Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH3:34])(=[O:33])=[O:32])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(C)(=O)=O)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product was isolated as a white solid (34 mg, 31%). LCMS 504.08 (M+H), MP 184-188, HPLC purity, 99%, 1H-NMR (CDCl3, 400 MHz) δ 11.70 (s, 1H), 10.25 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.98 (s, 1H), 7.58-7.54 (m, 1H), 7.50-7.42 (m, 2H), 7.34 (s, 1H), 7.12 (d, J=8.6 Hz, 1H), 3.98-3.88 (m, 2H), 3.85-3.78 (m, 2H), 3.65-3.50 (m, 2H), 3.37 (s, 5H), 2.92 (s, 3H), 2.98-2.80 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:16]=[CH:15][C:14]([CH:17]=[CH2:18])=[CH:13][C:10]=2[C:11]#[N:12])[N:5]=1)([O-:3])=[O:2].Br[CH:20]([C:25]1[CH:26]=[C:27]([Cl:33])[C:28]([Cl:32])=[C:29]([Cl:31])[CH:30]=1)[C:21]([F:24])([F:23])[F:22].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH:20]([C:25]3[CH:26]=[C:27]([Cl:33])[C:28]([Cl:32])=[C:29]([Cl:31])[CH:30]=3)[C:21]([F:23])([F:22])[F:24])=[CH:13][C:10]=2[C:11]#[N:12])[N:5]=1)([O-:3])=[O:2]
Reactant: C=Cc1ccc(-n2cnc([N+](=O)[O-])n2)c(C#N)c1
Reactant: FC(F)(F)C(Br)c1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc([N+](=O)[O-])n1
Temperature: 180 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(3-nitro-1H-1,2,4-triazol-1-yl)-5-vinylbenzonitrile (0.9 g, 3.7 mmol) in 1,2-dichlorobenzene (10 mL), were added 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (2.5 g, 7.5 mmol), CuCl (73 mg, 0.74 mmol) and 2,2-bipyridyl (0.23 g, 1.49 mmol) and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 14 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh, 25-30% EtOAc in Pet ether) afforded the title compound as an off white solid (0.9 g, 50%): mp 70-73° C.; 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 1H), 7.88 (m, 3H), 7.44 (s, 2H), 6.67 (d, J=16.0 Hz, 1H), 6.56 (dd, J=16.0, 7.6 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 436.11 ([M−2H]−).
Reaction SMILES: [CH3:1][CH:2]1[N:8]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[CH:11]=[C:7]2[C:6](=[O:19])[NH:5][CH2:4][CH2:3]1.ClC(N(C)C)=C(C)C.[CH2:28]([C:35]1[O:39][N:38]=[C:37]([NH2:40])[CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:28]([C:35]1[O:39][N:38]=[C:37]([NH:40][C:16]([C:14]2[CH:13]=[CH:12][C:10]3[CH:11]=[C:7]4[C:6](=[O:19])[NH:5][CH2:4][CH2:3][CH:2]([CH3:1])[N:8]4[C:9]=3[N:15]=2)=[O:18])[CH:36]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1CCNC(=O)c2cc3ccc(C(=O)O)nc3n21
Reactant: Nc1cc(Cc2ccccc2)on1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1CCNC(=O)c2cc3ccc(C(=O)Nc4cc(Cc5ccccc5)on4)nc3n21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a suspension of 10-methyl-6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxylic acid (Intermediate G, 75 mg, 0.29 mmol) in CH2Cl2 (5 mL) is added 1-chloro-N,N,2-trimethylpropenylamine (138 μL, 1.01 mmol) and the mixture is stirred at room temperature for 30 min. 5-benzyl-1,2-oxazol-3-amine (Intermediate W, 252 mg, 1.45 mmol) and pyridine (94 μL, 1.16 mmol) are added and the reaction is stirred at room temperature for 20 h. The mixture is concentrated under reduced pressure and the residue is purified via preparative HPLC using a gradient elution from 10-90% acetonitrile/H2O with 0.1% TFA to afford the title compound (19 mg, 16%). LCMS: 416.20 (M+H+). (System V-med polar)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[CH:8][CH:7]=1.I[CH3:26].[OH-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[N:23]=[N:22][N:21]([CH3:26])[N:20]=2)=[CH:10][CH:11]=1.[CH3:1][O:2][C:3](=[O:24])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[N:20]([CH3:26])[N:21]=[N:22][N:23]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2CCc2nnn[nH]2)cc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2nnn(C)n2)cc1
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2nnnn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %
Yield: 27 %

