Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:3]1[OH:23].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O>>[OH:23][C@H:3]1[C@@H:2]([O:1][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Reactant: COCCOCCO
Product: COCCOCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O

Procedure:
350 mg of the title compound are obtained by column chromatographic purification on silica gel (eluent: diethyl ether/2-propanol=10/1) of the crude product from the above reaction of (7R,8R,9R)-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine with 2-(2-methoxyethoxy)ethanol. 1H-NMR (200 MHz, DMSO): δ=2.26 (s, 3H), 2.33 (s, 3H), 3.23 (s, 3H), 3.39-4.01 (m, 8H), 3.59-3.69 (m, 2H), 4.25-4.26 (d, 1H), 4.45-4.50 (m, 1H), 4.64-4.68 (d, 1 OH), 5.94-5.95 (d, 1 NH), 6.76-6.79 (d, 1H), 7.24-7.44 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[N:23]=1.O>CN(C)C=O>[Cl:34][C:30]1[CH:29]=[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[N:23]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: ClCc1cccc(-c2cccc(Cl)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cccc(-c3cccc(Cl)c3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 2-Chloromethyl-6-(3-chloro-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 8 ml water, the mixture was extracted with ethyl acetate tree times. The combined organic phases were dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 2:1) gave 0.151 g (83%) the title compound as white powder.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([Br:13])=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.O>C(O)C>[Br:13][C:8]1[C:7]([CH2:6][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Brc1ncccc1Cn1ccnc1
Temperature: 50 °C
Yield: 63.5 %

Procedure:
To a solution of (2-bromo-3-pyridyl)methyl methanesulfonate (2.5 g, 9.39 mmol) in ethanol (46.97 mL) at room temperature, potassium carbonate (2.62 g) and 1H-imidazole (1.31 g) are added. The mixture is stirred at 50° C. A thick sort of emulsion is formed and 10 mL of ethanol is added and the kind of emulsion is stirred at 50° C. overnight. Water is added until all solids are dissolved. Then, it is concentrated under reduced pressure and the residue is diluted with ethyl acetate and washed with sodium bicarbonate (saturated aqueous solution). Organic layer is decanted, dried over magnesium sulfate and solvent evaporated in vacuo. Crude material is purified by normal phase Isco chromatography using as eluent dichloromethane and methanol (98/2 to 90/10) to yield 1.42 g of the title compound. MS (m/z): 238, 240 (M+1, M+3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[N:40][CH:41]=1)=[C:34]=[O:35]>ClCCl.C1(C)C=CC=CC=1>[CH3:43][O:42][C:39]1[N:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1
Reactant: COc1ccc(N=C=O)cn1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of solution of 5-isocyanato-2-methoxy-pyridine (1.28 mL, 0.26 mmol) in toluene (from Example 62a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (6-methoxy-pyridin-3-yl)-amide as a white solid. (Yield 55 mg, 49.1%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][O:7]2)[CH2:3][CH2:2]1.C1O[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH:19](Cl)[CH2:20][CH3:21])[O:17]C1.C(=O)([O-])[O-:32].[K+].[K+]>C(O)CCC>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]([CH2:19][CH2:20][CH2:21][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:32])[O:7]3)[CH2:3][CH2:2]2)=[O:17])=[CH:28][CH:27]=1
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: O=C([O-])[O-]
Reactant: CCC(Cl)C1(c2ccc(F)cc2)OCCO1
Agent: [K+]
Solvent: CCCCO
Product: O=C(CCCN1CCC2(CC1)OC(=O)c1ccccc12)c1ccc(F)cc1
Reaction time: 65 h

