Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([CH3:22])([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH3:14])[C:7](=[O:23])[CH:6]3[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1.IC.[CH3:30]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([CH3:14])([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH3:22])[C:7](=[O:23])[C:6]3([CH3:30])[CH2:24][O:25][CH2:26][CH2:27][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(CN1C(=O)C2COCCN2c2nc(Cl)ncc21)OC1CCCCO1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC(C)(CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21)OC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 133.1 %

Procedure:
To a mixture of 2-chloro-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (96.2 mg, 0.242 mmol) and iodomethane (0.076 ml, 1.21 mmol) in DMSO (4 ml) at 0° C. was added sodium 2-methylpropan-2-olate (46.6 mg, 0.485 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 h, followed by being poured into water. Extraction with EtOAc, washing with water, drying and concentration in vacuo gave crude 2-chloro-6a-methyl-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (133 mg, 0.322 mmol) as a red oil which was used without further purification. MS [M+H] found 411.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:15][C:16]([NH2:18])=[S:17]>>[CH3:1][O:2][C:3]([C:4]1[N:15]=[C:16]([NH2:18])[S:17][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: NC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1
Product: COC(=O)c1nc(N)sc1-c1ccccc1

Procedure:
prepared by reaction of 3-chloro-3-phenyl-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.77 min; [M+H]+=235.
Reaction SMILES: [CH2:1]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[F:22][B-:23]([F:26])([F:25])[F:24].[N:27]#[O+].[K+].[Br-]>C(#N)C.C(Cl)Cl>[F:22][B-:23]([F:26])([F:25])[F:24].[CH2:1]([C:15]1[CH:16]=[CH:17][C:18]([N+:19]#[N:27])=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCc1ccc(N)cc1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCCCCCc1ccc([N+]#N)cc1
Yield: 69 %

Procedure:
The 4-tetradecylaniline was dissolved in a 1:1 mixture of acetonitrile and dry methylene chloride prior to addition to the nitrosonium tetrafluoroborate. Yield: 69%. MP 82° C. IR (KBr) 3103.8, 2919.5, 2289.6, 1577.8, 1473.7, 1070.8, 1024.8, 844.5, 813.8, 716.9, 541.0, 510.2 cm−1. IR (KBr) 3103.8, 2919.5, 2289.6, 1577.8, 1473.7, 1070.8, 1024.8, 844.5, 813.8, 716.9, 541.0, 510.2 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.02 (ABq, J=8.8 Hz, Δv=370.6 Hz, 4H), 2.76 (t, J=7.7 Hz, 2H), 1.61 (quin, J=7.8 Hz, 2H), 1.23 (s, 22H), 0.85 (t, J=7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 159.92, 133.26, 131.94, 110.96, 37.49, 32.34, 30.87, 30.12, 30.10, 30.07, 30.04, 29.91, 29.78, 29.75, 29.72, 23.11, 14.55.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:25])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCSc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCS(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
The product from Example 70 Step B (70 mg) was stirred in 2 mL of dichloromethane with 3-chloroperoxybenzoic acid (MCPBA) (40 mg) for 1 hour at 0° C. An additional 5 mg of MCPBA was added and the reaction stirred 30 minutes more, then diluted with EtOAc and washed with saturated NaHCO3 and brine. The solution was dried over Na2SO4 and concentrated in vacuo to give the titled compound. ESI+ MS: 218 [MH-Boc]+.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16].C(N(CC)CC)C>CN(C=O)C>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4][C:9](=[CH:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(=O)NC(=Cc2cccc([N+](=O)[O-])c2)C1=O
Yield: 66 %