Procedure:
To a solution of (E)-3-(4-{1-[2-(1H-tetrazol-5-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (1.0 g, 2.1 mmol) in dimethylformamide (5 mL) was added iodomethane (1.91 mL, 30.6 mmol) and sodium hydroxide (1.64 g, 30.7 mmol). The reaction was stirred at room temperature for 2 h, ice water was added, and the resulting mixture was extracted several times with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography to give (E)-3-(4-{1-[2-(2-methyl-2H-tetrazol-5-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (0.15 g, 21%, LCMS (m/z): 342.1 (M+1)) and (E)-3-(4-{1-[2-(1-methyl-1H-tetrazol-5-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (0.20 g, 27%, LCMS (m/z): 342.1 (M+1)).
Reaction SMILES: [C:1]([O:4][CH:5]=[C:6]1[CH:12]2[CH:9]([C:10](Cl)(Cl)[C:11]2=[O:13])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].C(O)(=O)C>C(Cl)Cl.[Zn]>[C:1]([O:4][CH:5]=[C:6]1[CH:12]2[CH:9]([CH2:10][C:11]2=[O:13])[CH:8]=[CH:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC=C1C=CC2C1C(=O)C2(Cl)Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)OC=C1C=CC2CC(=O)C12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
A mixture of 540 mg of 4-(acetoxymethylene)-7,7-dichloro-6-oxobicyclo[3.2.0]hept-2-ene, 600 mg of zinc dust and 10 mL of acetic acid was stirred at room temperature for 15 min under argon. An additional 500 mg of zinc was then added; the mixture was stirred between 75° and 80° for 1 hr. The temperature was raised to between 85° and 90° and after addition of 1 g of zinc dust the mixture was stirred for 1 hr. The cooled reaction mixture was diluted with methylene chloride, filtered and evaporated to dryness on a rotary evaporator. The product was purified by preparative thin layer chromatography on three 20×20×0.2 cm silica gel plates, eluting with methylene chloride-hexane (2:1), to afford 246 mg (63.0%) of 4-(acetoxymethylene)-6-oxobicyclo[3.2.0]hept-2-ene (cis, trans mixture) as an oil. NMR (220 MHz; CDCl3): δ2.02 (3 H, s), 2.05 (3H, s), 2.59 (1H, t, J=3.3), 2.68 (1H, t, J=3.3), 3.25 (2H, m), 3.50 (2H, m), 4.25 (1H, m), 4.55 (1H, m), 6.11 (3H, m), 6.43 (1H, d, J=5.5), 7.0 (1H, broad s), and 7.25 (1H broad s). A small amount of this mixture was successfully separated by preparative thin layer chromatography on a 0.25 mm silica gel plate. The mass spectra of the two components were identical. HRMS: Calcd for C10H10O3, 178.0630; found, 178.0617.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH2:18][CH2:19][CH3:20])(=[O:15])[CH2:13][CH3:14]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH2:18][CH2:19][CH3:20])(=[O:15])[CH2:13][CH3:14]
Reactant: CCCC(OC(=O)CC)OC(=O)ON1C(=O)CCC1=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CCCC(OC(=O)CC)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]butyl propanoate (686 mg, 2.38 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 34 (144 mg, 18% yield) as a brittle off-white solid after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 5H), 1.01 (t, J=7.2 Hz, 3H), 1.17-1.38 (br. m, 5H), 1.63-1.73 (br. m, 4H), 1.84-1.92 (br. m, 2H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.22-2.38 (m, 2H), 2.75-2.87 (m, 2H), 6.60 (t, J=6.0 Hz, 1H), 7.42 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 352.18 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=O)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[CH:9][C:10]#[N:11])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1
Reactant: COc1ccc(C(=O)c2cc(OC)cc(OC)c2)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of cyanomethylphosphonic acid diethyl ester (2.15 ml, 13.66 mmol) in anhydrous THF (10 ml) in an ice bath was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 13.66 ml, 13.66 mmol) slowly. The mixture was stirred in rt for 40 min. To the mixture, a solution of (3,5-dimethoxyphenyl)-(4-methoxyphenyl)methanone (5193-23-B, 1.86 g, 6.83 mmol) in anhydrous THF (20 ml) was added. The mixture was refluxed overnight. The solution was poured into ice water (20 ml) and the two phases were separated. The THF phase was evaporated and combined with the aqueous phase, which were then extracted with CH2Cl2 (2×40 ml), washed with water (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (20% EtOAc in hexane) to give 3-(3,5-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile as a yellow oil which was solidified slowly (1.97 g, 98%): mp, 79-81° C.; 1HNMR (DMSO-d6) δ 7.35-7.31 (m, 2H, Ar), 7.07-6.96 (m, 2H, Ar), 6.65-6.62 (m, 1H, Ar), 6.46-6.44 (m, 2H, Ar), 6.23 (s, 0.43H, double bond H of one isomer), 6.20 (s, 0.58H, double bond H of the other isomer), 3.82-3.68 (multiple singlets, 9H, OCH3); 13C NMR (CDCl3) δ 162.8, 162.6, 161.7, 161.3, 160.9, 160.8, 141.7, 139.2, 131.5, 131.0, 130.1, 129.3, 118.4, 118.2, 114.2, 114.0, 107.8, 107.2, 102.2, 102.1, 93.8, 93.0, 55.6, 55.5, 55.5; Anal. Calcd. for C18H17NO3+0.05H2O: C, 72.92; H, 5.89; N, 4.65. Found: C, 72.90; H, 5.52; N, 4.67.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[N:21]=[C:20]([C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:24]([F:35])[CH:23]=3)[C:19]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[N:18][CH:17]=2)[CH2:12][C:11]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CCN([S+](F)F)CC.[FH:65].[FH:66].F.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[N:21]=[C:20]([C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[C:24]([F:35])[CH:23]=3)[C:19]([N:36]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[N:18][CH:17]=2)[CH2:12][C:11]1([F:66])[F:65])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc([C@H]3CC[C@H](OC(=O)c4ccccc4)C(=O)C3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Reactant: F
Agent: CCN(CC)[S+](F)F
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(OC(=O)c4ccccc4)C(F)(F)C3)cnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Yield: 87.2 %

