Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Cc1c[nH]cn1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cnc(C)c2)cc1
Temperature: 150 °C
Yield: 20 %

Procedure:
A mixture of 4'-fluoroacetophenone (13.8 g. 100 mmol), 4-methylimidazole (8.2 g, 100 ml) and potassium carbonate (20.7 g, 150 mmol) in dry dimethylformamide (190 ml) was heated at 150° C. for 23 hours. Most of the solvent was evaporated at reduced pressure and the residue was partitioned between ethyl acetate and brine. The organic layer was washed (3×) with brine, dried (magnesium sulphate) and evaporated to leave a sticky solid which was purified by flash chromatography (eluting 5% diethylamine in ethylacetate). Recrystallization from ethyl acetate/hexane afforded the title compound (yield 4 g, 20%), m.p. 100° C.
Reaction SMILES: S(Cl)(Cl)=[O:2].[O:5]=[C:6]1[CH:10]([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][N:7]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[OH:2][C:10]1([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(c2ccccc2)C1=O
Solvent: CCO
Product: O=C(O)C1(O)CCN(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (5.8 g) is added dropwise at 0° C. to a solution of 2-oxo-1-phenylpyrrolidine-3-carboxylic acid (5 g) in 5 ml of ethanol, and the mixture is stirred at 80° C. for 4 h.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C@H:11]2[C@@H:16]([CH2:17][OH:18])[C@H:15]3[CH2:19][C@@H:12]2[CH2:13][CH2:14]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl[Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32]>C1COCC1>[NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C@H:11]2[C@@H:16]([CH2:17][O:18][Si:30]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:31][CH3:32])[C@H:15]3[CH2:19][C@@H:12]2[CH2:13][CH2:14]3)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: N#Cc1cnc(N)cc1N[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC[C@H]1[C@@H]2CC[C@@H](C2)[C@H]1Nc1cc(N)ncc1C#N
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Racemic 6-amino-4-(((1S*,2R*,3S*,4R*)-3-(hydroxymethyl)bicyclo[2.2.1]heptan-2-yl)amino)nicotinonitrile (intermediate 57, 420 mg, 1.63 mmol) was dissolved in THF (8 ml), treated with DIPEA (1.99 ml, 11.4 mmol) and chlorotriethylsilane (1.36 ml, 8.13 mmol). The reaction mixture was then stirred at 70° C. for 2 h. The reaction mixture was quenched with water and diluted in EtOAc. The org layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.41 (s, 2H), 6.08 (d, 1H), 5.64 (s, 1H), 3.72 (d, 2H), 3.43 (t, 1H), 2.10-2.20 (m, 2H), 1.85-1.92 (m, 1H), 1.73 (d, 1H), 1.43-1.58 (m, 2H), 1.21 (t, 2H), 1.06 (d, 1H), 0.91 (t, 9H), 0.55-0.64 (m, 6H).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[CH2:13]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15].[CH2:22]=[O:23]>CC(O)C>[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][N:9]=[N:10][C:11]=1[CH:22]=[O:23].[CH2:13]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15]
Reactant: C=O
Reactant: Cc1ccccc1-c1c[nH]nn1
Agent: CC(C)CNCC(C)C
Solvent: CC(C)O
Product: Cc1ccccc1-c1[nH]nnc1C=O
Temperature: 82 °C

Procedure:
Approximately 80.1 gm (0.6 mole) of tolyltriazole, 200 ml 2-propanol, and 78.0 gm (0.6 mole) diisobutylamine were mixed in a 500 ml reactor until a homogeneous phase was formed. 51.0 gm (0.618 mole) of aqueous formaldehyde was slowly added while maintaining a reactor temperature ≤40° C. Thereafter, the reactants were heated at 82±2° C. for 4 hrs., then at 110±2° C. for two additional hours during which isopropanol and water were removed by distillation. The final product (163.5 gm) is a yellowish liquid which solidifies upon standing at ambient temperature (m.p. 49°-51° C.). A final filtration to remove possibly unreacted tolyltriazole is optional. However, small amounts of residual water could make the final product appear hazy.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:28]4[CH2:27][CH2:26][NH:25][CH:24]([CH3:23])[CH2:29]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)C4)cc3nc21

