Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:13]([Cl:30])=[CH:14][C:15]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][C@H:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:29]=1>C1COCC1>[CH:1]([NH:11][C:12]1[C:13]([Cl:30])=[CH:14][C:15]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][C@H:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:29]=1)=[O:3]
Reactant: CN1CCc2cc(Cl)c(N)cc2[C@@H](c2ccccc2)C1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CN1CCc2cc(Cl)c(NC=O)cc2[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Formic acid (2.25 g, 95-97%) was added dropwise to acetic anhydride (4.10 g.) at 0° C. with stirring. The resulting solution was heated under nitrogen in a water bath at 50°-60° C. with stirring for 2 hours longer. The solution was cooled down to room temperature and diluted with 5 ml of THF. A solution of (R)-8-amino-7-chloro-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (5.10 g, 0.018 mol) in 25 ml of THF was added dropwise with stirring to the above solution. The resulting solution was stirred at room temperature for 3.5 hours longer and left standing at room temperature for 24 hours. The THF was evaporated in vacuo and the residue was treated with ether and 1N Na2CO3. The dried ether solution was evaporated in vacuo. The residue crystallized from acetonitrile, m.p. 135°-136° C. [α]26D +72.6° C. (DMF, c=1).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3=[CH:17][C:18]4[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:26])([CH3:25])[C:23]=4[CH:24]=[C:15]3[N:14]([CH3:29])[C:13]3[CH:30]=[CH:31][C:32]([C:34](=[O:36])[CH3:35])=[CH:33][C:12]=3[N:11]=2)=[C:6]([F:37])[CH:5]=1.C1COCC1.[OH-].[Na+].Cl>CO>[C:34]([C:32]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]3[C:16]([C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][C:6]=4[F:37])=[N:11][C:12]=2[CH:33]=1)=[CH:17][C:18]1[C:19]([CH3:28])([CH3:27])[CH2:20][CH2:21][C:22]([CH3:25])([CH3:26])[C:23]=1[CH:24]=3)(=[O:36])[CH3:35]
Reactant: COC(=O)c1ccc(C2=Nc3cc(C(C)=O)ccc3N(C)c3cc4c(cc32)C(C)(C)CCC4(C)C)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)N=C(c1ccc(C(=O)O)cc1F)c1cc3c(cc1N2C)C(C)(C)CCC3(C)C
Reaction time: 12 h

Procedure:
A solution of 4-(2-acetyl-5,7,7,10,10-pentamethyl-7,8,9,10-tetrahydro-5H-5,13-diazabenzo[4,5]cyclohepta[1,2-b]naphthalen-12-yl)-3-fluorobenzoic acid methyl ester (19) (R4=CH3, Z=3-F, 0.25 mmol) in the mixture of THF (2.5 mL) and MeOH (0.14 mL) is treated with 1N NaOH (0.41 mL) and the mixture is stirred for 12 h. The mixture is poured into 1N HCl and extracted with EtOAc. The extract is washed with brine, dried over MgSO4 and evaporated in vacuo. The resulting solids are collected by filtration and washed with Et2O to give the acid (20) (R4=CH3, Z=3-F) as yellow solid: 1H-NMR (DMSO-d6) δ: 1.00 (6H, s), 1.26 (6H, s), 1.53-1.62 (4H, m), 2.55 (3H, s), 3.29 (3H, s), 6.75 (1H, s), 7.03 (1H, s), 7.18 (1H, d), 7.71 (1H, d), 7.75 (1H, d), 7.81 (1H, dd), 7.90-7.98 (2H, m), 13.47 (1H, br).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][S:7][C:6]=2[CH:17]=1.CN1CCOCC1.[CH3:25][NH:26][C:27]1[N:32]=[C:31]([CH2:33][CH2:34]O)[CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:25][NH:26][C:27]1[N:32]=[C:31]([CH2:33][CH2:34][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:9]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][S:7][C:6]=3[CH:17]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CCc1csc2cc(O)ccc12
Reactant: CNc1cccc(CCO)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1csc2cc(OCCc3cccc(NC)n3)ccc12
Reaction time: 0.08 h
Yield: 19.5 %

