Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[CH:11]([NH2:13])=[O:12].BrBr.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:11][O:12][CH:9]=1
Reactant: CC(=O)c1ccccc1F
Reactant: NC=O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccccc1-c1cocn1
Temperature: 60 °C
Yield: 21.9 %

Procedure:
1-(2-Fluoro-phenyl)-ethanone (2.24 g, 16.23 mmol) and formamide (3.9 mL 97.4 mmol) were added to a flame-dried flask, stirred, and heated to 60° C. Bromine (832 μL, 16.23 mmol) was added dropwise. Upon completion of the bromine addition, the reaction was stirred for 30 minutes, and then the temperature was increased to 125° C. After 3.5 hour further stirring, the reaction mixture was cooled and diluted with 100 mL water. 1N sodium hydroxide was added to increase the pH to about 10. The aqueous layer was extracted twice with diethylether, the combined ether layers were washed with water, dried with magnesium sulfate and concentrated under vacuum. The crude material obtained was chromatographed on silica gel (ISCO MPLC purification, 40 minutes, 0-50% ethyl acetate gradient, Biotage flash 40 m column) to provide 580 mg (22%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 8.22 (d, 1H, J=9.9 Hz), 8.0 (m, 1H), 7.3 (m, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][SH:9].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([N+]([O-])=O)=[C:21]([CH3:28])[N:20]=1)=[O:18].C(O)(=O)C>CN(C)C=O>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([C:4]([F:13])([F:14])[F:3])[CH:6]=2)=[C:21]([CH3:28])[N:20]=1)=[O:18]
Reactant: FC(F)(F)c1cccc(CS)c1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCc2cccc(C(F)(F)F)c2)c(C)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To the stirred suspension of 1.08 g of sodium hydride in 25 ml of dimethylformamide the solution of 9.0 g of m-trifluoromethylbenzylmercaptan in 50 ml of dimethylformamide is added during 3 minutes and the mixture stirred for 10 minutes. It is combined with 7.75 g of 6-methyl-5-nitropyridine-2-carboxylic acid methyl ester and the whole stirred on the steam bath for 30 minutes and allowed to stand overnight at room temperature. 2 ml of acetic acid are added and the solution is mixed with ice water to produce a dense, grainy precipitate. It is filtered off and recrystallized from isopropanol-diethyl ether, to yield the 6-methyl-5-(m-trifluoromethylbenzylmercapto)-pyridine-2-carboxylic acid methyl ester melting at 91°-93°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)C(O)=O.BrC1C=NC=[C:16](C=1)[C:17]([NH2:19])=[O:18].NC1C=NC=C(Br)C=1.C(OC(=O)C)(=O)C>>[C:17]([NH:19][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:10]=1)(=[O:18])[CH3:16]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: NC(=O)c1cncc(Br)c1
Agent: Nc1cncc(Br)c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cncc(Br)c1

Procedure:
Other representative compounds include (E)-N-methyl-4-[3-(5-acetamidopyridinyl)]-3-buten-1-amine and (E)-N-methyl-4-[3-(5-carbamoylpyridinyl)]-3-buten-1-amine. These compounds may be produced according to the techniques set forth in C. V. Greco et al., J. Heterocyclic Chem. 7(4):761 (1970). More specifically, the commercially available starting material, 5-bromonicotinic acid is converted to both 5-bromonicotinamide and 3-amino-5-bromopyridine. The 3-amino-5-bromopyridine can be acylated with acetic anhydride to give 3-acetamido-5-bromopyridine. 3-Acetamido-5-bromopyridine may then be reacted with N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine (prepared according to the preceeding techniques) using the Heck reaction described hereinabove and set forth in W. C. Frank et al., J. Org. Chem. 43(15):2947 (1978). The reaction gives (E)-N-methyl-N-(tert-butoxycarbonyl)-4-[3-(5-acetamidopyridinyl)]-3-buten-1-amine. The Heck reaction of 5-bromonicotinic acid with N-methyl-N-(tert-butoxycarbonyl)-3-buten-1-amine gives (E)-N-methyl-N-(tert-butoxycarbonyl)-4-[3-(5-carbamoylpyridinyl)]-3-buten-1-amine. The treatment of either product with aqueous acid effects the removal of the tert-butoxycarbonyl groups from these compounds, giving the 5-acetamido and 5-carbamoyl substituted metanicotinic compounds respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[NH2:21])[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2.[O-]S([O-])(=O)=O.[Na+].[Na+].[O:31]=[C:32]1[CH2:37][S:36][C:35]2[CH:38]=[CH:39][C:40]([CH:42]=O)=[N:41][C:34]=2[NH:33]1.[BH4-].[Na+]>CCO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][N:14]1[CH2:20][C@H:19]3[C@H:16]([CH2:17][C@@H:18]3[NH:21][CH2:42][C:40]3[CH:39]=[CH:38][C:35]4[S:36][CH2:37][C:32](=[O:31])[NH:33][C:34]=4[N:41]=3)[CH2:15]1)=[N:9][C:8]([O:22][CH3:23])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](N)[C@H]4C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3C[C@H]4C[C@H](NCc5ccc6c(n5)NC(=O)CS6)[C@H]4C3)c2n1
Reaction time: 12 h
Yield: 35.4 %

