Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=3)[C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.[ClH:35]>CO.O1CCOCC1.[Pd]>[ClH:35].[C:32]([CH2:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH2:22][CH2:23][NH:11][CH2:12][C:13]2=3)=[CH:26][CH:27]=1)([OH:34])=[O:33]
Reactant: O=C(O)Cc1ccc(Cn2c3c(c4ccccc42)CCN(C(=O)OCc2ccccc2)C3)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)Cc1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 2-benzyloxycarbonyl-9-{[4-(carboxymethyl)phenyl]methyl}-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (6.91 g, 15.22 mmole) in methanol (50 mL), dioxane (50 mL) and HCl (19 mL, 1M in dioxane) at RT in a Parr hydrogenation flask was added 10% Pd/C (0.5 g). The reaction mixture was shaken under 45 psi of H2 for 6 hr. The suspension was filtered through celite®, and the filter pad was washed with methanol. The filtrate was concentrated on the rotavap, and the residue was dried under high vacuum to afford the titled compound (5.22 g, 90%) as a white solid: MS (ES) m/e 345 (M+H−HCl)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)=[O:18]
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 ml dry DMF, p-chlorophenylisocyanate (15.36 g, 0.100 mole) is added dropwise with cooling. The mixture is stirred for 16 hours and then poured into about 500 ml of iced-water to yield the crystalline product which is filtered off, washed with water and recrystallized twice from acetone-methanol, once from tetrahydrofuran (THF) and then from DMF-methanol. The resultant pure 1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-p-chlorophenylurea is dried in vacuo for 24 hours; m.p. 190°-2°C dec.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>C1C=CC=CC=1>[C:7]1([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH:8]=1
Reactant: O=C1CCCC1
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: C1=C(N2CCCCC2)CCC1
Temperature: 80 °C

Procedure:
Piperidine (4.0 g, 46.9 8 mmol) was added to a solution of cyclopentanone Compound 1a (4.0 g, 46.50 mmol) in benzene (100 mL) at ambient temperature under a N2 atmosphere. The mixture was refluxed at 80° C. for 5 hrs using a Dean Stark apparatus, then concentrated to dryness to provide 1-cyclopent-1-enyl-piperidine Compound 1b (7.0 g) as a crude oil which was used in the next step without further purification.
Reaction SMILES: CC1(C)CC(N)=C(C)C=C1C1C=C(C)C(N)=CC=1.[O:19]=[CH:20][C@@H:21]([C@H:23]([C@@H:25]([C@@H:27]([CH2:29][OH:30])[OH:28])[OH:26])[OH:24])[OH:22].[O:31]=[O:32]>C(O)C>[O:19]=[C:20]([OH:31])[C@@H:21]([C@H:23]([C@@H:25]([C@@H:27]([CH2:29][OH:30])[OH:28])[OH:26])[OH:24])[OH:22].[OH:31][OH:32]
Reactant: O=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC1=C(N)CC(C)(C)C(c2ccc(N)c(C)c2)=C1
Solvent: CCO
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OO

Procedure:
The NPs were removed by washing the tube. Next, a second cycle of ML was performed to protect the GOx binding sites by magnetic NPs using a multi-peg magnet that induced the magnetic field at the GOx binding sites. Then, the covalent coupling of HRP to amino propyl silane was performed by injecting buffer solution (e.g. 0.05M HEPES buffer solution) containing 0.3 mg ml−1 HRP (RC. 1.11.1.7) in the presence of EDC (e.g. 0.01 M EDC with an incubation time of 2 h at room temperature). Consequently, the HRP covalently bound to the amine groups, which are located in-between GOx binding sites. The sequential enzymatic reaction in the tube was initiated by injecting to the tube glucose with 2,2,5,5′ tetramethyl-benzidine (TMB). TMB was dissolved in ethanol then diluted with 0.1M buffer phosphate pH 6.0 with 50 mM glucose to yield the glucose solution that includes 1 mM TMB and 2%(v/v) ethanol. The glucose was oxidized by the GOx and O2 to yield gluconic acid and H2O2. The H2O2 diffused to the HRP binding sites and there the HRB biocatalyzed the oxidation of TMB by H2O2, yielding an insoluble product.
Reaction SMILES: Cl.C([NH:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]3[CH:20]=[N:21][CH:22]=[C:15]23)=[CH:10][CH:9]=1)(C)(C)C.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH:22]1[N:21]=[CH:20][N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]#[N:6])=[CH:13][CH:12]=3)[C:15]=12
Reactant: CC(C)(C)NC(=O)c1ccc(C2CCCn3cncc32)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(C2CCCn3cncc32)cc1
Temperature: 25 °C