Procedure:
To a solution of tert-butyl 4-(6-((1S,45)-4-(benzoyloxy)-3-oxocyclohexyl)-3-(bis(tert-butoxycarbonyl)amino)pyrazin-2-yl)-2-fluorobenzoate (730 mg, 1.034 mmol) in DCM (7 mL) at RT was added XtalFlour-E (939 mg, 4.14 mmol) followed by triethylamine trihydrofluoride (0.674 mL, 4.14 mmol). The resultant mixture was stirred at RT for 5 hours. The mixture was filtered and the filtered solution was directly applied for ISCO separation: 24 g silica gel, 0 to 70% EtOAc in Heptane, 30 min. A light yellow solid (670 mg, 0.902 mmol, 87% yield) was obtained. LC-MS (m/z): (MH+) 728.0 at 0.95 min (non-polar MS method). 1H NMR (400 MHz, CDCl3) δ ppm 0.88 (s, 2H) 1.19-1.39 (m, 21H) 1.48-1.68 (m, 11H) 1.86-2.08 (m, 2H) 2.08-2.21 (m, 1H) 2.26-2.47 (m, 2H) 2.47-2.63 (m, 1H) 3.21-3.44 (m, 1H) 5.22-5.51 (m, 1H) 7.41-7.55 (m, 4H) 7.60 (s, 1H) 7.96 (d, J=7.82 Hz, 1H) 8.06-8.19 (m, 2H) 8.42 (s, 1H).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]2)[CH2:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:2]1[C:3]2([CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]2)[CH2:1]1
Reactant: OCC1CCC2(CC1)CC2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC1CCC2(CC1)CC2
Temperature: 25 °C

Procedure:
Spiro[2.5]oct-6-yl-methanol (2.57 g, 18.3 mmol, 1.0 eq.) was dissolved in CH2Cl2 (30 mL) and placed in a ice-water bath at 0° C. Pyridinium dichromate (PCC) (7.9 g, 36.6 mmol, 2.0 eq.) was added and the reaction warmed to room temperature for 4 hours with stirring. The crude reaction was filtered through a Celite pad and washed with CH2Cl2 and evaporated. The crude material was dissolved in diethyl ether and filtered through Celite, washing with diethyl ether several times. Evaporated solvent to provide Spiro[2.5]octane-6-carbaldehyde as a brown oil (2.98 g, quantitative) that was used directly. 1H NMR (CHCl3, 400 MHz) δ 0.17-0.27 (m, 4H), 0.88-0.91 (m, 2H), 1.09-1.25 (m, 2H), 1.52-1.54 (m, 2H), 1.69-1.75 (m, 3H), 9.44 (d, 1H, J=1.2 Hz).
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[Cl:16][C:17]1[C:22]([NH:23][CH:24]=[O:25])=[C:21](Cl)[N:20]=[C:19]([NH:27][CH:28]=[O:29])[N:18]=1.C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:16][C:17]1[C:22]([NH:23][CH:24]=[O:25])=[C:21]([NH:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][P:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:15])[N:20]=[C:19]([NH:27][CH:28]=[O:29])[N:18]=1
Reactant: CCOP(=O)(COCCCON)OCC
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: CCOP(=O)(COCCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Temperature: 100 °C
Yield: 63.1 %