Procedure:
To a solution of (±)-(1S,5R,6S)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-azabicyclo[3.2.0]heptan-6-amine (31 mg, 0.098 mmol) in EtOH:DCM (1 mL, 1:1) were added Na2SO4 (21 mg, 0.15 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (19 mg, 0.097 mmol). After 12 h at 25° C., NaBH4 (6 mg, 0.15 mmol) was added. After an additional 1 hr, the reaction was concentrated and the residue was partitioned between DCM/H2O. The combined organic fractions were dried over MgSO4, concentrated and purified via column chromatography (silica, 0-3% MeOH in DCM (1% NH4OH)) yielding the title compound (17 mg, 35%) as a yellow oil: LC/MS (ES) m/e 495 (M+H)+; 1H NMR (CD3OD, 400 Hz) δ 8.62 (s, 1H), 8.20 (d, J=9.1 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.18 (d, J=9.1 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 4.92 (s, 3H), 3.66-3.7 (m, 2H), 3.50-3.58 (m, 4H), 2.88-3.09 (m, 5H), 2.79-2.88 (m, 1H), 2.6-2.63 (m, 1H), 2.19-2.24 (m, 2H), 1.88-1.94 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH:19]=[O:20])=[C:12]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Li])[CH2:22][CH2:23][CH3:24].CCCCCC.[Cl-].[NH4+]>C1COCC1>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:12]1[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[S:10][C:11]=1[CH:19]([OH:20])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccco2)c(C=O)s1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC(O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Compound 92 (298 mg, 1.01 mmol) was dissolved in THF (10 mL), and a 1.59 mol/L solution of n-butyllithium in n-hexane (5.70 mL, 9.06 mmol) was added thereto in a stream of argon at −78° C., followed by stirring at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to afford the entitled Compound 395 (224 mg, 63%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH:39]1([NH:42][CH2:43][CH2:44][C:45]#[N:46])[CH2:41][CH2:40]1>CN(C=O)C>[C:45]([CH2:44][CH2:43][N:42]([CH:39]1[CH2:41][CH2:40]1)[C:16]1[C:17]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:8][CH:9]=2)[N:15]=1)#[N:46]
Reactant: N#CCCNC1CC1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCC#N)C4CC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). 3-(cyclopropylamino)propanenitrile (49.7 mg, 0.45 mmol) was added and the reaction mixture was stirred at 85° C. overnight. The mixture was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The crude tert-butyl 4-((2-cyanoethyl)(cyclopropyl)amino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5H)-carboxylate (241 mg, 104%) was used as such in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:23]2[CH:24]=[CH:25][NH:26][C:27]=2[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2[nH]cc(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.2 mmol, 1-chloro-3-(1H-indole-4-oxy)propane (0.45 g, 2.2 mmol and potassium carbonate (0.35 g, 2.5 mmol). The product was isolated as a white foam. Yield 220 mg (25%). mp 198°-202° C. FDMS m/e=406 (M+ of free base).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:15]([C:19]1([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[O:24][C:23](=[O:25])[CH:22](Cl)[C:21](=[O:27])[CH2:20]1)[CH2:16][C:17]#[CH:18]>CN(C=O)C>[CH2:15]([C:19]1([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[O:24][C:23](=[O:25])[CH:22]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21](=[O:27])[CH2:20]1)[CH2:16][C:17]#[CH:18]
Reactant: Sc1ccccc1
Reactant: C#CCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCCC1(C2CCCC2)CC(=O)C(Sc2ccccc2)C(=O)O1
Yield: 35.8 %