Procedure:
A solution of 1.74 mmol of N-tert-Butyl-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-yl)-benzamide hydrochloride and 1.4 ml of thionyl chloride in 30 ml of chloroform is stirred under reflux for 7 hours. The reaction mixture is cooled to room temperature and evaporated. The residue is taken up in dichloromethane and mixed with saturated aqueous sodium bicarbonate solution. The organic phase is separated off and the aqueous phase is extracted with dichloromethane (2×). The combined organic phases are dried with sodium sulphate and evaporated. Following flash chromatography (SiO2 60F) of the residue, the resulting solid is stirred in 1:1 diethyl ether/tert-butyl methyl ether, filtered and dried. The title compound is obtained as a cream-colored solid. Rf=0.37 (toluene:methanol=85:15); Rt=4.88
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14]COC)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]1([C:32]2[CH:36]=[C:35]([NH:37][C:38](=[O:46])OC3C=CC=CC=3)[O:34][N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:38]([NH:37][C:35]2[O:34][N:33]=[C:32]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:36]=2)=[O:46])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1cc(-c2ccccc2)no1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CO
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(-c5ccccc5)no4)c3)c2cc1OC

Procedure:
The title compound was prepared according to the procedure described in Example 207 by using 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (102 mg, 0.3 mmol) and phenyl 3-phenylisoxazol-5-ylcarbamate from Example 114B (109 mg, 0.45 mmol) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-phenylisoxazol-5-yl)urea as a white solid upon trituration with methanol (26 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.13 (s, 1H), 9.13 (s, 1H), 7.83 (m, 2H), 7.59 (d, 2H), 7.50-7.41 (m, 5H), 7.33 (d, 2H), 7.00 (d, 1H), 6.56 (s, 1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.35 (s, 3H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: CC(NC(=O)/C=C/C=[CH:11]/[C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[C:22](Br)Br)=[CH:17][CH:16]=1)C(C)C.C([Li])CCC.[OH2:31]>O1CCCC1>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C@@H:13]2[CH2:14][C@H:12]2[CH2:11][OH:31])=[CH:16][CH:17]=1)#[CH:22]
Reactant: O
Reactant: CC(C)C(C)NC(=O)/C=C/C=C/[C@@H]1C[C@H]1c1ccc(C=C(Br)Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1ccc([C@@H]2C[C@H]2CO)cc1

Procedure:
(±)-Trans-2-[4-(2,2-dibromoethenyl)phenyl]cyclopropylmethanol (1.43 g) (prepared as in example 16) in dry tetrahydrofuran under nitrogen at -40° was treated with n-butyllithium (8.1 ml) After 4 hours at 25° water was added and the mixture worked up in the usual manner. Purification by chromatography (silica ether/hexane) gave (±)-trans-2-(4-ethynylphenyl)cyclopropane methanol (0.62 g). NMR 1H: 7.41(2H,d), 6.90(2H,d), 3.30(2H,d), 2.95(1H,s), 2.59(1H,s), 1.85(1H,m), 1.34(1H,m), 0.90(2H,m).
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)([O:3]CC)=O.[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[NH2:23][CH2:22][CH2:21][NH:24][C:1]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)=[O:3]
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Reactant: NCCN
Product: NCCNC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 60 °C
Yield: 80.3 %

Procedure:
A mixture of 2.85 g (10.3 mmol) of 6-(4-carbethoxymethoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as described in Example 13) and 9.3 g (155 mmol) of ethylenediamine is heated at 60° C. under N2 for 30 min. Volatile materials are removed in vacuo, and the residue is recrystallized from methanol-EtOAc to give 2.40 g of 6-[4-[2-aminoethylcarbamoylmethoxy]phenyl]-4,5-dihydro3(2H)-pyridazinone as a white solid, m.p. 176°-177.5° C. Yield, 80%.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:23]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH2:31])=[O:30])=[CH:32][CH:33]=4)[C:14](=[O:16])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:2][CH3:3]
Reactant: NCc1ccc(C(N)=O)cc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(C(N)=O)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 4-(aminomethyl)benzamide (0.26 g, 1.4 mmol). Purification using silica gel, eluting with 19:1 CH2Cl2 /MeOH, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH to give 111 as a white solid (m.p. 294° C.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14].[OH-].[Na+].C(O)=O>CO>[CH3:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:14])([F:15])[F:16]
Reactant: COC(=O)c1c[nH]c(-c2ccccc2C(F)(F)F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: Cc1c(C(=O)O)c[nH]c1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 83.4 %