Procedure:
1-Ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 1 but starting from 2.1 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid, 20 cm3 of pyridine and 2.4 g of 2-methylpiperazine.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH2:24][OH:25]>CO>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:22]2[CH2:28][CH2:27][CH2:26][C@@H:23]2[CH2:24][OH:25])[CH:11]=1
Reactant: Clc1cc(N2CCc3ccccc3C2)c2ccccc2n1
Reactant: OC[C@H]1CCCN1
Solvent: CO
Product: OC[C@H]1CCCN1c1cc(N2CCc3ccccc3C2)c2ccccc2n1

Procedure:
The title compound, m.p. 74-80° C., [α]D20 =30 63.2° (c=0.53, methanol) and MS: m/e=360.3 (M+H+), was prepared from 2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline and D-prolinol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[O:5][CH:6]=1.C(Cl)Cl.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[O:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc(Br)co1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Br)co2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of 4-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and CH2Cl2 (10 mL) was added tert-butyl piperazine-1-carboxylate (1.06 g, 5.74 mmol) and sodium triacetoxyborohydride (1.2 g, 5.74 mmol). The mixture was stirred at room temperature overnight. The resultant mixture was diluted with EtOAc (100 mL), washed with brine then dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to afford the sub-title compound (900 mg, 91%).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:29][CH:28]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(F)cc1
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+]
Product: CN(Cc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-fluorophenyl)boronic acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 293 mg, 94%).
Reaction SMILES: CO[C:3]([O:15][CH3:16])([OH:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1.[C:17](=[O:20])([O-])[O-].[K+].[K+].[CH3:23]I>>[CH3:17][O:20][CH:12]([O:13][CH3:23])[C:9]1[CH:8]=[CH:7][C:6](/[CH:5]=[CH:4]/[C:3]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: CI
Reactant: COC(O)(C=Cc1ccc(C=O)cc1)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)/C=C/c1ccc(C(OC)OC)cc1
Temperature: 40 °C
Yield: 89 %

Procedure:
4-Formylcinnamic acid dimethyl acetal (Cleeland, Jr., et al., U.S. Pat. No. 3,969,373) (20.00 g) and anhydrous potassium carbonate (12.44 g) were stirred in anhydrous N,N-dimethylfornamide (189 ml) for 5 minutes. Methyl iodide (12.8 g) was added and the resulting mixture was stirred vigorously with gentle heating (oil bath at 40° C.) for 18 h. Volatiles were evaporated in vacuo and the residue partitioned between hexanes (400 ml) and water (100 ml). The hexanes layer was dried (magnesium sulfate) and evaporated to give (E)-methyl 4-(dimethoxymethyl)cinnamate as a pale yellow oil (18.98 g, 89%), 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[NH:4][C:5](=[S:19])[N:6]([CH2:9][C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]=2)[C:7]=1[NH2:8].[C:21](O)(=O)C.C(N)=N>CS(C)=O>[NH:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[CH2:9][N:6]1[C:7]2[N:8]=[CH:21][NH:1][C:2]=2[C:3](=[O:20])[NH:4][C:5]1=[S:19]
Reactant: Nc1c(N)n(Cc2nc3ccccc3[nH]2)c(=S)[nH]c1=O
Reactant: CC(=O)O
Agent: N=CN
Solvent: CS(C)=O
Product: O=c1[nH]c(=S)n(Cc2nc3ccccc3[nH]2)c2nc[nH]c12
Temperature: 70 °C
Yield: 15 %