Procedure:
A mixture of diethyl 3-aminooxypropoxymethylphosphonate (4 g,16.6 mmol), 4,6-dichloro-2,5-diformamidopyrimidine (3.9 g, 16.6 mmol) and diisopropylethylamine (8.67 ml, 49.8 mmol) in diglyme (80 ml) was heated at 100° C. for 2 h. After removal of the solvent under reduced pressure, the residue was chromatographed in chloroform/methanol (100:1, 50:1, 10:1) affording 4-chloro-6-[3-(diethoxyphosphorylmethoxy)propoxyamino]-2,5-diformamidopyrimidine as a yellow oil (4.61 g, 63%); νmax (film) 3200, 2990, 1690, 1590, 1220, 1040 cm-1 ; δH [(CD3)2SO] 1.22(6H, t, J7 Hz, (CH3CH2O)2), 1.85(2H, m, CH2CH2CH2), 3.65(2H, t, J6.3 Hz, CH2OCH2P), 3.40(2H, d, J8.2 Hz, CH2P), 3.92(2H, t, J6 Hz, CH2ON), 4.04(4H, m, (CH3CH2O)2), 8.15(1H, s, CHO), 9.25(1H, br.s, CHO), 9.43(1H, br.s, D2O exchangeable, NH), 10.76(1H, br s, D2O exchangeable, NH), 10.86(1H, br.s,D2O exchangeable, NH); Found: M+ 439.1015; C14H23ClN5O7P requires: M+ 439.1024.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][NH:8][C:9]([C:11]1[C:16]([OH:17])=[CH:15][C:14]([OH:18])=[CH:13][N:12]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:17][C:16]1[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:19])=[O:5])=[O:10])=[N:12][CH:13]=[C:14]([OH:18])[CH:15]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ncc(O)cc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1ncc(O)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester, 28, (0.10 g, 0.37 mmol) in CH2Cl2 (4 mL) at room temperature is added trifluoroacetic acid (1 mL). The reaction is stirred for 16 hours at room temperature and then concentrated under reduced pressure. The solid that remains is collected by filtration, washed with Et2O to afford 0.070 g (89% yield) of the desired compound as a colorless solid. 1H NMR (250 MHz, DMSO-d6) δ ppm 10.86 (1H, br s), 9.00 (1H, t, J=6.1 Hz), 7.77 (1H, d, J=2.4 Hz), 6.69 (1H, d, J=2.4 Hz), 3.95 (1H, d, J=6.2 Hz). HPLC-MS: m/z 213 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[NH:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)C.[OH-].[Na+]>C(O)C.O>[C:24]1([C:15]2[N:14]=[C:13]([S:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[NH:17][C:16]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 41.7 %

Procedure:
To a solution of 5.0 g (0.012 mole) 8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanoic acid ethyl ester in 125 ml ethanol was added, dropwise, a solution of 5.0 g sodium hydroxide in 125 ml water. The reaction mixture was stirred at reflux under nitrogen for 4 hours. The solvent was concentrated to half the volume and the remaining solution was extracted with diethyl ether. This organic layer was discarded. The aqueous layer was acidified to pH=1.0 using 1N hydrochloric acid and then extracted with diethyl ether. The organic layer was dried over magnesium sulfate and the solvent removed under vacuum. The resulting solid was crystallized from ethanol and triturated with hexane to give 2.13 g (0.005 mole) of the title compound as a white solid, mp=160°-162° C. 1H NMR(DMSO-d6): δ12.7(s,1H), 12.0(s,1H), 7.6-7.1(m,10H), 3.1(t,2H,J=7Hz), 2.3(t,2H,J=7Hz), 1.8-1.2 (m,10H).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1Cl.Cl.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C.CN(C=O)C>CC(O)C>[NH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:6]2[N:5]([CH2:4][C:3]3[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=3[Br:1])[C:13]3[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=3[N:7]=2)[CH2:27]1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2Br)n(C)c1=O
Reactant: NC1CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cn1c(=O)c2c(nc(N3CCCC(N)C3)n2Cc2ccccc2Br)n(C)c1=O