Procedure:
Methyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (1.4 g, 4.9 mmol) was dissolved in methanol (12 mL), and a 5 M aqueous sodium hydroxide solution (10 mL) was added thereto, and the resulting mixture was heated under reflux for 3 hours. After the mixture was cooled to room temperature, formic acid (5 mL) was added thereto to stop the reaction. After the mixture was concentrated under reduced pressure, water (10 mL) was added thereto to suspend the resulting residue. The precipitated solid was collected by filtration and washed 3 times with water. The obtained solid was dried under reduced pressure, whereby 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (1.1 g, 83%) was obtained as a solid. The thus obtained solid was suspended in dichloromethane (10 mL), oxalyl chloride (0.86 mL, 10 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 2 hours. After the mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL), and 4-(methylsulfonyl)aniline hydrochloride (1.0 g, 4.9 mmol) and N,N-diisopropylethylamine (2.8 mL, 16 mmol) were sequentially added to the solution, and the resulting mixture was heated under reflux for 18 hours. After the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and acetonitrile (10 mL) and 3 M hydrochloric acid (100 mL) were added to the residue. A precipitated solid was triturated, collected by filtration and washed with water, and then, dried under reduced pressure, whereby 4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (1.4 g, 89%) was obtained as a solid.
Reaction SMILES: C[Si](Br)(C)C.C([NH:8][CH:9](/[CH:20]=[C:21](\[CH3:33])/[CH2:22][P:23]([O:29]C(C)C)([O:25]C(C)C)=[O:24])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O.C(O)C1C=CC=CC=1>ClCCl>[NH2:8]/[C:9](=[CH:20]/[CH:21]([CH3:33])[CH2:22][P:23]([OH:29])([OH:25])=[O:24])/[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: C/C(=C\C(NC=O)C(=O)OCc1ccccc1)CP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: OCc1ccccc1
Solvent: ClCCl
Product: CC(/C=C(/N)C(=O)OCc1ccccc1)CP(=O)(O)O
Reaction time: 20 h

Procedure:
23 ml (178 mmols) of trimethylsilyl bromide are added dropwise at room temperature to a solution of 18.3 g (44.5 mmols) of benzyl E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoate in 73 ml of dichloromethane. After 20 hours at room temperature 46 ml of benzyl alcohol are added dropwise, and the reaction mixture is allowed to stand for additional 20 hours at room temperature. The dichloromethane is distilled off, first 40 ml of ethanol and then dropwise 40 ml of propyleneoxide in 40 ml of ethanol are added. The crystalline precipitate formed is filtered off, triturated with 200 ml of water and filtrated off again. Benzyl E-2-amino-4-methyl-5-phosphono-pentenoate of m.p. 196°-197° (decomp.) is thus obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10](/[CH:11]=[CH:12]/[CH3:13])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:14].C[N+]1([O-])CC[O:19]CC1.C(#N)C.[OH2:26]>O.O.[O-][Os]([O-])(=O)=O.[K+].[K+]>[OH:26][CH:11]([C:10]1[C:2]([CH3:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:14])[O:5][CH2:4]2)[CH:12]([OH:19])[CH3:13]
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C/C=C/c1ccc2c(c1C)COC2=O
Agent: O=[Os](=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(C(O)C(C)O)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (E)-4-methyl-5-(prop-1-en-1-yl)isobenzofuran-1(3H)-one (300 mg, 1.59 mmol) in acetonitrile/water (10/1, 18 mL) was added NMO (243 mg, 2.07 mmol) and potassium osmate(VI) dihydrate (29.4 mg, 0.080 mmol) at 0° C. The reaction mixture was allowed to warm to rt and stirred at rt for 2 h. TLC showed the reaction completed. The reaction mixture was filtered through a pad of silica gel, rinsed with 10% MeOH/DCM. The crude product was purified with column chromatography (0-10% MeOH/DCM) to give the title compound. LC/MS: [(M+1)]+=223
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:13][C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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:13][C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:23]([CH3:26])=[CH:22][CH:21]=1)=[O:18]
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1I
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Yield: 97.8 %