Procedure:
To a solution of 5,6-diamino-1-(1H-benzimidazol-2-ylmethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.19 g, 0.65 mmol, obtained from Example 8(c)) in DMSO (2 mL) was added formamidine acetate (0.10 g, 0.98 mmol). The reaction mixture was heated to 70° C. for 2 h. Purification of the crude product using preparative HPLC gave the title compound (0.029 g, 15%) as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]#[N:11].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[O:7]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:9]1[C:10]#[N:11]
Reactant: O=C1CCOCC1
Reactant: N#CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: N#CC1OC12CCOCC2
Reaction time: 0.17 h

Procedure:
A mixture of tetrahydropyran-4-one (10 mL) and chloroacetonitrile (6.4 mL) in tert-butanol (10 mL) was stirred for 10 minutes. To this solution was added a solution of potassium tert-butoxide (12.11 g) in 200 mL of tert-butanol at room temperature over 40 minutes. The reaction mixture was stirred for 16 hours, diluted with water and quenched slowly with 1 N aqueous HCl. The solvent was partially removed by rotary evaporation. It was then extracted with ether (5×200 mL). The combined extracts was washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated and purified by flash chomatography on silica with 3:7 to 1:1 ethyl acetate:hexanes to provide the title compound.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:16]([OH:17])=[C:14]([OH:15])[CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:20][I:21]>CO>[I-:21].[CH3:20][N+:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1](=[O:8])[NH:9][CH2:10][CH2:11][C:12]2[CH:19]=[CH:18][C:16]([OH:17])=[C:14]([OH:15])[CH:13]=2)[CH:3]=1
Reactant: O=C(NCCc1ccc(O)c(O)c1)c1cccnc1
Reactant: CI
Solvent: CO
Product: C[n+]1cccc(C(=O)NCCc2ccc(O)c(O)c2)c1
Product: [I-]
Reaction time: 6 h