Procedure:
7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (10A) (100 mg, 0.26 mmol) and 3-aminopiperidine dihydrochloride (226 mg, 1.31 mmol) were dissolved in 2-propanol (20 ml), triethylamine (0.109 ml, 0.78 mmol) and DMF (5 ml) and subjected to microwaves (method F, 130° C., 300 W) for ten hours. The solvents were evaporated and the crude product was purified by preparative HPLC, (method A1, Rt=7.52 min.) to give the title compound as a brown oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[OH:11].S(OC)(O[CH3:16])(=O)=O>O>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[O:11][CH3:16]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cccc1C
Temperature: 60 °C
Yield: 57.3 %

Procedure:
Sodium hydroxide (20 g, 500 mmol) was dissolved in distilled water (200 mL) and placed in a round-bottom flask fitted with a reflux condenser. To the solution were added sequentially 2,6-dimethylphenol (1, 61 g, 500 mmol) and dimethyl sulfate (48 mL, 500 mmol). The mixture was heated at 60° C. for about 17 h, cooled, and transferred to a separatory funnel. The organic layer was separated, and the aqueous layer was extracted with benzene. The combined organic layers were washed sequentially with 10% aq. sodium hydroxide and brine, and dried (MgSO4). Concentration of the solution gave 2,6-dimethylanisole (2, 39 g, 57% yield), bp 179°-182° C./750 torr (lit.: Burton, G. W.; Joyce, A.; Ingold, K. U. Arch. Biochem. Biophys., 1982, 221, 281; 181° C.), as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:24])[N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:4]1[N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=2)[N:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cc(Br)nc2C)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cc(-c3ccc(N)nc3)nc2C)n1

Procedure:
The title compound was prepared from 2-(4-bromo-2-methyl-imidazol-1-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.64) (0.2 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.11 g, 55%). MS (ISP) 411.0 [(M+H)+]; mp 227.5° C.
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16]C)=[O:14])[C:5]([O:7][CH2:8]C)=[O:6].[C:19]1([N:25]2[C:37]3[CH:36]=[CH:35][C:34](=[C:38]4[CH:50]=[C:49]5[C:41](=[N:42][C:43]6[C:48]5=[CH:47][CH:46]=[CH:45][CH:44]=6)[CH:40]=[CH:39]4)[CH2:33][C:32]=3[C:31]3[C:26]2=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([N:25]2[C:37]3[CH:36]=[CH:35][C:34]([C:38]4[CH:39]=[CH:40][C:41]5[N:42]([C:3]6[CH:2]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:11]([N:42]7[C:41]8[CH:40]=[CH:39][C:38]([C:34]9[CH:35]=[CH:36][C:37]%10[N:25]([C:19]%11[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=%11)[C:26]%11[C:31]([C:32]=%10[CH:33]=9)=[CH:30][CH:29]=[CH:28][CH:27]=%11)=[CH:50][C:49]=8[C:48]8[C:43]7=[CH:44][CH:45]=[CH:46][CH:47]=8)=[CH:10][C:4]=6[C:5]([O:7][CH3:8])=[O:6])[C:43]6[C:48]([C:49]=5[CH:50]=4)=[CH:47][CH:46]=[CH:45][CH:44]=6)=[CH:33][C:32]=3[C:31]3[C:26]2=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1Br
Reactant: C1=Cc2c(c3ccccc3n2-c2ccccc2)CC1=c1ccc2c(c1)-c1ccccc1N=2
Product: COC(=O)c1cc(-n2c3ccccc3c3cc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)ccc32)c(C(=O)OC)cc1-n1c2ccccc2c2cc(-c3ccc4c(c3)c3ccccc3n4-c3ccccc3)ccc21

Procedure:
The compound is synthesised by the same procedure as for the corresponding step of Example 5 by reaction of 13.6 g (43 mmol) of diethyl dibromoterephthalate and 39 g (95.9 mmol) of 9-phenyl-3,3′-bicarbazole. The pure product is obtained by recrystallisation. The yield is 31 g (31 mmol), corresponding to 80% of theory.