Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Yield: 89.5 %

Procedure:
2-Methyl-benzoic acid methyl ester (1.50 g 10 mmol), N-bromosuccinimide (1.96 g, 11 mmol) and 2,2′-azobis(2-methylpropionitrile) (AIBN) (25 mg, 0.15 mmol) were dissolved in chloroform (3 ml). The solution was heated at reflux for 16 h. cooled and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (1–2%) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 2.05 g (89%) of 2-bromomethyl-benzoic acid methyl ester as a solid.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClC(Cl)C.[C:19]1([N:25](COCC[Si](C)(C)C)[S:26]([C:29]2[C:34]([CH:35]=O)=[CH:33][CH:32]=[CH:31][N:30]=2)(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:45][O:46][C:47](=[O:60])[CH2:48][N:49]1[C:57]2[C:52](=[CH:53][C:54]([F:58])=[CH:55][CH:56]=2)[CH:51]=[C:50]1[CH3:59]>>[CH3:45][O:46][C:47](=[O:60])[CH2:48][N:49]1[C:57]2[C:52](=[CH:53][C:54]([F:58])=[CH:55][CH:56]=2)[C:51]([CH2:35][C:34]2[C:29]([S:26](=[O:27])(=[O:28])[NH:25][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:50]1[CH3:59]
Reactant: C[Si](C)(C)CCOCN(c1ccccc1)S(=O)(=O)c1ncccc1C=O
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)Nc2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
A mixture of triethylsilane (3.1 mL), trifluoroacetic acid (0.88 mL) and dichloroethane (12 mL) at −15° C. was treated dropwise with a mixture of 3-formylpyridine-2-sulfonic acid phenyl[2-(trimethylsilanyl)ethoxymethyl]amide (0.55 g), (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (0.29 g) and dichloroethane (18 mL), and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, cyclohexane, ethyl acetate and methanol (9:1:0:0 to 0:0:9:1 by volume) to afford the title compound (0.20 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[CH2:13][C:12](=[O:14])[NH:11][C:6]=2[N:7]=[C:8]([SH:10])[N:9]=1.[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.O>CN(C=O)C>[NH2:3][C:4]1[C:5]2[CH2:13][C:12](=[O:14])[NH:11][C:6]=2[N:7]=[C:8]([S:10][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])[N:9]=1
Reactant: Fc1cccc(CBr)c1F
Reactant: Nc1nc(S)nc2c1CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(SCc2cccc(F)c2F)nc2c1CC(=O)N2
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (125 mg) in dry DMF (5 ml) was added a solution of the product from example 3, step (a) (0.57 g) in DMF (10 ml). The mixture was allowed to stir for 30 mins. To the solution was added 2,3-difluorobenzyl bromide (0.39 ml) and the mixture stirred for 2 hours. Poured into water and the crude product extracted into ethyl acetate. Chromatography on silica eluting with 10% ethyl acetate/dichloromethane afforded the title compound (0.35 g).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17]C3C=NC=CC=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1.Br[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1>>[F:25][C:2]([F:1])([F:26])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Reactant: Fc1cc(F)cc(Br)c1
Product: Cc1ccc(Nc2cc(F)cc(F)c2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide (example 18) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=414.6 (M+H+).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Nc1ccc(S)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(S)cc2)C(=O)OC1=O