Procedure:
To a solution of 2 g (7.7 mmol) of N-nicotinoyldopamine in 40 mL of dry methanol were added 2.5 g (17.6 mmol) of methyl iodide. The reaction mixture was refluxed with stirring for 6 hours. Methyl iodide (1.5 g, 1.05 mmol) was added and refluxing was continued overnight. Methanol was removed and ethyl acetate was added, affording yellowish crystals of the desired product. Yield 2.4 g (77%), m.p. 173°-174° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:20]1([CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O.CO>[C:20]1([CH2:26][CH2:27][CH2:28][C:29]([NH:2][CH:3]2[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12](=[O:19])[NH:11][C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]2=3)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: O=C(Cl)CCCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCc1ccccc1)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
To a suspension of 0.55 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 30 ml of anhydrous dimethylformamide are added successively, at a temperature in the region of 5° C., 0.73 g of 4-phenylbutyryl chloride and, over 5 minutes, a solution of 0.4 g of triethylamine in 2 ml of anhydrous dimethylformamide. After stirring for 1 hour 30 minutes at the same temperature and then for 1 hour at 20° C., the insoluble product formed is isolated by filtration and washed twice with 3 ml in total of dimethylformamide. The filtrate and washing are combined, 80 ml of distilled water are added and the insoluble product formed is isolated by filtration, washed twice with 2 ml in total of distilled water and with 3 ml of acetone and then air-dried. The product obtained (0.27 g) is suspended for 5 minutes in 3 ml of boiling methanol and, after cooling and storing for 1 hour at 5° C., the solid formed is isolated by filtration, washed with 0.5 ml of methanol and dried under reduced pressure (5 mmHg; 0.65 kPa) at 60° C. 0.15 g of 10-(4-phenylbutyramido)-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, decomposing without melting above 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 2.92 (mt, 2H: --CH2 --); 2.28 (t, J=7.5 Hz, 2H: --CH2 --Ar); 2.62 (t, J=7.5 Hz, 2H: --CO--CH2 --); 6.18 (d, J=8.5 Hz, 1H: --CH-- 10); from 7.10 to 7.55 (mt, 7H: --H of the phenyl-- --H7 and --H 8); 7.50 and 7.87 (2 broad d, J=8 Hz, 1H each: --H 6 and --H 9); 7.55 and 7.60 (2s, 1H each; --H of the imidazole); 8.53 (d, J=8.5 Hz, 1H: --NHCO-- at 10); 12.47 (broad s, 1H: --CONH-- of the ring)).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][OH:14].[Br:15][CH:16]([CH3:20])[C:17](Br)=[O:18]>C(Cl)(Cl)Cl>[Br:15][CH:16]([CH3:20])[C:17]([O:14][CH2:13][C:9]1[O:8][CH:12]=[CH:11][CH:10]=1)=[O:18]
Reactant: OCc1ccco1
Reactant: CC(Br)C(=O)Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)OCc1ccco1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
Triethylamine (5.26 g, 0.052 mol) is added to an ice-cooled solution of 2 furylmethanol (5.10 g, 0.052 mol) in 70 ml of chloroform. This is followed by the gradual addition of 2-bromopropionyl bromide (9.93 g, 0.046 mol) in 10 ml of chloroform. The reaction mixture is stirred at RT for 24 h. To workup, the reaction mixture is washed with water (1 times 80 ml), 10% sulfuric acid (1 times 80 ml) and with saturated NaHCO3 solution (2 times 50 ml). The organic phase is dried over magnesium sulfate, concentrated and dried in a high vacuum. The yield is 67%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)[CH2:8][CH2:7]1.[C@@H:22]12[C:31](=O)[O:30][C:28](=[O:29])[C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27]2.[ClH:33]>N1C=CC=CC=1.C(O)C>[ClH:33].[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]4[C:28](=[O:29])[C@H:23]5[C@H:22]([CH2:27][CH2:26][CH2:25][CH2:24]5)[C:31]4=[O:30])[CH2:7][CH2:8]3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g, 16.1 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (3.23 g, 21 mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the end of the reaction, pyridine was removed to dryness. The crude product was purified on a silica gel column. The material thus obtained weighed 3.18 g (45%) as a clear oil. This oil was dissolved in ethanol (15 ml), then was treated with HCl in ethanol (45 ml). Crystallization took place upon cooling. The crystals were collected, 3.2 g, m.p.=229°-231° C.
Reaction SMILES: [CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=[CH:7][C:5](=O)[CH2:4][CH2:3]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([SH:28])[CH2:26][SH:27].O>C(O)(=O)C>[CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH:9]=[C:8]1[CH2:7][C:5]1([S:28][CH2:25][CH2:26][S:27]1)[CH2:4][CH2:3]2
Reactant: SCCS
Reactant: CC12CCC(=O)C=C1CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC12CCC3(CC1=CCCC2=O)SCCS3
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
To a solution of Wieland-Miescher ketone (5.87 g, 33.0 mmol) in glacial acetic acid (40 mL) was added p-toluenesulfonic acid (2.94 g) followed by dropwise addition of 1,2-ethanedithiol over a 1 hour period. The reaction mixture was stirred at room temperature for another 4 hours, poured into 30 mL water, and stirred for 15 minutes. The white solid was filtered off, washed successively with water, diluted with NaHCO3 solution and water, and then dried to yield thioketal 239 (7.33 g, 87.3%) as a white solid. 1H NMR (CDCl3) δ 1.50-2.70 (m, 10H), 3.20-3.40 (m, 4H), 5.67 (s, 1H); 13C NMR (CDCl3) 212.92, 141.23, 128.04, 64.81, 49.43, 40.11, 39.62, 37.92, 37.57, 30.81, 30.69, 24.73, 24.57.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=1)[C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:37](=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(OCC)(=O)C.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:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:16][CH:15]=1)[C:10]([O:12][CH3:37])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C(=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Nitrogen is passed through a suspension of (R)-2-(t-butoxycarbonylamino)-3-[4-(trifluoromethylsulfonyloxy)-phenyl]-propionate (1.75 mmol), phenylboronic acid (3.5 mmol), anhydrous potassium carbonate (2.63 mmol) and toluene (17 mL) for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) is added, and the mixture is heated at 85°-90° for 3 hours. The reaction mixture is cooled to 25° C., diluted with ethyl acetate (17 mL) and washed sequentially with saturated sodium bicarbonate (1×20 mL), water (1×20 mL), 10% citric acid (1×20 mL), water (1×20 mL) and saturated sodium chloride solution (1×20 mL). The organic phase is concentrated, and the residue is purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield methyl (R)-2-(t-butoxycarbonylamino)-3-(p-phenylphenyl)-propionate which can also be called N-(R)-t-butoxycarbonyl-(p-phenylphenyl)-alanine methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[C:17]([F:23])[CH:16]=2)[O:3]1.ClC1C=C(C=CC=1)C(OO)=[O:30].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:24])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:22])=[O:30])=[C:17]([F:23])[CH:16]=2)[O:3]1
Reactant: CSc1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1F
Yield: 95.6 %

