Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH2:16](O)[CH3:17]>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCO
Reactant: O=C(O)CCCCCCCBr
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCCCCCCBr
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Thionylchloride (8.15 ml, 0.112 mols) was added dropwise to an ethanol (500 ml) solution of 8-bromooctanoic acid (50.0 g, 0.224 mols) with cooling with ice, and the reaction mixture was then stirred for 12 hours at room temperature. The reaction mixture was concentrated in vacuo, and a saturated aqueous sodium bicarbonate solution was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated in vacuo. The thus-obtained crude product was purified by alumina column chromatography (hexane) to obtain the entitled compound (51.6 g) as an oil.
Reaction SMILES: C(O)C.[C:4]([C:7]1[C:12]2[CH2:13][C:14](=O)[C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1)([OH:6])=[O:5].O.NN>O1CCOCC1>[C:4]([C:7]1[C:12]2[CH2:13][CH2:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1)([OH:6])=[O:5]
Reactant: COc1ccc2c(c1)C(=O)Cc1c(cccc1C(=O)O)S2
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCc1c(cccc1C(=O)O)S2

Procedure:
To the mixed solvent of 16ml of ethanol and 16ml of dioxane were added 1.8g of 9-carboxy-2-methoxy-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin and 2.0g of hydrazine hydrate and the resulting mixture was heated under reflux for 8 hours. After the completion of reaction, the solvent was distilled off and 1.8g of sodium hydroxide and 30ml of diethylene glycol was added to the residue. The thus obtained mixture was heated under reflux at 190°-200° C for 5 hours. After cooling, water was added to the mixture which was extracted benzene. The aqueous layer was acidified with hydrochloric acid and extracted with benzene. The extract was washed with water, dried and the solvent was distilled off. The thus obtained residue was chromatographed over silica gel, eluted with chloroform-diethylether (10:1), there was obtained 0.5G of 9-carboxy-2-methoxy-10,11-dihydrodibenzo[b,f]thiepin as colorless needles having a melting point of 185°-187° C.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][CH:8]1[CH2:12][S:11][C:10]([NH:13]C(=O)OC(C)(C)C)=[N:9]1.CO>O1CCOCC1>[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][CH:8]1[CH2:12][S:11][C:10]([NH2:13])=[N:9]1
Reactant: CC(C)(C)OC(=O)NC1=NC(Cc2ncc[nH]2)CS1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1=NC(Cc2ncc[nH]2)CS1
Temperature: 20 °C
Reaction time: 48 h
Yield: 36.8 %

Procedure:
5 cm3 of 4N hydrochloric acid in dioxane are added to a solution of 1.39 g of tert-butyl N-[(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl]carbamate in 5 cm3 of dioxane, followed by addition of methanol to dissolve the reaction medium. After stirring at a temperature in the region of 20° C. for 48 hours, the reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. and washed with isopropyl ether, with ethyl acetate and then with methanol. The suspension obtained is filtered and the filtrate is evaporated as above and then chromatographed on a column of silica gel, eluting with a mixture of dichloromethane/methanol/28% aqueous ammonia (50/5/1 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions to give 0.33 g of (4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolylamine in the form of a viscous yellow oil [1H NMR spectrum (300 MHz, CD3)2SO-d6, δ in ppm): 2.93 (mt: 1H) 3.26 (mt: 1H); 4.03 (d, J=6 Hz: 2H); 4.39 (mt: 1H); 6.49 (unresolved complex: 2H); 6.87 (mt: 1H); 7.20 (mt: 1H); 7.63 (broad s: 1H)].
Reaction SMILES: C([N:14]1[C:17](=[O:18])[C@H:16]([N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[C@@H:15]1[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])(C1C=CC=CC=1)C1C=CC=CC=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].O.O.O.O.O.O.O.O.O.O.O.O.P(O)([O-])([O-])=O.[Na+].[Na+].O>C(#N)C>[C:20]1(=[O:29])[N:19]([C@H:16]2[C:17](=[O:18])[NH:14][C@H:15]2[C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: CCCCOC(=O)[C@H]1[C@@H](N2C(=O)c3ccccc3C2=O)C(=O)N1C(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCOC(=O)[C@@H]1NC(=O)[C@@H]1N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 250 mg of butyl cis-1-benzhydryl-3-phthalimido-4-oxo-2-azetidine carboxylate, 473 mg (1.75 mmole) of potassium persulfate, 307 mg (0.858 mmole) of disodium phosphate dodecahydrate, 9.2 ml of water and 8.4 ml of acetonitrile is thoroughly degassed with argon and then heated to 80°-85° under argon for three hours. The reaction mixture is cooled and the acetonitrile removed on the rotary evaporator. The aqueous residue is saturated with solid sodium chloride and extracted three times with ethyl acetate. The combined organic extractions are washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude butyl cis-3-phthalimido-4-oxo-2-azetidinecarboxylate.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.[C:15]([OH:20])(=[O:19])[C:16]([CH3:18])=[O:17].Cl>C(Cl)Cl.CO.C(O)(=O)C.O.C(O)C>[O:17]=[C:16]([CH:18]=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:5]=1[O:4][CH3:3])[C:15]([OH:20])=[O:19]
Reactant: COc1cccc(C=O)c1OC
Reactant: CC(=O)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COc1cccc(C=CC(=O)C(=O)O)c1OC

