Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12]([C:14]2[C:15]([OH:26])=[N:16][C:17]([C:20]3[N:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:18][CH:19]=2)=[O:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:27]([O:29][P:30]([O-:34])[O:31][CH2:32][CH3:33])[CH3:28].CCN(CC)CC>C1(C)C=CC=CC=1.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>[OH:26][C:15]1[C:14]([C:12]([NH:11][C:8]([C:5]2[CH:6]=[CH:7][C:2]([P:30](=[O:34])([O:31][CH2:32][CH3:33])[O:29][CH2:27][CH3:28])=[CH:3][CH:4]=2)([CH3:10])[CH3:9])=[O:13])=[CH:19][N:18]=[C:17]([C:20]2[N:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:16]=1
Reactant: CCOP([O-])OCC
Reactant: CC(C)(NC(=O)c1cnc(-c2cccnn2)nc1O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(C)(C)NC(=O)c2cnc(-c3cccnn3)nc2O)cc1

Procedure:
A mixture of N-(2-(4-bromophenyl)propan-2-yl)-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (36-c, 200 mg, 0.484 mmol), diethylphosphite (195 mg, 1.45 mmol), Et3N (146 mg, 1.45 mmol) and Pd (PPh3)4 (0.1 g) in toluene (10 mL) was refluxed overnight. The reaction mixture was concentrated in vacuum. The residue was purified by pre-HPLC to afford the product 36-d, (3.0 mg). 1H NMR (300 MHz, DMSO) δ10.85 (s, 1H), 9.08 (s, 1H), 8.75 (d, J=8.4 Hz), 7.86 (m, 1H), 7.61-7.52 (m, 2H), 7.43-7.42 (m, 2H), 4.00-3.92 (m, 4H), 1.61 (s, 6H), 1.20 (t, J=6.9 Hz, 6H). LC-MS: (M+H)+ 472.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(O[C@@H:20]1[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:31]([O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:21]1[O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([O-])(O)=O.[Na+]>C[Si](N[Si](C)(C)C)(C)C.ClCCCl>[CH3:1][C:2]1[N:3]([C@@H:20]2[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:52])[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@@H:31]([O:32][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]2[O:22][C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:4]=[CH:5][C:6](=[O:8])[N:7]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Cc1nccc(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Product: Cc1nc(=O)ccn1[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methylpyrimidin-4-one (4.42 g, 40 mmol) and a few crystals of ammonium sulfate were refluxed in HMDS overnight. After cooling to room temperature the colorless solution was evaporated. A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribose (40 mmol, 20.18 g) in 1,2-dichloroethane (200 ml) was added to the residue. Trimethylsilyl trifluoromethanesulfonate (TMSOTfl, 9.78 g, 44 mmol) was added and the resulting clear solution was stirred at room temperature for 2 hrs. The reaction mixture was poured in to saturated NaHCO3 (300 ml) and extracted with chloroform (2×200 ml). The organic phase was evaporated to give a colorless homogeneous foam (23.04 g, 104%, pure by NMR).
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9]([CH3:11])=O>>[CH3:6][C:5](=[CH:4][C:2](=[O:1])[CH:3]=[C:9]([CH3:11])[CH3:8])[CH3:7]
Reactant: CC(C)=O
Reactant: CC(=O)C=C(C)C
Product: CC(C)=CC(=O)C=C(C)C

Procedure:
Acetone, first percolated through a bed of alumina, was passed through a reactor containing 0.54 g of ZSM-5 zeolite having a silica-to-alumina ratio of 26,000 to 1 and an Na content of 1.48%. No condensation products were observed at reaction temperatures below 200° C. (392° F.). When the reactor containing zeolite was heated to 280° to 370° C. (536°-698° F.), about 10% of the acetone fed was converted to mesityl oxide. Some phorone was also formed.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(O)c1ccc(-c2ccc(F)cc2)cn1

Procedure:
Operations similar to those of Production Example 14 were conducted using 5-bromo-2-pyridinecarboxylic acid and 4-fluorophenylboronic acid, to provide the title compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([NH:18][C:19](=[O:28])[C:20]2[C:25](F)=[CH:24]C=[CH:22][C:21]=2F)=[N:16][CH:17]=1.CC1C=[N:37][CH:36]=CC=1C(Cl)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([NH:18][C:19](=[O:28])[C:20]2[CH:21]=[CH:22][N:37]=[CH:36][C:25]=2[CH3:24])=[N:16][CH:17]=1
Reactant: O=C(Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1)c1c(F)cccc1F
Reactant: Cc1cnccc1C(=O)Cl
Product: Cc1cnccc1C(=O)Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1