Procedure:
A solution of thiophenol (0.23 mL, 2.2 mmol), triethyl amine (0.156 mL, 1.1 mmol), and 6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione (0.30 g, 1.1 mmol; prepared as described in step 1 above) in DMF (3 mL) was stirred at room temperature for 2 hours. The reaction was then concentrated by rotary evaporation, and then chromatographed (40 g silica gel, gradient elution from 40% EtOAc/Hexanes to 75% EtOAc/Hexanes) to yield the title compound (135 mg, 36%). 1H NMR (CDCl3): δ1.31-1.80 (m, 9H); δ1.96-2.00 (m, 2 H); δ2.03-2.11 (3H, m); δ2.85 (2H, dd, J1=17.94, J2=27.03); δ7.13-7.36 (5H, m). Anal. Calcd. for C20H22O3S.0.1 MeOH.0.15 CH2Cl2: C, 67.86; H, 6.38; S, 8.95. Found C, 68.08; H, 6.48; S, 8.52. ESIMS (M+Na+): 365.
Reaction SMILES: C(OCC)(=O)C.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:25]([N:27]=[N+]=[N-])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[OH:52][CH2:53][CH2:54][NH:55][C:56]([C@@H:58]1[CH2:62][CH2:61][CH2:60]N1)=[O:57]>CN(C=O)C>[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:25]([N:27]1[CH2:60][CH2:61][CH2:62][C@H:58]1[C:56]([NH:55][CH2:54][CH2:53][OH:52])=[O:57])=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCCO)[C@@H]1CCCN1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO)OCc1ccccc1

Procedure:
To an ethyl acetate solution of Nα -benzyloxycarbonyl-L-histidinazide (4) prepared from Nα -benzyloxycarbonyl-L-histidine hydrazide (3) (6.07 g) by a known method was added 10 ml of a DMF solution of 2.31 g of (S)-N-(2-hydroxyethyl)-2-pyrrolidinecarboxamide (53) under ice-cooling and they were reacted overnight in a refrigerator. The reaction mixture was concentrated and the residue thus formed was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol-aqueous ammonia (90:10:1), 3.43 g of Nα -benzyloxycarbonyl-L-histidyl-N-(2-hydroxyethyl)-L-prolinamide (54) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]#[N:29])[C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[C:17](C(O)=O)=[N:16]3)=[CH:11][C:10]=2OC)=[CH:4][CH:3]=1.SC[C:32](O)=[O:33]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]3)=[C:13]([O:33][CH3:32])[CH:14]=2)[C:28]#[N:29])=[CH:4][CH:3]=1
Reactant: COc1cc(-n2nc(C(=O)O)c(=O)[nH]c2=O)ccc1C(C#N)c1ccc(Cl)cc1
Reactant: O=C(O)CS
Solvent: O
Product: COc1cc(C(C#N)c2ccc(Cl)cc2)ccc1-n1ncc(=O)[nH]c1=O
Temperature: 175 °C

Procedure:
A mixture of 4.2 parts of 2-[4-[(4-chlorophenyl)cyanomethyl]3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid and 13 parts of 2-mercaptoacetic acid is stirred and heated for 2 hours at 175° C. After cooling, 150 parts of water are added. The aqueous phase is decanted and the remaining oil is stirred in water. The whole is treated with sodium hydrogen carbonate. The product is extracted with a mixture of trichloromethane and methanol (90:10 by volume). The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated in vacuo. The residue is crystallized from 8 parts of acetonitrile. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-3-methoxybenzeneacetonitrile (intermediate 2).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:50][C@@H:51]([CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:50][C@@H:51]([CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH2:52][N:53]2[C:61](=[O:62])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]2=[O:63])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reaction time: 16 h
Yield: 45.5 %

Procedure:
To a solution of 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (0.21 g, 0.87 mmol), PyBrOP (610 mg, 1.3 mmol) and diisopropylethyl amine (0.76 mL, 4.35 mmol) in DCM (20 mL) at 25° C. was added 2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione HCl (380 mg, 0.96 mmol) [prepared according to Preparation 5]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (200 mg, 46%) as a white solid: LC-MS (ES) m/z=505 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(-c2cccc(C)c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(-c2cccc(CBr)c2)c1
Yield: 15.7 %