Procedure:
Ethyl 3-(6-hydroxybenzo[b]thiophen-3-yl)propanoate (100 mg, 0.4 mmol) and 4-methylmorpholine (0.05 ml, 0.44 mmol) were dissolved in THF (5 ml) and stirred for 5 minutes. 2-[6-(Methylamino)-2-pyridyl]ethan-1-ol (91 mg, 0.6 mmol), triphenylphosphine (210 mg, 0.8 mmol) and diisopropyl azodicarboxylate (0.16 ml, 0.8 mmol) were added to the mixture sequentially. After stirring overnight under argon, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate, filtered and evaporated under vacuum. The crude product was chromatographed over silica gel to yield 30 mg (19%) of Ethyl 3-(6-{2-[6-(methylamino)-2-pyridyl]ethoxy}benzo[b]thiophen-3-yl)propanoate.
Reaction SMILES: [CH:1](=[N:3]/[OH:4])\[CH3:2].[CH3:5][C:6]([NH2:10])([C:8]#[CH:9])[CH3:7].C(N(CC)CC)C.Cl[O-].[Na+]>C(Cl)Cl>[CH3:5][C:6]([NH2:10])([C:8]1[O:4][N:3]=[C:1]([CH3:2])[CH:9]=1)[CH3:7]
Reactant: C/C=N/O
Reactant: C#CC(C)(C)N
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(C)(C)N)on1
Temperature: 4 °C
Reaction time: 5 h
Yield: 4.2 %

Procedure:
To a solution of (E)-acetaldehyde oxime (CAN 107-29-9, 1.0 g, 16.9 mmol), 2-methylbut-3-yn-2-amine (CAN 2978-58-7, 1.4 g, 16.9 mmol) and triethylamine (CAN 121-44-8, 0.17 g, 1.69 mmol) in methylene chloride (25 mL) at 0° C. was added a 5% aqueous solution of sodium hypochlorite (5%, 42.6 g) over 3 h. The reaction was allowed to warm to 4° C. and stirring continued for 5 h. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (50 mL). The combined methylene chloride extracts were washed with saturated aqueous sodium chloride (60 mL) and dried over anhydrous magnesium sulfate. The solvent was removed to give a yellow oil. The crude product was purified by column chromatography (silica gel 30 g, eluting with 30% ethyl acetate in petroleum ether) to yield the product as yellow solid (0.1 g, 4.2%); MS (EI): m/e=141.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>CCO.[H][H].[OH-].[OH-].[Pd+2]>[NH:1]1[CH2:6][CH2:5][NH:4][CH:3]=[C:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: [H][H]
Reactant: CCOC(=O)c1cnccn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=CNCCN1
Yield: 102 %

Procedure:
A solution of ethyl pyrazine-2-carboxylate (60 g) in EtOH (500 ml) was subjected to catalytic reduction using palladium hydroxide on carbon (5.0 g), in hydrogen at 3 atm for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 62.8 g of ethyl 1,4,5,6-tetrahydropyrazine-2-carboxylate as an oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:27]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:42][CH:41]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(NC(=O)c2ccc(Cc3ccccc3)cc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.1 %

Procedure:
To a solution of 2-amino-4-methyl-thiazole-5-carboxylic acid benzylamide (0.054 g, 0.22 mmol) and diisopropylethylamine (0.40 mL, 2.3 mmol) in dichloromethane (5 mL) was added 4-benzylbenzoic acid (0.057 g, 0.27 mmol), followed by the addition of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.11 g, 0.28 mmol). The reaction was stirred at ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by preparative HPLC (acetone/water gradient) to afford the title compound (0.003 g); MS (ES+) m/z 442 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][C:12]2[N:16]([C:17]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][N:18]=3)[N:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[C:26](#N)C.O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][C:12]2[N:16]([C:17]3[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][N:18]=3)[N:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CC#N
Reactant: CCc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1Cl
Solvent: O
Product: CCc1ccc(COc2ccnn2-c2cc(C(=O)OC)ccn2)cc1Cl