Procedure:
300 ml of deionized water and 50 g of potassium hydroxide are placed into a 3 l flask. The mixture is stirred until dissolution, then 150 ml of ethanol and 100 g of 2,3-dimethoxybenzaldehyde are added. After that, 60.0 g of pyruvic acid are dropped therein (in about 30 minutes) and the mixture is stirred for about 15 minutes at a temperature from 35° to 40° C., then it is poured into 6500 ml of water and brought to markedly acid pH with about 140 ml of concentrated HCl. The mixture is cooled with stirring for about 30 minutes, then filtered washing with water and dried under Vacuum at 60° C. to obtain an orange solid. Yield: 115 g, 81% (moles), 115% (weight); TLC: methylene chloride/methanol/acetic acid 80/20/2; Rf=0,5; M.P.: 136°-138° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].I[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:32][C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:21][C:20]=3[O:32][C:33]([F:34])([F:36])[F:35])[N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(-c2ccnc(N)n2)c1
Reactant: CN1CCN(c2ccc(I)c(OC(F)(F)F)c2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1c[nH]c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC(F)(F)F)n2)c1
Temperature: 80 °C
Yield: 14.9 %

Procedure:
To a solution of 5-(2-amino-pyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid ethyl ester (400 mg, 1.72 mmol) in dioxane (40 mL), 1-(4-iodo-3-trifluoromethoxy-phenyl)-4-methyl-piperazine (732 mg, 1.90 mmol) and cesium carbonate (1.1 g, 3.45 mmol) were added and the flask was evacuated and backfilled with argon. [Pd2(dba)3] (158 mg, 0.17 mmol) and Xantphos (299 mg, 0.52 mmol) were then charged and the mixture was heated at 80° C. under argon for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, suspended in water (50 mL) and extracted with ethyl acetate. The organic phase was acidified on Na2SO4, filtered and evaporated to dryness, the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) to afford 126 mg (15% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[N:10]1([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Oc1ccc(CN2CCCCC2)cc1
Reaction time: 16 h

Procedure:
A solution of 4-hydroxybenzaldehyde (10 g), piperidine (8.9 mL), and acetic acid (4.7 mL) in DCE (200 mL) was treated with sodium triacetoxyborohydride (24 g). After 16 h, the resulting mixture was treated with saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (5×100 mL). The combined organic phases were dried (magnesium sulfate) and evaporated. Trituration of the residue with ethyl acetate gave the title compound as a white crystalline solid (5.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1>CC(C)=O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:26][C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(Br)c(OCc2ccccc2)c1
Yield: 84.3 %