Procedure:
1,4-Diacetyl-2,5-piperazinedione (1 equivalent), prepared by the published procedure mentioned in Example 3, was treated with 3-nitrobenzaldehyde (1 equivalent) in the presence of triethylamine (1 equivalent) in DMF at room temperature for 18-20 hrs. The title compound was obtained in 9% yield together with 1-acetyl-3-(3-nitrobenzylidene)-2,5-piperazinedione (66% yield). Characterising data are set out in Example 16.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cnn(-c2ccc(C=O)cc2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: Cc1cnn(-c2ccc(/C=C/C=O)cc2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methyl-1H-pyrazol-1-yl)-benzaldehyde (prepared as described in Reference Example 4) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1CC([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:44].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OC(C)C)(C)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[Br:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: O=C([O-])CC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: Br[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
2,3,4,6-tetra-O-benzyl-D-galactopyranosylacetate (79.8 g) was dissolved in a mixture of toluene (160 ml) and isopropyl ether (520 ml), and the solution was cooled to −10 to 0° C. To this solution, an isopropyl ether solution (2.8 mmol/ml, about 100 ml) containing 2.0 equivalent volumes of HBr was added. After stirring for about 90 minutes at −10 to 0° C., an aqueous 5% sodium hydrogencarbonate solution was poured into the reaction solution, and excessive HBr was neutralized by stirring. The whole volume was transferred into a separation funnel for separation, then the water layer was discarded and washing was carried 2 times with an aqueous 10% sodium chloride solution. After concentration under vacuum, 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide (GalBr) was obtained as a syrup.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
3-Pyridinamine (123 mg, 1.30 mmol) in DCM (15 ml) was added to a stirred solution of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method A; 200 mg, 0.65 mmol), HOBT (150 mg, 0.98 mmol) and EDC (187 mg, 0.98 mmol) in DCM (15 ml) under nitrogen at room temperature. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was partitioned between DCM (50 ml) and water (25 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulphate and evaporated in vacuo to give the crude product as a yellow solid. The crude product was added to a Biotage column and was eluted with petroleum ether:ethyl acetate (3:1) to yield the title compound as a white solid. 75 mg. MS (electrospray): m/z [M+H]+=383
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=O.C(O)C.[O-][Si]([O-])=O.[Mg+2].[N+:16]([CH3:19])([O-:18])=[O:17]>C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[CH:19][N+:16]([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: CC1CCNC1=O
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1CCNC1=C[N+](=O)[O-]

Procedure:
A solution of 12.7 grams (0.10 mole) of the ethyl imidate of 3-methyl-2-pyrrolidone in 30 milliliters of nitromethane was refluxed for four days with occasional distillation of ethanol by-product to bring the reflux temperature back to 100°C. Excess nitromethane (and ethanol present) then was evaporated under reduced pressure to give a dark oily residue. The residue was dissolved in ethyl acetate and passed through a Florisil column. Evaporation of the solvent from the filtrate left a crystalline residue, which when recrystallized from ether, gave 4.6 grams of 3-methyl-2-(nitromethylene)pyrrolidine, as a white solid, melting point: 47- 47.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)=[C:17]([NH:20][C:21](=[O:31])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.Br[CH2:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH:34]4[CH2:35][CH2:36]4)=[C:17]([NH:20][C:21](=[O:31])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[O:47])[CH2:27][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C(C=CCN1CCNCC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(C=CCN1CCN(CC(=O)OCc2ccccc2)CC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
500 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(piperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline are dissolved in 5 ml of acetonitrile, and 0.35 ml of triethylamine followed by 0.17 ml of benzyl bromo-acetate are added dropwise at room temperature. The reaction mixture is stirred for approximately 45 minutes at room temperature and then concentrated in vacuo. The solid residue is triturated with water and filtered off. The crude product is purified by column chromatography on silica gel with methylene chloride/methanol (20:1) followed by recrystallization from ethyl acetate. Yield: 380 mg (59% of theory), Melting point: 174° C. Mass spectrum (ESI−): m/z=657, 659 [M−H]−
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[N:14]=[C:15]([CH3:25])[S:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:12].Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.CCN(C(C)C)C(C)C>C(#N)C>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[NH:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[N:14]=[C:15]([CH3:25])[S:16][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[O:12]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1nc(C(=O)N2CC3CCCC3C2CN)c(-c2ccc(F)cc2)s1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CC3CCCC3C2CNc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of (1-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chlorobenzoxazole, and DIPEA in ACN was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 477.4 (M+H).
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][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[CH3:29][NH:30][CH3:31].C(O)C>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:30]([CH3:31])[CH3:29])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CN(C)C
Temperature: 60 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and 2.0 M dimethylamine in ethanol (4.60 ml, 9.30 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-dimethylaminopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (308 mg, 78%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[NH:12]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1)[NH2:13]
Reactant: COCc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COCc1ccc(NN)nc1