Procedure:
A mixture of 4.0 g. of 1,3-dihydrospiro[isobenzofuran-1,4'-piperidine], 6.04 g. of α-chloro-p-fluorobutyrophenone ethylene ketal, 10 g. of potassium carbonate, and 50 ml. of 1-butanol is heated under reflux with stirring for 65 hours, cooled, and filtered. The filtrate is concentrated to an oil which is dissolved in 50 ml. of ethanol and 50 ml. of 3N hydrochloric acid. After 2 hours, the solution is made basic and extracted with benzene. Concentration of the benzene solution provides 1,3-dihydro1'-[3-(4-fluorobenzoyl)propyl]spiro[isobenzofuran-1,4'-piperidine]-3-one as an oil; hydrochloride salt, m.p. 183°-184°.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([C:15]1([N:14]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18][O:17][C:16]1=[O:20])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1OCCC1N=C(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCC1(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-[(diphenylmethylene)amino]dihydrofuran-2(3H)-one (1 g, 3.8 mmol) in DMF (10 mL) cooled to 0° C. was added NaHMDS (4.7 mL, 4.7 mmol, 1M THF) via serynge slowly. The resulting bright orange solution was stirred at 0° C. for 2 min at which point benzyl bromide (0.47 mL, 4 mmol) was addedvia serynge. After 5 min stirring at 0° C., the reaction was quenched with water, extracted with EtOAc, washed with aqueous LiCl, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (90 g silica gel, 0 to 40% EtOAc in hexane) to give 3-benzyl-3-[(diphenylmethylene)amino]dihydrofuran-2(3H)-one as a white solid. MS M+1=356.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:18][Mg]Cl.FC1C=C(C=CC=1)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>C(OCC)C.O=[Pt]=O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Fc1cc(Cl)cc(C[Mg]Cl)c1
Agent: O=[Pt]=O
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cccc(F)c1
Solvent: CCOCC
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cc(F)cc(Cl)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.40 g, 2.23 mmol) was reacted with 3-chloro-5-fluorobenzylmagnesium chloride ((0.25 M in diethyl ether, 23.0 mL, 5.6 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3-chloro-5-fluorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with PtO2). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 0.045 g The material was taken on to hydrolysis in impure form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11]
Reactant: COc1ccc(OC)c(C)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(OC)cc1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
2,5-dimethoxy toluene (6.0 g) was dissolved in acetic acid (20 mL). To the solution, a solution of fuming nitric acid (d=1.50, 4.32 g) in acetic acid (10 mL) was added dropwise at 40° C. over a period of 5 min. The mixture was stirred at 40° C. for 30 min. The reaction mixture was then allowed to cool to room temperature, which was stirred for another 30 min. Then the reaction mixture was diluted with cold water (300 mL). The resulting precipitate was filtered washed with cold water (100 mL) and dried under reduced pressure to afford the title compound (7.5 g).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=2)[CH:15]=[CH:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:22]([C:19]3[CH:20]=[C:21]4[C:16]([CH:15]=[CH:14][NH:13]4)=[CH:17][CH:18]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2cc[nH]c2c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and indole-6-carboxylic acid (Lancaster) according to methods A and C; yield 91 mg, 0.25 mmol (69%): 1H NMR (300 MHz, methanol-d4) δ 1.98 (d, J=13 Hz, 2H), 2.21 (s, 1H), 2.36 (d, J=13 Hz, 2H), 2.49 (s, 2H), 3.58 (s, 2H), 3.69 (s, 4H), 4.42 (s, 1H), 6.52 (dd, J=3, 1 Hz, 1H), 7.41 (d, J=3 Hz, 1H), 7.52 (dd, J=8, 2 Hz, 1H), 7.63 (dd, J=8, 1 Hz, 1H), 7.93-7.99 (m, 1H); MS (DCI/NH3) m/z 296 (M+H)+; Anal. C18H21N3O.HCl.1.1H2O.0.2C4H8O2: C, H, N.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCc1ccccn1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccn(CCc3ccccn3)n2)sc1C(=O)NCc1ccccc1
Temperature: 90 °C
Yield: 42.1 %