Procedure:
A mixture of 2.12 g. of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 1.25 g. of p-aminothiophenol and 75 ml. of methanol is refluxed for 2 hours, cooled and filtered to yield 5-acetyl-4-hydroxy-3-[1-(p-mercaptophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 207° -210° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1([C:28]#[C:29][C:30]#[N:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>>[CH:23]1(/[C:28](/[N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)=[CH:29]/[C:30]#[N:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#CC#CC1CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(/C(=C\C#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred solution of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (17, 7.260 g, 23.01 mmol) and 3-cyclopentylprop-2-ynenitrile (8, 6.140 g, 34.52 mmol, 1.5 equiv) in N,N-Dimethylformamide (DMF, 40.0 mL, 516 mmol) at room temperature was added solid potassium carbonate (K2CO3, 318 mg, 2.30 mmol, 0.1 equiv). The resulting reaction mixture was stirred at room temperature for 30 min. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (80 mL), extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (80 mL) and brine (50 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-30% EtOAc/hexane gradient elution) to give (Z)-3-cyclopentyl-3-(4-(7((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylonitrile (19, 8.256 g, 10.0 g theoretical, 82.6% yield) as a colorless syrup. For 19: 1H NMR (CDCl3, 300 MHz) δ ppm 9.15 (bs, 1H), 8.96 (s, 1H), 8.56 (s, 1H), 7.51 (d, 1H, J=3.5 Hz), 6.93 (d, 1H, J=3.5 Hz), 5.75 (s, 2H), 5.29 (s, 1H), 3.62 (m, 1H), 3.60 (t, 2H, J=8.2 Hz), 2.16 (m, 2H), 1.81 (m, 4H), 1.59 (m, 2H), 0.98 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C23H30N6OSi (MW, 434.61), LCMS (EI) m/e 435.2 (M++H).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)=O.[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([SH:17])([CH3:16])[CH3:15]>CO>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=[C:3]1[CH:1]1[NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([CH3:16])([CH3:15])[S:17]1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1cc2ccccc2o1
Solvent: CO
Product: CC1(C)SC(c2cc3ccccc3o2)N[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
1.46 g (1.39 ml, 10 mmoles) of 2-formylbenzofuran are added to a solution containing 1.5 g (10 mmoles) of D-penicillamine in 150 ml of methanol while stirring. After 48 hours, the solution is evaporated to dryness under reduced pressure. The syrupic residue is dissolved in hot benzene and filtered. After adding petroleum ether, the title compound is precipitated in a crystalline form with a yield of 1.9 g (68.6%), m.p.: 96° C., [α]D20 =+215° (c=0.511, dimethylsulphoxide).
Reaction SMILES: S(=O)(=O)(O)O.[C:6](O)(=O)[C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:13][NH:14][C:15](=[S:18])[NH:16][NH2:17].N>C1(C)C=CC=CC=1.O>[C:7]([C:6]1[S:18][C:15]([NH:14][CH3:13])=[N:16][N:17]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CNC(=S)NN
Reactant: CC(C)(C)C(=O)O
Agent: N
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CNc1nnc(C(C)(C)C)s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Into a four-necked, 1-liter flask equipped with a stirrer, thermometer and a drying tube was charged a solution of 115% polyphosphoric acid (63.98 g) and 96.2% sulfuric acid (21.33 g). A solution of pivalic acid (21.48 g, 0.2107 mole) and toluene (1.82 g) was added followed by 4-methyl-3-thiosemicarbazide (22.1 g, 0.2102 mole). The mixture was stirred with the initial reaction exotherm being controlled with cooling if necessary such that the reaction temperature did not rise above 70° C. The reaction mixture was then maintained with stirring and heating for about 1 hour at 70° C. The reaction flask was then fitted with two dropping funnels. The first funnel contained 256 g of a solution consisting of 192 g of 115% polyphosphoric acid and 64 g of 96.2% sulfuric acid. The second funnel contained a mechanically stirred slurry of 4-methyl-3-thiosemicarbazide (66.3 g, 0.631 mole) in pivalic acid (64.45 g, 0.632 mole) and toluene (5.45 g). The contents of the two dropping funnels were added simultaneously to the stirred reaction mixture (reaction "heel") over a period of 45 minutes, the reaction temperature being maintained at 70° C. The temperature was then increased to 80° C. and held for about 1 hour. The contents of the flask were then poured slowly into a stirred mixture of 28% aqueous ammonia (445 ml), water (210 ml) and toluene (40 ml) contained in a 2-liter beaker. The temperature was allowed to rise to 75°-80° C. and the pH of the aqueous phase was adjusted to 6.1 by the addition of 150 ml of 28% ammonia. The aqueous and organic phases were separated while hot (75° C.). The product, 5-t-butyl-2-methylamino-1,3,4-thiadiazole was isolated as a yellow to orange solid in 98% yield, melting point 78°-80° C., by evaporation of the organic phase to dryness under reduced pressure.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[F:24])[N:14]=[C:13]2[N:25]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:26]=[C:27]([CH3:28])[C:12]=12)=[O:10].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH:41]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)[C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[F:24])[N:14]=[C:13]2[N:25]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[N:26]=[C:27]([CH3:28])[C:12]=12)=[O:10]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)N3C[C@@H](C)NC[C@@H]3C)c12
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(C(=O)N3C[C@@H](C)N(Cc4ccccn4)C[C@@H]3C)c12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a mixture of ((2S,5R)-2,5-Dimethyl-piperazin-1-yl)-[6-(2-fluoro-4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone (200 mg, precursor of example 543) and pyridine-2-carboxaldehyde (46 mg) in dichloroethane (5 mL) containing acetic acid (7.4 μL) was added sodium triacetoxy borohydride (136 mg) at r.t., then the mixture was stirred at 40° C. overnight. Water was added carefully and the mixture was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated to dryness giving ((2S,5R)-2,5-Dimethyl-4-pyridin-2-ylmethyl-piperazin-1-yl)-[6-(2-fluoro-4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone. This was dissolved in THF (7 mL) containing conc. hydrochloric acid (1.5 mL) and stirred r.t. overnight. The precipitate formed was filtered off and dried in air. ((2S,5R)-2,5-Dimethyl-4-pyridin-2-ylmethyl-piperazin-1-yl)-[6-(2-fluoro-4-hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone was obtained as a hydrochloride salt (263 mg, 100%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][CH2:2]1.[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-].Cl[CH2:21]Cl>CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:21][O:11][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH2:2][CH:3]=1)[CH3:19]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: ClCCl
Reactant: OC1CCOc2ccccc21
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CCOC(=O)CCOC1=CCOc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chromanol (1.5 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt for 30 min. The reaction mixture is diluted with heptane, filtered through celite, and the filtrate is evaporated and the residue purified by chromatography on silica gel; elution with EtOAc:dichloromethane:hexane (10:20:70) gives 1.81 g of the product 475. 1H NMR (CDCl3) δ 7.35 (dd, 1H), 7.22 (dt, 1H), 6.90 (t, 1H), 6.84 (d, 1H), 4.56 (m, 1H), 4.36 (dd, 1H), 4.29 (dd, 1H), 4.23 (q, 2H), 4.19 (s, 2H), 2.18 (m, 1H), 2.05 (m, 1H), 1.30 (t, 3H); MS: m/z 236 (M++1).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([OH:24])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6]1.[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([O:36][CH3:37])[CH:27]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:30]([NH:3][CH2:4][C:5]2([OH:24])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7][CH2:6]2)=[O:31])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: NCC1(O)CCN(CCCCCC(=O)c2ccccc2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1(O)CCN(CCCCCC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.5 %

