.O1CCOCC1.C(O)COCCO>[F:19][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[P:13](=[O:18])([OH:17])[O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=1
Reactant: [F-]
Reactant: O=P1(O)Oc2ccccc2-c2cc(Br)ccc21
Agent: [Br-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: OCCOCCO
Solvent: C1COCCO1
Product: O=P1(O)Oc2ccccc2-c2cc(F)ccc21
Temperature: 25 °C

Procedure:
Into a 200 ml capacity 3-neck flask equipped with a thermometer, a reflux condenser and a stirrer are fed 50 g of potassium salt of 9,10-dihydro-6-bromo-9-hydroxy-9-phospha-10-oxaphenanthrene-9-oxide (CA-B6-K), 30 g of potassium fluoride and 100 g of diethylene glycol, and the flask is heated with stirring so that the contents boil slowly. Dioxane and water are formed little by little to reduce the temperature of the contents. Thus, while they are taken out, the initial boiling temperature is maintained to carry out the reaction for 8 hours. The reaction mixture is cooled down to room temperature to deposit an excess amount of potassium fluoride and potassium bromide formed by the reaction, which are then filtered off. To the resulting filtrate are added 100 ml of water and thereafter 30 ml of 10 N hydrochloric acid to deposit an acid, which is then filtered, dried and recrystallized from ethanol to give about 20 g of 9,10-dihydro-6-fluoro-9-hydroxy-9-phospha-10-oxaphenanthrene-9-oxide, exhibiting a phosphorus content of 12.3% (theoretical value: 12.4%), an acid value of 224 (theoretical value: 224.3) and a melting point of 240° C. or higher, which will be hereinafter referred to as CA-F6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:12][C:13]#[N:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.OO.C(=O)([O-])[O-:18].[K+].[K+].O>CS(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:12][C:13]([NH2:14])=[O:18])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(CC#N)CC2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(C2(CC(N)=O)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of [1-(4-methoxyphenyl)cyclopropyl]acetonitrile (60.4 mmol) in DMSO (75 mL) is treated with H2O2 (50% w/w) (434 mmol) and potassium carbonate (121 mmol) at zero degrees Celsius. The reaction mixture is stirred at room temperature over the weekend. The reaction mixture is transferred into a separatory funnel using water (100 mL) and CH2Cl2 (200 mL). The mixture is equilibrated and the CH2Cl2 layer is removed. The aqueous layer is extracted two additional times with CH2Cl2 (2×300 mL). The combined CH2Cl2 extracts are washed 5 consecutive times with water (5×200 mL) followed by a brine (500 mL) wash, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure, which affords 2-[1-(4-methoxyphenyl)-cyclopropyl]-acetamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:30]4[CH:29]=[CH:28][N:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccnc(C(F)(F)F)c4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-(trifluoromethyl)pyridine-4-boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.82 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)#[N:2].[C:9](=[S:11])=[S:10].[OH-].[K+].Br[CH2:15][CH:16](Br)[CH2:17][Cl:18]>O.CS(C)=O>[N:4]1([C:3](=[C:9]2[S:11][CH:16]([CH2:17][Cl:18])[CH2:15][S:10]2)[C:1]#[N:2])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: S=C=S
Reactant: ClCC(Br)CBr
Reactant: N#CCn1ccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(=C1SCC(CCl)S1)n1ccnc1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a mixed solution of 0.55 g (0.005 mole) of 1-cyanomethylimidazole, 0.4 g (0.005 mole) of carbon disulfide and 10 ml of dimethyl sulfoxide was added 0.8 g (0.014 mole) of potassium hydroxide power with stirring, and the reaction was carried out at room temperature for 1 hour. Then, 1.4 g (0.006 mole) of 1,2-dibromo-3-chloropropane was added dropwise with stirring, and the resulting solution was subjected to reaction for 2 hours. After completion of the reaction, 20 ml of water was added to the reaction solution, after which the resulting mixture was subjected to extraction with ethyl acetate, and the organic layer was washed with water and dried. The solvent was distilled off and the residue was purified by silica gel chromatography and recrystallized from ethyl acetate-n-hexane to obtain 0.8 g of the desired compound in the form of colorless crystals: melting point 96.2° C., yield 62%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[O:26]1[CH2:27][CH2:28][N:23]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=2)[CH2:24][CH2:25]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCc1cccc2ccccc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1NCc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A mixture of 6-chloro-N-(naphthalen-1-ylmethyl)-3-nitropyridin-2-amine (3.21 g, 10.2 mmol), morpholine (2.66 g, 30.6 mmol) and K2CO3 (2.11 g, 15.3 mmol) in DMF (50 mL) was stirred at 80° C. for 1 h. It was cooled to room temperature and poured into water (300 mL). It was extracted with EA (300 mL×2). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with EtOAc/Pet ether=1/1 to afford the desired product as a yellow solid (3.56 g, 96%); LC/MS: MS (ES+) m/e 365 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.53 (t, J=4.2 Hz, 4H), 3.60 (t, J=4.2 Hz, 4H), 5.19 (d, J=5.7 Hz, 2H), 6.33 (d, J=9.6 Hz, 1H), 7.44-7.61 (m, 4H), 7.85 (d, J=7.5 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 8.12 (d, J=9.6 Hz, 1H), 8.21 (d, J=7.5 Hz, 1H), 9.25 (t, J=5.7 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](C)=[CH2:3].[CH2:7](N(CC)CC)C.[OH:14][C:15]1[C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][C:18]([CH2:25][CH2:26][CH2:27][OH:28])=[CH:17][C:16]=1[N:29]1[N:33]=[C:32]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:31]2=[N:30]1>C(Cl)Cl>[OH:14][C:15]1[C:20]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:19][C:18]([CH2:25][CH2:26][CH2:27][O:28][C:1](=[O:5])[CH:2]=[CH:3][CH3:7])=[CH:17][C:16]=1[N:29]1[N:33]=[C:32]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:31]2=[N:30]1
Reactant: CC(C)(C)c1cc(CCCO)cc(-n2nc3ccc(Cl)cc3n2)c1O
Reactant: CCN(CC)CC
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Product: CC=CC(=O)OCCCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methacrylyl chloride (5.9 ml) and triethylamine (8.5 ml) were added dropwise at -5° C. to a solution of 2-(2'-hydroxy-5'-hydroxypropyl-3'-tert-butylphenyl)-5-chloro-2H-benzotriazole (20 g) in 250 ml of methylene chloride. The reaction mixture was stirred at 0° C. overnight and then washed with 1N hydrochloric acid and water. The methylene chloride solution of the product was dried with sodium sulfate, passed through alumina column and evaporated. The crude yield of the product was 22 g (90%). A polymerization grade sample was obtained by recrystallization from methanol--methylene chloride mixture, m.p. 74.5°-76.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[H][H].[I:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[C:22]=1[CH:29]=O>[Pd].CO>[I:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[C:22]=1[CH:29]=[N:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:5][C:6]=1[CH3:11]
Reactant: Cc1nc(N2CCOCC2)nc(N)c1[N+](=O)[O-]
Reactant: COc1nccc(I)c1C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1nccc(I)c1C=Nc1c(C)nc(N2CCOCC2)nc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To 4-amino-6-methyl-2-morpholin-4-yl-5nitropyrimidine (500 mg, 2.09 mmol) and 10% palladium on carbon (100 mg) were added methanol (10 mL) under nitrogen. The reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) for 22 hours. The solution was filtered through a pad of celite and the filtercake was washed with a small amount of MeOH. The product in MeOH was used for the next step without purification; LCMS (+ESI, M+H+) m/z 210; HPLC: 97% (220 nm). To the crude diamino in MeOH (50 mL) was added a solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (604 mg, 2.30 mmol) in MeOH (10 mL) at 0° C. and stirred for 0.5 hour. The resulting mixture was allowed to warm to ambient temperature and stirred for 6 days in an open system exposed to air. The reaction mixture was cooled to 0° C. to afford a crystalline yellow solid, which was collected by filtration to give the title compound (830 mg, 87%): 1H NMR (400 MHz, DMSO) δ 8.43 (s, 1H), 7.85 and 7.62 (d, J=5.3, 1H), 6.23 (br s, 2H), 3.91 (s, 3H), 3.61 (s, 8H), 2.26 (s, 3H); LCMS (+ESI, M+H+) m/z 455.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([N:21]([CH2:22][CH3:23])[C:16]([CH:13]1[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1)=[O:18])[CH3:20]
Reactant: CCNCC
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.1 %