Procedure:
A solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (0.1 g, 0.33 mmol) in dimethyl sulfoxide (5 mL) was treated with 2-(2-bromo-ethyl)-pyridine (0.089 g, 0.33 mmol) and potassium carbonate (0.140 g, 1.0 mmol), and the reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue, was purified by preparative thin layer chromatography over silica gel eluting with (5% methanol, 95% methylene chloride) to provide 4-methyl-2-[1-(2-pyridin-2-yl-ethyl)-1H-pyrazol-3-yl]-thiazole-5-carboxylic acid benzylamide (56 mg, 43% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=4.0 Hz, 1H), 7.50-7.57 (m, 1H), 7.29-7.42 (m, 5H), 7.21 (s, 1H), 7.12-7.19 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 6.01 (bs, 1H), 4.62 (d, J=8.0 Hz, 2H), 4.61 (t, J=8.0 Hz, 2H), 3.36 (t, J=8.0 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=404.2; Rt=1.25 min; HRMS (M+H)+=404.15.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([OH:24])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[C:36]([O:39][CH2:40]Br)(=[O:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([O:24][CH2:40][O:39][C:36](=[O:38])[CH3:37])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC/C=C\C1=C(C(=O)OCOC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (300 mg, 0.69 m mole) and K2CO3 (95 mg, 0.69 m mole) in dry DMF (3 ml) was added dropwise at 0° C. a solution of bromomethyl acetate (105 mg, 0.69 m mole) in dry DMF (0.25 ml) and the mixture was stirred at 0° C. for 15 minutes. To the mixture was added again a solution of bromomethyl acetate (105 mg, 0.69 m mole) in dry DMF (0.25 ml). The reaction mixture was stirred for another 30 minutes and diluted with ethyl acetate (20 ml). The dilute was washed with water and a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was dissolved in methanol and passed through a column of the packing (40 ml) of a PrepPAK cartridge (Waters), which was washed with water and then eluted with 50% methanol. The eluate was monitored by HPLC. The desired fractions were collected and evaporated to give 96 mg (27%) of the title compound. Estimated purity 90% (by HPLC). M.p. 149°-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]=[C:13]([CH3:18])[C:14]([O:16]C)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]2[C:3]=1[NH:11][CH:12]=[C:13]([CH3:18])[C:14]2=[O:16]
Reactant: COC(=O)C(C)=CNc1cc([N+](=O)[O-])ccc1Br
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1c[nH]c2c(Br)ccc([N+](=O)[O-])c2c1=O
Temperature: 250 °C
Reaction time: 2 h
Yield: 309.1 %

Procedure:
A mixture of methyl 3-[(2-bromo-5-nitrophenyl)amino]-2-methylprop-2-enoate (Compound 304F, 10 g, 3.2 mmol) and PhOPh (6 mL) was stirred at 250° C. for 2 h. The reaction mixture was allowed to cool to room temperature. Petroleum ether (60 mL) was added to the reaction mixture and the precipitate was filtered. The material was purified by column chromatography to afford 2.8 g of the desired product (yield: 28%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ=1.95 (s, 3H), 7.48 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 11.46 (s, br, 1H).
Reaction SMILES: [CH3:1][NH:2][CH:3]=[N:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[CH3:12].[S:13](Cl)Cl.[CH3:16][NH:17][CH:18]=[N:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[CH3:27]>CCCCCC.C(N(CC)CC)C.C(Cl)Cl>[CH3:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[N:4]=[CH:3][N:2]([S:13][N:17]([CH3:16])[CH:18]=[N:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[CH3:27])[CH3:1]
Reactant: CNC=Nc1ccc(Cl)cc1C
Reactant: CNC=Nc1ccc(C)cc1C
Reactant: ClSCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1ccc(N=CN(C)SN(C)C=Nc2ccc(Cl)cc2C)c(C)c1
Temperature: -10 °C

Procedure:
To a solution of 9.13 g. (0.05 mole) of N-methyl-N'-(2-methyl-4-chlorophenyl)formamidine in 200 ml. of methylene chloride is added 5.05 g. (0.05 mole) of triethylamine. The reaction mixture is cooled to -10° C. and a solution of 5.15 g. (0.05 mole) sulfur dichloride in 5 ml. methylene dichloride is added dropwise keeping the temperature below 0° c. After addition the reaction mixture is allowed to warm to 15° C. About two-thirds of the methylene chloride is removed and 200 ml. of hexane added. The remainder of the methylene chloride is removed and an additional 100 ml. of hexane added. This suspension containing the formamidine sulfenyl chloride is added quickly to a solution of 8.1 g. (0.05 mole) N-methyl-N'-2,4-xylylformamidine and 5.05 g. triethylamine in 300 ml. of hexane with cooling and stirring. The reaction mixture is stirred for 1 hour at room temperature, filtered, and the solvent removed to leave a solid. The crude product is taken up in 200 ml. hexane solution and extracted with 6 g. of citric acid in 100 ml. of water. The hexane solution is dried over MgSO4, filtered, the solvent removed, and the residue recrystallized from Skellysolve B to yield 3.5 g. (18.6%) of product, m.p. 96°-98° C.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)([CH3:4])[CH3:3].[OH-].[K+]>C(O)(C)C.O>[NH:14]1[CH2:15][CH2:16][CH:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:2]([OH:1])([CH3:3])[CH3:4])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(C)(C)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(O)c1ccccc1C1CCNCC1
Temperature: 25 °C