Procedure:
3-Bromomethyl-3'-methyl[1,1'-biphenyl] was prepared by treating 3,3'-dimethyl[1,1'-biphenyl] (20.0 g, 0.11 mole) with N-bromosuccinimide (18.9 g, 0.11 mole) in the presence of 0.1 g of benzoyl peroxide in 130 ml of carbon tetrachloride. Irradiation of the reaction mixture with white light afforded 3-bromomethyl-3'-methyl[1,1'-biphenyl] (4.5 g). The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH:1]1(/[CH:5]=[N:6]/[S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:4][CH2:3][CH2:2]1.[CH3:13][Mg]Br.CCOCC>O1CCCC1>[CH:1]1([C@H:5]([NH:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH3:13])[CH2:2][CH2:3][CH2:4]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@](=O)/N=C/C1CCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](N[S@@](=O)C(C)(C)C)C1CCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Into a 10-L 4-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (S)—N-[(1E)-cyclobutylmethylidene]-2-methylpropane-2-sulfinamide (200 g, 1.07 mol) in tetrahydrofuran (3000 mL). This was followed by the addition of methylmagnesium bromide in ether (1070 mL, 3.00 equiv) dropwise with stirring at −78° C. over 1 hr. The resulting solution was stirred for 1 h at −70° C., 1 h at −60° C., 1 h at −50° C. and 2 h at −40° C. The reaction was then quenched by the addition of 10 L of saturated aqueous NH4Cl solution. The resulting solution was extracted with 2×3 L of ether. The organic layers were combined, washed with 2×3 L of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was diluted with 250 mL of n-hexane. The resulting solid was collected and washed with 2×100 mL of cold n-hexane to afford (S)—N-[(1R)-1-cyclobutylethyl]-2-methylpropane-2-sulfinamide.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.O>CN(C)C=O>[CH3:9][C:8](=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([CH3:18])=[CH:20][CH:21]=1)[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: Cc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)=Cc1ccc(C)cc1
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a suspension of sodium hydride (a 60% dispersion in liquid paraffin, 15.0 g, 375 mmol) in N,N-dimethylformamide (160 ml) was added at 0° C. a solution of triethyl 2-phosphonopropionate (87.7 g, 368 mmol) in N,N-dimethylformamide (10 ml) and the resulting mixture was stirred at the same temperature for 1 hour. To the reaction solution was added 4-methylbenzaldehyde (43.3 g, 361 mmol) and the resulting mixture was stirred at room temperature for 1 hour. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure to obtain 66.7 g (91% yield) of the oily title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9](O)[N:8]=1.C(=O)([O-])O.[Na+]>O>[Cl:3][C:9]1[N:8]=[C:7]([CH3:6])[CH:12]=[C:11]([CH3:13])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)nc(O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, phosphorus oxychloride (2 ml) was added to 4,6-dimethyl-2-hydroxypyrimidine (400 mg), and the resulting mixture was stirred for 1 hour while heating the mixture to reflux. The reaction solution was cooled to room temperature, and the cooled solution was added in small portions to water. After adding sodium hydrogen carbonate in small portions to the resulting mixture to neutralize it, the mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to obtain 2-chloro-4,6-dimethylpyrimidine (350 mg). (2) In the same manner as in Reference Example 8, 4-iodophenol (223 mg) and 2-chloro-4,6-dimethylpyrimidine (157 mg) were reacted by using sodium hydride to obtain 2-(4-iodophenoxy)-4,6-dimethylpyrimidine (226 mg).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C1(C)C=CC=CC=1.CC(C)=O>[C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:26](=[O:27])[CH2:25][C:24]([CH3:23])=[O:28])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C1CC(=O)O1
Reactant: OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
23.6 g of 3-(4,4-diphenylpiperid-1-yl)-propanol was dissolved in 100 ml of absolute toluene, and 16 ml of a 50% strength solution of diketene in acetone was added with stirring. After standing for several days at room temperature (monitored by thin layer chromatography), the mixture was concentrated, and the residue was dried under high vacuum. The pale yellow, viscous oil which remains was employed without further purification for the next stage.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([CH:20]=[O:21])[CH2:8]2)=[CH:4][CH:3]=1.[C:22]([Si](C)(C)C)([F:25])([F:24])[F:23].Cl>O1CCCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([CH:20]([OH:21])[C:22]([F:25])([F:24])[F:23])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=CC1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 5-(5-bromo-thiophen-2-yl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbaldehyde (9.1 g, 22.4 mmol) prepared in Step 5 and CF3TMS (5.7 mL, 38.1 mmol) in tetrahydrofuran (100.0 mL), was slowly added a solution of TBAF (1.0 M, in tetrahydrofuran 0.5 mL, 0.5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and then a 6N hydrochloric acid solution was added thereto. The reaction mixture was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The extract was washed distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 9.9 g of the titled compound as a yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[NH:18]C(=O)C>>[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:4](=[O:6])[C:3]3[C:2]([NH:18][C:17]=2[CH:16]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=3
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Product: Nc1ccc2c(=O)c3ccc([N+](=O)[O-])cc3[nH]c2c1

Procedure:
The compound S3 (Y═NH) was prepared using 2-chloro-4-nitrobenzoic acid and 3′-aminoacetanilide in the same way as S3 (Y═O). 1H-NMR (DMSO-d6) δ 11.54 (s, 1H), 8.32 (d, J=8.8, 1H), 8.26 (d, J=2.0, 1H), 7.92 (d, J=8.8, 1H), 7.86 (d, J=2.0, 8.4, 1H), 6.60 (dd, J=2.0, 8.8, 1H), 6.43 (d, J=2.0, 1H), 6.36 (bs, 2H). ESI-MS m/z (M+H) calc'd: 256.1. found 256.1.