Procedure:
2.2 g (14.0 mmol) of the compound from Example 12A are initially charged in 10 ml of ethanol. 7.0 g (140.0 mmol) of hydrazine hydrate are added, and the mixture is stirred under reflux for 16 h. The reaction mixture is then reacted again in a single-mode microwave oven (CEM Explorer) at 150° C. for 2 h. The mixture is then concentrated on a rotary evaporator, taken up in ethyl acetate, washed once with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated again, and the residue is dried under high vacuum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[CH2:10]([N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:28]([C:30]1[CH:31]=[N:32][CH:33]=CC=1)#[N:29].B(O)(O)C1C=CC=C(F)C=1>ClCCl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:33]2[N:29]=[CH:28][C:30]([C:21]3[NH:17][C:18]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[N:19][CH:20]=3)=[CH:31][N:32]=2)[CH:2]=1.[CH2:10]([N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1cccnc1
Reactant: N#Cc1cccnc1
Agent: OB(O)c1cccc(F)c1
Agent: c1ccc(Cn2ccnc2-c2cccnc2)cc1
Solvent: CO
Solvent: ClCCl
Product: c1cncc(-c2ncc(-c3cnc(-c4cccnc4)[nH]3)cn2)c1

Procedure:
The title compound was prepared by the method described in Example 1, except that (i) commercially available 3-pyridyl boronic acid was used instead of benzene boronic acid in Step A, and (ii) 3-(1-benzyl-1H-imidazol-2-yl)pyridine was used instead of 1-benzyl-2-phenyl-1H-imidazole in Step C. 3-(1-Benzyl-1H-imidazol-2-yl)pyridine was prepared by the method described in Example 8, Steps A and B except the commercially available 3-cyanopyridine was used instead of 3-fluorobenzonitrile; Rf 0.35 with 92.5:7.5 v/v dichloromethane-methanol; melting point 299° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.52 (s, 1H), 9.35 (s, 2H), 9.21 (s, 1H), 8.72-8.65 (m, 2H), 8.60-8.56 (m, 1H), 8.37-8.32 (m, 1H), 8.15 (s, 1H), 7.58-7.50 (m, 2H); LC/MS (ESI+) m/z 301.1 (M+1); H-PGDS FPBA IC50: 1.3 μM.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:18])=[C:11]([CH:15]([CH3:17])[CH3:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cccc(OCc2ccccc2)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 36 h
Yield: 92.4 %

Procedure:
To a solution of 33 (452 mg, 2.00 mmol) in CCl4 (20 mL) were added N-bromosuccinimide (373 mg, 2.10 mmol) and silica gel (1 g) and the mixture was stirred in the dark at room temperature for 36 hours. Then, the mixture was filtered and the filtrates were washed with satured solution of sodium thiosulphate (10 mL). The organic phase were dried over Na2SO4, filtered and concentrated on vacuo to give 564 mg of bromoaryl 34. Yield 93%. 1H NMR (300 MHz, CDCl3) δ ppm: 7.32-7.51 (m, 6H), 6.92 (d, J=3.0 Hz, 1H), 6.68 (dd, J1=8.7 Hz, J2=3.0 Hz, 1H), 5.04 (s, 2H), 3.31 (sep, J=6.9 Hz, 1H), 1.22 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ ppm: 158.4, 148.5, 136.7, 133.2, 128.6, 128.1, 127.5, 115.0, 114.0, 113.3, 70.2, 33.0, 22.7; HRMS (EI) m/z: calcd for C16H17BrO: 304.0463. found: 304.0465.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].C(N(CC)O)C.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:49])[C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([O:36][CH3:37])[C:30]=2[NH:38][C:39]([C:41]2[S:42][CH:43]=[C:44]([CH2:47]Cl)[C:45]=2[Cl:46])=[O:40])=[N:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:49])[C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([O:36][CH3:37])[C:30]=2[NH:38][C:39]([C:41]2[S:42][CH:43]=[C:44]([CH2:47][N:1]3[C:12](=[O:13])[CH:11]4[CH:6]([N:7]=[CH:8][N:9]4[CH3:10])[N:4]([CH3:5])[C:2]3=[O:3])[C:45]=2[Cl:46])=[O:40])=[N:25][CH:26]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: CCN(O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN2C(=O)C3C(N=CN3C)N(C)C2=O)c1Cl
Temperature: 40 °C
Reaction time: 144 h