Procedure:
To a suspension of 4.5 g (18.4 mmol) of 6 and 4.1 g (30 mmol) of K2CO3 in 150 ml of acetone under Ar was added 3.4 g (20 mmol) of BnBr. The mixture was heated at reflux for 15 h, concentrated, then diluted with 100 ml of CH2Cl2, washed (water, 1 N HCl, and brine), and dried (Na2SO4). Concentration and chromatography (EtOAc/hexane) afforded 5.2 g (84%) of 7 (white solid): 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=7.2 Hz, 3 H), 4.37 (q, J=7.2 Hz, 2 H), 5.21 (s, 2 H), 7.39 (m, 3 H), 7.50 (in, 3 H), 7.63 ppm (m, 2 H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:21])=[CH:16][CH:15]=1>>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:21])=[CH:16][CH:15]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=C(c1ccc(-c2ccc3c(c2)OCO3)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from 3,4-Methylenedioxybenzene boronic acid and (4-bromo-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone. MS (ES+) 379.4
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[CH:25][N:26]([CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11].O>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C:12]2[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18]([NH:20][C:21]([C:23]3[N:24]=[CH:25][N:26]([CH2:28][CH2:29][CH:30]([OH:32])[CH3:31])[CH:27]=3)=[O:22])[CH3:19])[N:13]=2)[CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: CC(=O)CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (9.8 mg, 0.26 mmol) was added to a solution of (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-oxobutyl)-1H-imidazole-4-carboxamide (100 mg, 0.24 mmol) in ethanol (3 ml) at RT. Thereafter the reaction mixture was stirred at RT for 3 h. Then water was added and the product was extracted into ethyl acetate. The combined organic layers were washed with water and dried. The solvent was evaporated to obtain the title compound. 1H NMR (400 MHz, CDCl3): 1.21 (31-1, d), 1.22 (3H, d), 1.89 (2H, m), 2.31 (1H, broad s), 3.73 (1H, m), 4.15 (2H, m), 4.28 (1H, distorted dd), 4.40 (1H, distorted dd), 4.56 (1H, m), 6.61 (1H, d), 7.51 (2H, m), 7.60 (1H, d), 7.66 (1H, distorted d), 7.79 (1H, m), 7.95 (1H, d), 8.18 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[Br:10]C1C(=O)C(Br)=CC(Br)(Br)C=1>ClCCl>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:9])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: COc1ccccc1N
Solvent: ClCCl
Product: COc1cc(Br)ccc1N
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A solution of o-Anisidine (5.46 g, 44.3 mmol) in dichloromethane (100 mL) was treated with 2,4,4,6-tetrabromo-2,5-cyclohexadiene-1-one (18.16 g, 44.3 mmol) portion-wise over 1 h at −5° C. Following the addition of the brominating agent, the dry ice/acetone bath was removed and the reaction mixture stirred over night at room temperature. Sodium hydroxide solution (1N) was added to the reaction mixture, and the layers were partitioned. The organic layer was washed with 1 N sodium hydroxide solution (1 L), washed with water (750 mL), dried over magnesium sulfate, filtered, and evaporated under reduced pressure, to give 8.096 g (89%) of 4-bromo-2-methoxyaniline. 1H NMR (DMSO-d6, 400 MHz) δ 6.90 (s, 1H), 6.83-6.76 (m, 1H), 6.57-6.55 (m, 1H), 4.86 (s, 2H), 3.76 (s, 3H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.635 min (89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[N+:15]([O-])=O)=[C:4]([N+:18]([O-])=O)[CH:3]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=3[N:15]=[N:18][C:4]=2[CH:3]=1
Reactant: Cc1ccc(-c2ccc(C)cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)nnc1cc(C)ccc12

Procedure:
64 g (0.235 mol) of 4,4'-dimethyl-2,2'-dinitrobiphenyl are dissolved in 700 ml of dry toluene, under argon. 313 g (1.084 mols) of sodium dihydro-bis-(2-methoxyethoxy)-aluminate (70% in toluene) are added slowly dropwise, with stirring; an exothermic reaction takes place. The mixture is stirred for a further 10 minutes at about 80° C. The solution is evaporated to dryness. The oily residue is ground with 500 ml of water and 100 ml of concentrated ammonia. The brown suspension is filtered through a glass filter and the precipitate is washed with water. The precipitate is then extracted with ethanol in a Soxhlet apparatus for 5 days. The resulting alcoholic solution is refluxed with active charcoal and filtered hot and the filtrate is evaporated to dryness. The crude product thus obtained is finally recrystallised from a mixture of toluene/isooctane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].CC#N.Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+]>O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[CH3:27]
Reactant: CCOC(=O)CCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCOc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 85 °C
Yield: 109 %