Procedure:
The title compound was prepared from 2-[5-[(3-chloro-4-ethylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 95) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=7.6 Hz), 2.76 (2H, q, J=7.6 Hz), 3.97 (3H, s), 5.18 (2H, s), 5.75 (1H, s), 7.26 (2H, s), 7.45 (1H, s), 7.58 (1H,$), 7.78 (1H, d, J=8.0 Hz), 8.33 (1H, s), 8.72 (1H, d, J=0.8 Hz). LCMS (mobile phase: 20%-95% Acetonitrile-Water-0.02% NH4OH): purity is >95%, Rt=4.602 min.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.C1COCC1.[BH4-].[Na+]>C(O)C>[Cl:1][CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:5][C:6]1[CH:7]=[C:8]([F:13])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Reaction time: 2 h

Procedure:
To a 250 mL 3-neck round bottom flask equipped with magnetic stir bar, nitrogen inlet and thermocouple, is added tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III, Step 2, 4.4 g, 0.0132 moles, 1 equivalent) followed by THF (20 mL) and ethanol (30 mL) then cooled to −78°. Once the mixture is cooled, sodium borohydride (2.0 g, 0.0527 moles, 4 equivalents) is added as a solid portion wise over 30 min keeping the internal temperature below −70°. Once this addition is complete, the contents are stirred for 2 hr at −78° then warmed to 0° and stirred an additional 1 hr. The mixture is quenched by the addition of saturated potassium bisulfate (15 mL) and water (15 mL). This slurry is stirred for 30 min at 20–25° then concentrated under reduced pressure to half its volume. The mixture is then cooled to 0° and stirred for 30 min. After this time, the resultant solids are collected by filtration and washed with water (2×50 mL) then dried under reduced pressure at 50° to give crude product. A syn/anti ratio of 4–9:1 has been observed. The desired product is recrystallized from hexanes/ethanol (25/1) to give the title compound, NMR (DMSO-d6) δ 6.89–7.16, 5.61, 3.64–3.83, 3.19, 2.69 and 1.41; CMR (DMSO-d6) δ 163.67, 161.24, 155.44, 112.70, 101.55, 78.04, 72.99, 54.29, 48.24, 35.97 and 28.37.
Reaction SMILES: C[O:2][CH2:3][C:4]1[S:8][N:7]=[N:6][C:5]=1[C:9]([O:11][CH3:12])=[O:10].BrBr>C(Cl)(Cl)(Cl)Cl>[CH:3]([C:4]1[S:8][N:7]=[N:6][C:5]=1[C:9]([O:11][CH3:12])=[O:10])=[O:2]
Reactant: COCc1snnc1C(=O)OC
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nnsc1C=O
Yield: 71.3 %

Procedure:
Methyl 5-(methoxymethyl)-1,2,3-thiadiazole-4-carboxylate (4.18 g, 0.022 mol) was dissolved in carbon tetrachloride (60 mL). To the solution was added bromine (4.18 g, 0.026 mol) and the solution was refluxed upon irradiation with long wavelength UV light (100 watts) for 3 h. The volatiles were evaporated in vacuo and the crude material purified by flash chromatography to give the desired product (2.70 g, 71%) as a viscous oil. 1H NMR (400 MHz, CDCl3): δ□ 10.67 (s, 1H), 4.15 (s, 3H). MF=C5H4N2O3S; LCMS calculated for C5H5N2O3S (M+H)+: m/z=173.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([N+:20]([O-])=O)=[C:16]([CH:19]=2)[C:17]#[N:18])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.O.[NH2:24]N>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:19]=[C:16]3[C:15](=[CH:14][CH:13]=2)[NH:20][N:18]=[C:17]3[NH2:24])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NN
Reactant: N#Cc1cc(S(=O)(=O)c2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12
Yield: 73 %