Procedure:
To a solution of 4-aminomethyl-4-hydroxy-1-(6-oxo-6-phenylhexyl)-piperidine dihydrochloride (2.9 g) in dimethylformamide (50 ml) were added triethylamine (3.2 ml), 4-amino-5-chloro-2-methoxybenzoic acid (1.55 g) and 1-hydroxybenzotriazole (1.09 g), which was followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.55 g) under ice cooling, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was added with water and extracted with chloroform. The organic layer was washed successively with 10% aqueous solution of potassium carbonate and brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by a silica gel column chromatography (chloroform:methanol=10:1) to give 2.98 g of 4-amino-5-chloro-N-((4-hydroxy-1-(6-oxo-6-phenylhexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:35]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccnc(N5CCN(C)CC5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine (from Boron Molecular). LCMS calculated for C26H31N6O2 (M+H)+: m/z=459.2. Found 459.1.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[O:5]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:14]2[CH:13]=[C:12]([O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3ccccc3)cc2s1
Temperature: 15 °C
Yield: 65.3 %

Procedure:
20.5 g of ammonium thiocyanate were added to a solution of 25 g of 4-phenoxyaniline in 250 ml of acetic acid, and the mixture was stirred, whilst cooling. While the internal temperature was maintained at 12 to 18° C., 6.95 ml of bromine was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for 2 hours, after which the solvent was removed by evaporation under reduced pressure. 300ml of ethyl acetate and 200 ml of water were added to the residue, and the resulting mixture was neutralized with sodium bicarbonate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, and then dehydrated over anhydrous magnesium sulfate after which it was concentrated by evaporation under reduced pressure. The solid obtained was triturated in diisopropyl ether, and filtered to give 21.34 g of the title compound, melting at 171-172° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[Na].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Cl>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: [O-][n+]1ccccc1S
Reactant: ClCc1c(Cl)cccc1Cl
Agent: [Na]
Solvent: CCO
Product: [O-][n+]1ccccc1SCc1c(Cl)cccc1Cl