Procedure:
A mixture of 4′-cyano-4-hydroxybiphenyl (4.0 g, 20.5 mmol), MeCN (30 ml), ethyl 4-bromobutyrate (3.75 ml, 5.11 g, 26.2 mmol), and K2CO3 (3.86 g, 27.9 mmol) was stirred at 85° C. After 20 h water (150 ml) was added, and the product was extracted with AcOEt. The combined extracts were washed with brine, dried over MgSO4, and concentrated, to yield 6.91 g (100%) of 4-(4′-cyanobiphenyl-4-yloxy)butyric acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[H-].[Na+].[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)C1C=CC=CC=1>C(OCC)(=O)C>[CH2:29]([NH:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccccc1
Reactant: Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1c(NCc2ccccc2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
40 mg of 3-amino-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one and 10 mg of sodium hydride were added to 1 ml of toluene, to which 30 mg of benzyl chloride was added dropwise at 70° C. The mixture was stirred for 30 minutes, and heated for 1 hour under reflux. The reaction mixture was left to cool to room temperature, diluted with ethyl acetate, and washed with a water and a saturated saline water. The organic layer was dried by magnesium sulfate, and refined by NH silica gel chromatography (ethyl acetate/hexane-based solvent), to obtain 13 mg of the subject compound.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][C:6]=1[Cl:25].[OH-].[Na+]>CO.O1CCCC1.O>[Cl:25][C:6]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[CH:9]=[CH:10][C:5]=1[C:4](=[O:26])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1Cl
Yield: 80.6 %

Procedure:
A solution of 2-chloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.56 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.435 g of purified 2-chloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 152°-153° C.
Reaction SMILES: C[Si](C)(C)[O:3][C:4](=[CH2:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(=O)(O)[O-].[Na+].[Br:27]N1C(=O)CCC1=O>C1COCC1>[Br:27][CH2:3][C:4](=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(CC1CCN(C(=O)OC(C)(C)C)CC1)O[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)CBr)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.7 %

Procedure:
To a solution of tert-butyl 4-(2-(trimethylsilyloxy)allyl)piperidine-1-carboxylate (6.43 g, 20.5 mmol) in THF (100 mL) at 0° C. was added sodium bicarbonate (2.58 g, 30.7 mmol) followed by 1-bromopyrrolidine-2,5-dione (3.65 g, 20.5 mmol). Warmed to ambient temperature and stirred 90 minutes. Partitioned between ether (150 mL) and saturated sodium bicarbonate. The aqueous layer was reextracted with ether (100 mL). The combined organic layers were washed with saturated bicarbonate, brine, dried, and concentrated to afford the title compound (7.2 g, 110% yield) as a yellow oil. Purity was 85% with the major impurity being succinimide. The crude material was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:4](=[O:17])[C:3]=1[NH:18][C:19](=[O:39])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[Cl:36])(=[O:30])=[O:29])=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][CH:48]1[CH2:51][CH2:50][CH2:49]1>CN(C=O)C>[NH2:1][C:2]1[N:7]([CH2:47][CH:48]2[CH2:51][CH2:50][CH2:49]2)[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:4](=[O:17])[C:3]=1[NH:18][C:19](=[O:39])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[Cl:36])(=[O:30])=[O:29])=[CH:23][N:22]=1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)nc1
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)Nc2c(N)n(CC3CCC3)c(=O)n(Cc3ccccc3F)c2=O)nc1
Temperature: 40 °C
Yield: 15 %

Procedure:
A solution of N-[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetamide in N,N,-dimethylformamide was treated with potassium carbonate (4.0 eq.) and (bromomethyl)cyclobutane (2.0 eq.). The reaction mixture was heated to 40° C. for 16 h. At this time, the N,N,-dimethylformamide was removed in vacuo. The residue was triturated with chloroform and then methanol to remove impurities. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 10/90 methanol/chloroform) afforded N-[6-amino-1-cyclobutylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetamide (15%) as a light brown solid; LRMS for C29H31ClFN7O5S (M+H)+ at m/z=645.
Reaction SMILES: [Na].Br[C:3]1[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=[C:5]([Cl:20])[C:4]=1[CH3:21].[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:5]1[C:4]([CH3:21])=[C:3]([C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)[C:8]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=1
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1-c1cc(F)cc(F)c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(-c2ccncc2)c1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 6.5 %

Procedure:
To a solution of sodium hydrogenecarbonate (0.093 g, 1.1 mmol) in water (2 mL) was added a solution of 1-(6-bromo-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.20 g, 0.56 mmol) in toluene (2 mL) followed by 4-pyridinylboronic Acid (0.082 g, 0.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.033 g, 0.029 mmol). The mixture was bubbled with N2 for 5 min and then heated at 80° C. overnight. The organic layer was concentrated and flashed on silica gel (eluting with 0-35% of ethyl acetate in hexanes) to afford the desired product (13 mg, 6.5%). LCMS calculated for C20H15ClF2NO (M+H)+: m/z=358.1. found: 358.1.