Procedure:
Under an argon atmosphere, 1-[(benzyloxy)carbonyl]-3-pyrrolidinecarboxylic acid (500 mg) was dissolved in DMF (5 mL), added with N,N-diethylamine (0.293 g), further with EDC (769 mg) and HOBt (542 mg) and stirred at room temperature for 72 hours. The reaction solution was diluted with ethyl acetate, sequentially washed with 1 N hydrochloric acid, a 1 N sodium hydroxide aqueous solution, water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate before distillation of the solvent. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=95:5→0:1) to give the titled compound (556 mg) having the following physical properties.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH:12]([F:14])[F:13].CC(C)([O-])C.[K+].[C:21]([N:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1>[F:13][CH:12]([F:14])[O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:34][CH:31]1[CH2:30][CH2:29][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(OC(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2OC(F)F)CC1
Yield: 28 %

Procedure:
Using similar procedure detailed below for Compound 133, but using 1-chloro-2-(difluoromethoxy)-4-nitrobenzene (prepared according to US patent application no. 2010/090875) (1.12 g, 5.0 mmol), potassium tert-butoxide (1.18 g, 10.0 mmol) and N-Boc-4-hydroxypiperidine (2.0 g, 10.0 mmol) in THF (30 mL) was stirred for a weekend at room temperature to give the product (406 mg, 28% yield) after workup and purification by column chromatography on silica gel using EtOAc/heptane (1:9 to 1:1) as eluent. The product was about 70% purity by LC/MS and 1H NMR.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18](=[O:33])[NH:19][CH2:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37]I>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18](=[O:33])[NH:19][CH:20]([CH3:37])[C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)[CH2:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(NCC1CCC(C(=O)NCC(=O)c2cccc(C(F)(F)F)c2)CC1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)C1CCC(CNC(=O)OCc2ccccc2)CC1)C(=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
This compound was prepared using a procedure similar to the one described by Moriya et. al. (J. Med. Chem. (1986) 29:333–341) for the alkylation of α-(N-acylamino) ketones: {4-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-cyclohexylmethyl}-carbamic acid benzyl ester (From Example 1A; 584 mg, 1.23 mmol) was dissolved in dry DMF and brought to −40° C. using a dry ice/acetonitrile cooling bath. NaH (61 mg, 1.53 mmol, 60% dispersion in oil) was added in one portion and the mixture was stirred for 15 minutes. MeI (192 mg, 1.35 mmol) was added all at once, the cooling bath was removed and the reaction mixture was allowed to come to room temperature. An excess of saturated aqueous NH4Cl solution was added and the resulting mixture extracted with EtOAc. The EtOAc layer was washed sequentially with 3N HCl, NaHCO3 (sat'd), and brine. The solution was dried (Na2SO4) and concentrated under reduced pressure to give {4-[1-Methyl-2-oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-cyclohexylmethyl}-carbamic acid benzyl ester.