Procedure:
5-(3,5-Difluoro-benzenesulfonyl)-2-nitro-benzonitrile (3.5 g, 10.8 mmol) was heated in anhydrous ethanol (175 mL) until completely dissolved. The solution was then treated with hydrazine hydrate (0.58 mL, 1.1 mol eq.) and refluxed for three hours. The reaction mixture was evaporated to dryness; the residue was dissolved in acetone, adsorbed onto flash chromatography-grade silica gel by rotoevaporation of the solvent. The silica was loaded onto a flash chromatography column conditioned with 10:1 dichloromethane/acetone. The column was then eluted with dichloromethane/acetone (gradient: from 10:1 to 2:1) followed by a final washing with dichloromethane/acetone/methanol. The pure fractions were collected and evaporated to afford the title compound as a whitish crystalline powder (2.44 g, 73%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[S:10].Br[C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C=O)C.[OH-].[Na+]>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10][C:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C)(Br)c1ccccc1
Reactant: S=C1Cc2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(Sc1cc2ccccc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Into a solution of 1,3-dihydroindol-2-thione (19.7 g) and ethyl 2-bromo-2-phenylpropionate (33.9 g) indimethylformamide (DMF, 200 ml), an aqueous 2 N sodium hydroxide solution (66 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and was extracted with ethyl acetate. The organic layer was washed with water, and then with saturated aqueous sodium chloride solution, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. n-Hexane was added to the evaporation residue to cause crystallization. The resulting crystalline matter was recrystallized from ethyl acetate/n-hexane to give 30.3 g (yield: 71%) of product compound as a pale yellow crystal form. The melting point was 97°-99° C.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]1[N:31]=[C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[O:29][N:28]=1>C(#N)C>[CH2:1]([C:4]1[N:5]([CH2:26][C:27]2[N:31]=[C:30]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[O:29][N:28]=2)[C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: BrCc1noc(-c2cccs2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccs2)n1
Yield: 64.2 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.150 g, 0.595 mmol) in anhydrous acetonitrile (25 mL) was added Cs2CO3 (0.193 g, 0.595 mmol) and 3-(bromomethyl)-5-(2-thienyl)-1,2,4-oxadiazole (0.213 g, 0.893 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.159 g, 64% yield): MS (ES) m/z 416 (M+).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][CH:6]=1)=[O:4].[C-]#N.[Na+].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:7][CH:6]=1)=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cnc(NC(=O)c2ccccc2)s1
Reactant: NCc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Product: O=C(Nc1ncc(C(=O)NCc2ccccc2)s1)c1ccccc1
Temperature: 80 °C
Reaction time: 70 h
Yield: 5 %

Procedure:
A mixture of 2-benzoylaminothiazole-5-carboxylic acid methyl ester (0.40 g, 1.52 mmol), sodium cyanide (0.19 g, 3.79 mmol) and benzylamine (4 mL) was stirred at 80° C. for 70 h. The mixture was filtered, washed with ethyl ether, and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of methanol and tetrahydrofuran and aqueous lithium hydroxide solution (0.24 g in 6 mL water) was added. The mixture was stirred at 50° C. for 4 d. The organic solvents were removed in vacuo. The solid obtained was collected by filtration, washed with water, methanol and dried. The title compound was obtained as a white solid in 5% yield (0.005 g); 1H NMR (DMSO-d6, 300 MHz) δ 8.93 (s, 1H), 8.20-8.03 (m, 3H), 7.62-7.41 (m, 3H), 7.39-7.14 (m, 6H), 4.43 (d, J=3.9 Hz, 2H); MS (ES+) m/z 338.5 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH:17][CH2:18][CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][CH:14]([N:17]([CH2:18][CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)NCCNC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)NCCN(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
p-Nitrobenzenesulfonyl chloride (22.1 g, 0.1 mole) in methylene chloride (150 ml) was added dropwise with stirring to N,N'-diisopropyl ethylene diamine (14.4 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in methylene chloride (400 ml). The reaction was stirred one hour at room temperature, washed with water and the solvent removed. The residue dissolved in diethyl ether precipitated the unwanted "bis" byproduct which was filtered and discarded. Chromatography of the filtrate on Dry Column Silica Gel (500 g) with ethyl acetate provided pure product free base as a gum (14.31 g). Conversion, using isopropanol/HCl, to the hydrochloride salt provided the title compound as the hydrochloride salt (14.85 g) m.r. 219°-222° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=3)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1.[OH-].[Na+].CO>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:30]=[CH:29][C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=3)[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1
Reactant: COC(=O)c1cccc(Cn2c(C)nc3cc(-c4nc5ccccc5o4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1Cc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-1-(3-methoxycarbonylphenylmethyl)-2-methylbenzimidazole (see Working Example 117-2) (125 mg, 0.315 mmol) in chloroform (3 mL) was added aqueous sodium hydroxide solution (1 M, 1 mL, 1 mmol). This two-layer solution was homogenized by the addition of methanol, and this was stirred at room temperature for 20 hours. After the reaction was complete, the solution was concentrated, aqueous acetic acid solution was added, and this was stirred at room temperature. The precipitated crystals were filtered, and after washing with water were dried to yield the title compound (120 mg, 99% yield) as white crystals.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[N:30]=[C:31](/[CH:34]=[CH:35]/[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:32][CH:33]=2)=[CH:23][CH:22]=1)(=O)=O>>[C:36]1(/[CH:35]=[CH:34]/[C:31]2[O:32][CH:33]=[C:29]([CH2:28][O:27][C:24]3[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][CH2:18][CH2:17][N:11]4[CH:10]=[CH:9][N:8]=[C:7]4[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:26][CH:25]=3)[N:30]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Product: C(=C/c1nc(COc2ccc(CCCCn3ccnc3-c3ccccc3)cc2)co1)\c1ccccc1
Yield: 40 %