Procedure:
A solution of intermediate D40 (27 g, 5.636 mmol) and KOH (2.433 g, 43.357 mmol) in isopropyl alcohol (13.5 ml) and water (27 ml) was heated at 180° C. under microwave irradiation for 60 min. After cooling to r.t., the mixture was washed with water and NaCl (aqueous saturated solution). The organic phase was dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 10% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D41 as a yellow solid (1.041. g, 84%). M.P. 219.5° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Cl[CH:13]([F:15])[F:14]>O1CCOCC1.O>[F:14][CH:13]([F:15])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(OC(F)F)cc1
Temperature: 70 °C
Yield: 59.4 %

Procedure:
Sodium hydroxide (48 g; 1.2 mole) is added to a stirred suspension of p-hydroxybenzaldehyde (48.9 g; 0.4 mole) in dioxane (142 ml) and water (87 ml). The mixture is heated to 70° C. and chlorodifluoromethane (33 g) added slowly. When this addition is completed, 50% sodium hydroxide solution (32 ml) is added to the reaction mixture, followed by the slow addition of chlorodifluoromethane (33 g). This recharging is repeated three times, and a total of 96 g (2.4 mole) of sodium hydroxide and 133 g (1.54 mole) of (1.54 mole) of chlorodifluoromethane is used in the reaction. The reaction mixture is cooled down, diluted with water (1500 ml) and extracted with ether several times. The ether layers are combined, washed with 10% sodium hydroxide and then dried over magnesium sulfate. Concentration of the ethereal solution yields 39 g (57%) of a yellow oil. This oil is purified by chromatography on a silica gel column using a mixture of hexane:methylene chloride (1:3), to afford 27 g (39%) of title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][O:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:15][CH2:16][O:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])=[CH:6][C:5]=1[OH:11]
Reactant: O=C1c2ccccc2C(=O)N1OCCCBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCON2C(=O)c3ccccc3C2=O)cc1O
Temperature: 25 °C
Yield: 29.1 %

Procedure:
To a solution of 2,4-dihydroxy-benzoic acid methyl ester (1.42 g, 8.45 mmol) and 2-(3-bromo-propoxy)-isoindole-1,3-dione (2.00 g, 7.04 mmol) ) in acetone (50 mL) was added cesium carbonate (6.88 g, 21.1 mmol). The mixture was heated to reflux for 3 hours and allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and brine and the layers were then separated. The aqueous layer was extracted with two additional portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using chloroform to give 4-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-propoxy]-2-hydroxy-benzoic acid methyl ester (0.76 g, 30%) as a white solid. 1H NMR (400 MHz, CDCl3); δ 10.86 (s, 1H), 7.76 (m, 2H), 7.68 (m, 3H), 6.40 (m, 2H), 4.35 (t, 2H), 4.21 (t, 2H), 3.85 (s, 3H), 2.20 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[N:9][C:10]([Cl:24])=[CH:11][N:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].[C:25]([O:29][C:30](=[O:37])[NH:31][C:32]([CH3:36])([CH3:35])[CH:33]=O)([CH3:28])([CH3:27])[CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:25]([O:29][C:30](=[O:37])[NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][NH:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[N:9][C:10]([Cl:24])=[CH:11][N:12]=2)[N:7]=1)[CH:3]([CH3:4])[CH3:5])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)C(N)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(NCC(C)(C)NC(=O)OC(C)(C)C)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
Formula 201 where R2 is H; R3 is Cl; R5 is Benzyl; R6 is Isopropyl; R6′ is H; Ra and Rb are Methyl; W and Z are —N═; X and Y are —C═: To a solution of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-pteridin-4-one (1.10 g, 3.19 mmol) and (1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (Seki et. al. Chem. Pharm. Bull. 1996, 44, 2061) (0.59 g, 3.19 mmol) in dichloromethane (80 mL) is added sodium triacetoxyborohydride (1.01 g, 4.79 mmol). The resultant mixture is maintained at ambient temperature for 4 hours, at which time it is quenched with brine (75 mL) and stirred vigorously for 10 minutes. The aqueous layer is extracted with dichloromethane (50 mL) and the combined extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give (±)-{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester which is used in the subsequent step without purification.