Procedure:
To a stirred solution of (2,2-dimethyl)-5-{3-fluoro-4-(methylthio)phenyl}-4-(3-fluorophenyl)-3(2H)-furanone (1.6 g) in 50 ml dichloromethane, which was prepared by a procedure similar to the procedure employed for Example 264, 1.25 g of m-chloroperoxybenzoic acid at 0° C. The reaction solution was stirred for one and half hours at the temperature, after which 30 ml 5% aqueous sodium bicarbonate was added and the solution was stirred for another 10 minutes. Then the reaction mixture was concentrated in vacuo, and the resulting residue was extracted with 50 ml water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo and was purified by column chromatography (hexane/ethylacetate=1:1) to give 1.6 g of 2,2-dimethyl-5-{3-fluoro-4-(methylsulfinyl)phenyl}-4-(3-fluorophenyl)-3(2H)-furanone as a solid. mp: 148-149° C. NMR: δ1.58 (s, 6H), 2.87 (s, 3H), 7.06 (m, 3H), 7.36(m, 1H), 7.42 (dd, J=10.5, 1.8 Hz, 1H), 7.66 (dd, J=8.4, 1.8 Hz, 1H), 7.87 (dd, J=8.1. 6.9 Hz, 1H). IR (cm−1): 1700, 1623, 1420, 1261, 1216, 1192, 1135, 1077.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[NH:4][C:3]=1[C:10]#[N:11].[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CC(C)=O>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[N:4]([CH3:12])[C:3]=1[C:10]#[N:11]
Reactant: N#Cc1[nH]c(Br)c(C#N)c1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: Cn1c(Br)c(C#N)c(Br)c1C#N

Procedure:
A sample (1.0 g, 0.0036 mol) of 3,5-dibromopyrrole-2,4-dicarbonitrile is readily soluble in 20 mL of acetone. Anhydrous potassium carbonate (0.64 g, 0.0046 mol) is added, and while the slurry is stirred, methyl iodide (0.68 g, 0.0047 mol) is added. The reaction can be followed by Tlc. When the reaction is complete, the mixture is poured into water precipitating a white solid. The product (0.77 g, 74%) has mp 175°-178° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C([N:24](CC)CC)C.N>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([NH2:24])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1(c2ccc(Cl)nc2)CC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC(=O)C1(c2ccc(Cl)nc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 1-(6-chloropyridin-3-yl)cyclopropanecarboxylic from Step 4 (1.0 g) in chloroform (50 mL) were slowly added isobutyl chloroformate (800 μL) and triethylamine (920 μL). The reaction mixture was stirred at 0° C. for 2 hours. Then it was saturated with ammonia gas and stirred at 0° C. for 10 minutes. The reaction mixture was allowed to stand at room temperature for 1 hour then poured into water (80 mL) and partitioned. The aqueous layer was extracted with dichloromethane (2×80 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by swish using diethyl ether and hexanes to yield the title compound.