Procedure:
In substantially the same manner as in Working Example 8, 2-phenylimidazole was allowed to react with 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl methanesulfonate to give 2-[(E)-2-phenylethenyl]-4-[4-[4-(2-phenyl-1-imidazolyl) butyl]phenoxymethyl]oxazole. The yield was 40%. Recrystallization from ethyl acetate-isopropyl ether gave colorless prisms, mp 85-86° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH4+].[OH-]>C(O)C.C(OCC)(=O)C.[Zn]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1ncc2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Yield: 29.6 %

Procedure:
2,4-Dichloro-5-phenyl-thieno[2,3-d]pyrimidine (1 g, 3.56 mmol) and zinc dust (2.34 g, 35.6 mmol) were combined and stirred in ethanol (10 mL). NH4OH (1 mL) was added and the reaction heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (50 mL) and filtered through celite. The filtrate was washed with water (100 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of petroleum ether to 90/10 petroleum ether/ethyl acetate to afford 2-chloro-5-phenyl-thieno[2,3-d]pyrimidine (260 mg).
Reaction SMILES: Cl.[CH:2]12[CH2:7][CH:6]1[CH2:5][NH:4][CH2:3]2.CC(C)=O.[C-]#N.[K+].CN(C)[C:17]1([C:22]#[N:23])[CH2:21]CC[CH2:18]1>O>[CH:2]12[CH2:7][CH:6]1[CH2:5][N:4]([C:17]([CH3:21])([CH3:18])[C:22]#[N:23])[CH2:3]2
Reactant: C1NCC2CC12
Reactant: CN(C)C1(C#N)CCCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C#N)N1CC2CC2C1
Yield: 84 %

Procedure:
The title compound (583 mg, 84%) was prepared from 3-azabicyclo[3.1.0]hexane hydrochloride (550 mg, 4.6 mmol) [Pestic. Chem: Hum. Welfar Environ., Proc, Int, Congr. Pestic. Che., 5th, 1982, 1,159-64, 1983], acetone (267 mg, 4.6 mmol) and potassium cyanide (300 mg, 4.6 mmol) in water (2.5 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 0.40 (1H, m), 0.58 (1H, m), 1.43 (8H, m), 2.64 (2H, m), 3.10 (2H, d, J=8 Hz).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=O)[CH3:35]>>[CH2:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:35]=[C:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(=CCc1ccccc1)c1ccccc1
Yield: 46.3 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.48 g, 7.78 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.9 mL, 7.78 mmol, 1.0 equiv.) and acetophenone (1.40 g, 11.7 mmol, 1.5 equiv.), 0.75 g (46%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).