Procedure:
A mixture of 37 gms (0.1 mole) of (40% solution) 2-mercaptopyridine N-oxide, sodium salt and 19.5 gms (0.1 mole) 2,6-dichlorobenzylchloride in 200 ml ethanol is warmed to 65° for thirty minutes, cooled and filtered. The filter cake is washed thoroughly with water and finally with 40 ml of acetone. Vacuum drying of the cake yields 25.3 gms (92% theory) of product, 2-(2,6-dichlorophenylmethylthio)pyridine N-oxide. Melting point 240° - 241° C. Structure confirmed by IR.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:14]=1)=O)(C)(C)C.C(OC(N1CC=C[C@H]1C(O)=O)=O)(C)(C)C.ClC(OCC(C)C)=O.C(N(CC)CC)C.C(C1C=C(C=CC=1)C(NO)=N)#N>C1COCC1.CN(C=O)C>[NH:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:24]#[N:25])[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CC=C[C@H]1c1nc(-c2cccc(C#N)c2)no1
Agent: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N#Cc1cccc(C(=N)NO)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2noc([C@@H]3C=CCN3)n2)c1
Temperature: 120 °C

Procedure:
(S)-2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (372 mg, 42%, slightly impure) was prepared according to the procedure in Example 25 from (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester (557.8 mg, 2.62 mmol) with isobutyl chloroformate (0.36 mL, 2.77 mmol) and triethylamine (0.73 mL, 5.2 mmol) in THF (7.5 mL). Then 3-cyano-N-hydroxy-benzamidine (424 mg, 2.6 mmol) and DMF (7 mL) were added and the mixture was heated at 120° C. for 16 h. 1H-NMR (CDCl3) was consistent with the expected product and showing a mixture of rotomers due to the Boc protecting group.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]([F:25])([F:24])[CH2:20][CH2:21][CH2:22][NH2:23]>>[C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([NH:23][CH2:22][CH2:21][CH2:20][C:19]([F:25])([F:24])[F:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCC(F)(F)F
Reactant: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Product: CC(C(=O)NCCCC(F)(F)F)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 82° C. and MS: m/e=336.2 (M+H+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl chloride and 4,4,4-trifluorobutyl-amine.
Reaction SMILES: ClC1C=CN=C(C(Cl)=O)C=1.C(N)C.Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])[CH:16]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[CH2:24]([NH:23][C:21]([C:17]1[CH:16]=[C:15]([O:33][C:30]2[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1)=[O:22])[CH3:25]
Reactant: CCNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: CCN
Agent: O=C(Cl)c1cc(Cl)ccn1
Product: CCNC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1.[CH2:19](Br)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:19][C:20](=[O:21])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1
Reactant: CC(C)=CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCn1c(Br)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
30 g of 8-bromo-3-methyl-7-(3-methylbut-2-enyl)-3,7-dihydropurine-2,6-dione, 20.6 g of phenacyl bromide and 25.4 g of potassium carbonate are introduced into 400 ml of DMF and heated at an internal temperature of 80° C. for 3 hours. The solution is cooled to about 50° C., and 400 ml of water are slowly added. The mixture is then stirred overnight, and the precipitated solid is filtered off with suction. After washing with water, the pale brown solid is recrystallized from 300 ml of isopropanol.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH:8]=[O:9].C12CC(CC1)CC2[Mg]Br>O1CCCC1>[CH:1]12[CH2:7][CH:4]([CH:3]=[CH:2]1)[CH2:5][CH2:6]2.[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][OH:9]
Reactant: O=CC1CC2C=CC1C2
Agent: Br[Mg]C1CC2CCC1C2
Solvent: C1CCOC1
Product: C1=CC2CCC1C2
Product: OCC1CC2CCC1C2

Procedure:
In this embodiment, a solution of 13 grams (0.1 mol) 5-norbornene-2-carboxaldehyde was slowly dropped into a solution of 0.1 mol of 2-norbornyl magnesium bromide which had been dissolved in tetrahydrofuran (THF) to form a reaction product. The reaction product was then refluxed for about 20 hours, and the THF was evaporated using a rotary evaporator. The reaction product was then dissolved in an excess amount of water to which diethyl ether was added to extract the reaction product. After drying the reaction product with a magnesiumsulfate solution, the 5-norbornene-2-norbornylmethanol was obtained through vacuum distillation.