Procedure:
(3-Nitrophenyl)boronic acid (1.7 g, 10.0 mmol) was mixed with 3-fluoro-N-(3-iodo-4-methylphenyl)-5-(trifluoromethyl)benzamide (4.30 g, 10.2 mmol) and potassium carbonate (2.5 g, 18 mmol) in toluene (75.00 mL), ethanol (11.00 mL) and water (10.00 mL) and was degassed. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.43 mmol) and the resulting mixture was heated to reflux for 18 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated in vacuo. The residue was purified by column chromatography using 20% EtOAc/hexanes to give the product (4.09 g, 96% yield). MS (EI) m/z=419 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (5.0 g, 27 mmol) and piperidine (2.3 g, 27 mmol) in tetrahydrofuran (50 mL) and N,N-diisopropylethylamine (3.5 g, 27 mmol) was stirred at room temperature for 24 hours. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with a gradient of hexane to yield ethyl acetate/hexane (1:4). The eluent was removed, giving 2,4-dichloro-6-(1-piperidinyl)pyrimidine (3.67 g, 15.8 mmol, 59%, Rf=0.58 in ethyl acetate/hexane, 1:4).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27]>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH:10][C:26](=[O:27])[C:25]3[C:24]([Cl:23])=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:33])[CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COc1ccc(N)cc1OC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
A stirred solution of 3-cyclopentyloxy-4-methoxyaniline (1 g) and triethylamine (0.69 mL) in dry dichloromethane (20 mL) at 0° C. is treated dropwise with 2,6-dichlorobenzoyl chloride (1.17 g). After stirring at this temperature for 30 minutes, the mixture is warmed to room temperature and stirred for a further 3 hours. The organic layer is washed with water (100 mL), dried and concentrated. The residue is recrystallized from a mixture of isopropanol and hexane, to give N-(3-cyclopentyloxy-4-methoxyphenyl)-2,6-dichlorobenzamide (0.6 g), m.p. 184°-185° C. [Elemental analysis: C,60.2,H,5.0; N,3.6; Cl,18.9%; calculated: C,60.0; H,5.0; N,3.7; Cl, 18.65%].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][CH2:42][CH3:43])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:42]([O:41][CH2:40][CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:33][CH:34]=1)[CH3:43]
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (5.0 g) was added toluene/ethanol/water (10/1/1, 188 ml) and then were added 4-(2-ethoxyethoxy)phenyl borate (4.1 g) and potassium carbonate (4.6 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.7 g), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give methyl 7-[4-(2-ethoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (4.6 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[NH:13][CH2:14][C:15]1[C:16]([NH2:23])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[NH:23][C:1]1=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(N)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)NC(=O)N(c1c(Cl)cccc1Cl)C2
Reaction time: 1 h
Yield: 89 %

Procedure:
A stirred solution, cooled in ice, of 5.8 ml (11.2 mmol) of phosgene (20% in toluene) in 80 ml of tetrahydrofuran was treated dropwise with a solution of 1.76 g (5.6 mmol) of 5-(2,6-dichlorophenyl)aminomethyl-4-amino-2-methylthiopyrimidine and 1.6 ml (11.2 mmol) of triethylamine in 80 ml of tetrahydrofuran. The mixture was stirred for 1 hour. 50 ml of tetrahydrofuran and 50 ml of saturated aqueous ammonium chloride solution were added. The phases were separated and the organic phase was washed with saturated aqueous ammonium chloride solution, dried over magnesium sulfate, filtered and evaporated to give 1.7 g (89%) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[Na+].[Na+].[C:7]([OH:10])(=[O:9])[CH3:8].[CH:11]1[N:12]=[C:13]([NH2:54])[C:14]2[N:19]=[CH:18][N:17]([C@@H:20]3[O:24][C@H:23]([CH2:25][O:26][P:27]([O:30][P:31]([O:34][CH2:35][C@H:36]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H:38](O)[C@@H:37]4[OH:51])([OH:33])=[O:32])([OH:29])=[O:28])[C@@H:22]([OH:52])[C@H:21]3[OH:53])[C:15]=2[N:16]=1>CC#N>[CH3:8][C:7]([O:10][C@H:38]1[CH:1]([OH:4])[O:2][C@H:36]([CH2:35][O:34][P:31]([O:30][P:27]([O:26][CH2:25][C@H:23]2[O:24][C@@H:20]([N:17]3[C:15]4[N:16]=[CH:11][N:12]=[C:13]([NH2:54])[C:14]=4[N:19]=[CH:18]3)[C@H:21]([OH:53])[C@@H:22]2[OH:52])([OH:29])=[O:28])([OH:33])=[O:32])[C@H:37]1[OH:51])=[O:9]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)O[C@H]1C(O)O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](O)[C@@H]2O)[C@H]1O
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
To 80 mg of Na2CO3 was added 2 mL of glacial acetic acid. The mixture was stirred at 85° C. until all the Na2CO3 reacted. 250 mg of NAD was added and the mixture was stirred at 85° C. for 15 min, cooled to below 75° C. and diluted with 20 mL of CH3CN. The precipitate was filtered, suspended in 5 mL of CH3CN, and filtered again to give crude OAADPR.