Procedure:
In a similar manner to that described in Paragraph F above, to a solution of theobromine (1.06 g, 5.9 mmol), N,N-diethylhydroxylamine (0.45 g, 5.0 mmol), N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.32 g, 0.6 mmol), and DMF (40 mL) was added K2CO3 (0.74 g, 5.3 mmol). The mixture was stirred at 40° C. for 6 days, then it was poured into water. The solid was isolated by filtration. Purification by recrystallization from CH2Cl2 and CH3OH afforded N-(5-chloropyridin-2-yl)-2-[((4-((2,3,4,5,6,7-hexahydro-3,7-dimethyl-2,6-dioxo-1H-purin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, as a white solid; NMR (DMSO-d6) 10.90 (s, 1H), 9.40 (s, 1H), 8.36 (d, 1H), 8.12 (d, 1H), 8.06 (s, 1H), 7.90 (dd, 1H), 7.55 (s, 1H), 7.38 (d, 1H), 7.27 (d, 1H), 4.97 (s, 2H), 3.90 (s, 6H), 3.40 (s, 3H) ppm.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH2:32]O)[CH:31]=1)[C:26]([NH2:28])=[O:27]>C(#N)C>[Br:20][CH2:32][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([Cl:22])[CH:31]=1)[C:26]([NH2:28])=[O:27]
Reactant: BrBr
Reactant: NC(=O)c1cc(Cl)cc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: NC(=O)c1cc(Cl)cc(CBr)c1
Reaction time: 0.5 h

Procedure:
(Step 2) Triphenylphosphine (1.27 g) was suspended in acetonitrile (50 ml), bromine (0.25 ml) was added, and the suspension was stirred for 30 min. 3-Chloro-5-(hydroxymethyl)benzamide (0.90 g) obtained in Step 1 was added to the reaction mixture, and the mixture was stirred at 85° C. for 2 hr. The reaction solution was quenched with water and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate:hexane=1:1) to give 3-(bromomethyl)-5-chlorobenzamide (0.54 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:5]([CH3:18])=[C:4]([CH3:19])[N:3]=1.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[N-:31]=[N+:32]=[N-:33].[Na+].C(#N)C>O>[CH3:19][C:4]1[N:3]2[N:31]=[N:32][N:33]=[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:5]=1[CH3:18]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCO)c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1c(NCCCCCO)c([N+](=O)[O-])c2nnnn2c1C
Temperature: 25 °C

Procedure:
The preparation of 5-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)pentan-1-ol was described in Part A of Example 85. Under a nitrogen atmosphere, cerium (III) chloride heptahydrate (8.08 g, 21.7 mmol) and sodium azide (5.64 g, 86.8 mmol) were added to a solution of 5-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)pentan-1-ol (12.48 g, 43.38 mmol) in a 9:1 mixture of acetonitrile and water (145 mL). The reaction was stirred and heated at reflux for two days then allowed to cool to room temperature. A precipitate was removed by filtration and washed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 12.13 g of 5-[(5,6-dimethyl-8-nitrotetrazolo[1,5-a]pyridin-7-yl)amino]pentan-1-ol as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][N:7]1[C:11](I)=[C:10]([C:13]#[N:14])[N:9]=[CH:8]1.C([Sn](CCCC)(CCCC)[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)CCC>C(#N)C.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][N:7]1[C:11]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[C:10]([C:13]#[N:14])[N:9]=[CH:8]1
Reactant: N#Cc1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: N#Cc1ccccc1
Product: N#Cc1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Reaction time: 72 h

Procedure:
In a pressure vessel dissolve 1-(3,5-Bis-trifluoromethyl-benzyl)-5-iodo-1H-imidazole-4-carbonitrile (0.52 g, 1.2 mmol) in acetonitrile. Add 3-tributylstannanyl-pyridine (0.64 g, 1.7 mmol) and bis(benzonitrile)dichloropalladium(II) (22 mg, 0.06 mmol), and stir at 100° C. After 72 h, quench with sat. aq. NaHCO3, and extract with ether. Wash the organic layer with brine, dry over MgSO4, filter, and concentrate. Purify by radial chromatography on silica gel to give the title compound: MS (ES) 397.2 (M+1); 1H NMR (300 MHz, CDCl3) δ 8.75 (d, J=4.6 Hz, 1H), 8.60 (ap d, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.66 (m, 1H), 7.44 (m, 1H), 7.36 (s, 2H), 5.30 (s, 2H).