Procedure:
Compound 3 was prepared in an analogous fashion to Compound 1 except that 3-methyl-isonicotinoyl chloride was used instead of 2,6-difluoro-benzoyl chloride.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH3:11])[NH:6][C:5]1=[O:12])[CH2:2][CH3:3].OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>O>[CH3:11][C:7]1[NH:6][C:5](=[O:12])[N:4]([CH2:1][CH2:2][CH3:3])[C:9](=[O:10])[C:8]=1[N+:18]([O-:20])=[O:19]
Reactant: CCCn1c(=O)cc(C)[nH]c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCn1c(=O)[nH]c(C)c([N+](=O)[O-])c1=O
Reaction time: 2 h

Procedure:
3-propyl-6-methyl-1,3-dihydropyrimidine-2,4-dione (3 g), as prepared in Example 3, was added to a solution of concentrated H2SO4 (12 ml) and HNO3 (9.6 ml) at 0° C. The reaction mixture was allowed to come to room temperature and continued stirring for another 2 h. The reaction mixture was then poured into water and extracted with ethyl acetate (3×50 mL). The organic layer was washed with water, brine and dried over Na2SO4. Removal of the solvent and recrystallization of the residue with ethylacetate/hexane mixture furnished the 6-methyl-5-nitro-3-propyl-1,3-dihydropyrimidine-2,4-dione(1.56 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:44])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:43])[CH:16]([OH:42])[CH:17]([CH3:41])[C:18](=[O:40])[CH:19]([CH2:38][CH3:39])[CH:20]2[CH:24]([CH3:25])[CH2:23][C:22]([CH2:36][CH3:37])([CH:26]3[CH2:31][CH2:30][C:29]([CH2:33][CH3:34])([OH:32])[CH:28]([CH3:35])[O:27]3)[O:21]2)=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:45].[Na].Cl.[N+](=[CH2:50])=[N-]>CCOCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:44])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:43])[CH:16]([OH:42])[CH:17]([CH3:41])[C:18](=[O:40])[CH:19]([CH2:38][CH3:39])[CH:20]2[CH:24]([CH3:25])[CH2:23][C:22]([CH2:36][CH3:37])([CH:26]3[CH2:31][CH2:30][C:29]([CH2:33][CH3:34])([OH:32])[CH:28]([CH3:35])[O:27]3)[O:21]2)=[C:4]([C:5]([O:7][CH3:50])=[O:6])[C:3]=1[OH:45]
Reactant: C=[N+]=[N-]
Reactant: CCC(C(=O)C(C)C(O)C(C)CCCC(=O)c1ccc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Product: CCC(C(=O)C(C)C(O)C(C)CCCC(=O)c1ccc(C)c(O)c1C(=O)OC)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
1.344 g (2 mole) of 3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}acetyl salicylic acid, sodium salt was treated with ether (30 ml) and 1N HCl (30 ml). The mixture was shaken in a separatory funnel until all the starting material had dissolved. The ether layer was then washed twice with water and treated with 20 ml solution of ethereal diazomethane (5 mmole). After drying (Na2SO4), the solution was evaporated to give 3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl}acetyl salicylic acid, methyl ester as an oil, [α]D25 +0.99° (1% in methanol).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:21]=[CH:20][C:10]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([OH:19])=O)[N:14]=[CH:13]3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:22]([O:26][C:27](=[O:39])[NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36][NH2:37])=[C:31]([CH3:38])[N:30]=1)([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([O:26][C:27](=[O:39])[NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36][NH:37][C:17]([C:15]2[N:14]=[CH:13][N:12]([CH2:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:21][CH:20]=3)[CH:16]=2)=[O:19])=[C:31]([CH3:38])[N:30]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(4-Pyrazol-1-ylmethyl-benzyl)-1H-imidazole-4-carboxylic acid (0.67 g, 2.4 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.61 g, 2.4 mmol), HATU (1.8 g, 4.8 mmol) and DIPEA (1.3 mL, 7.2 mmol) in 10 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). LCMS (method A) RtA=1.418 min; [M+H]+=516.1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22].[Cl-].[Na+]>CCOCC>[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1)[OH:22]
Reactant: Brc1cncc(Br)c1
Reactant: COC1CCCCC1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COC1CCCCC1(O)c1cncc(Br)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A solution of 3,5-dibromopyridine (30.45 g, 0.13 mol) in anhydrous ether (400 ml) was added dropwise to a stirred solution of n-butyllithium (1.6M in hexane, 88.3 ml) and anhydrous ether (40 ml) over 0.5 hours at -70° C. The pale yellow suspension was stirred at -70° C. for 1 hour, and a solution of 2-methoxycyclohexanone (16.5 g, 0.13 mol) in anhydrous ether (60 ml) was added dropwise. The reaction mixture was stirred at -70° C. for 2 hours and allowed to warm to room temperature. The reaction mixture was poured onto ice/water (11); sodium chloride (50 g) was added and the ether layer separated. The aqueous layer was extracted with ether (2×200ml). The combined ether layers were extracted with 2N hydrochloric acid (2×250 ml). The acid extract was washed with ether (200 ml), basified with 4N aqueous sodium hydroxide solution at room temperature (pH11), sodium chloride (50 g) was added and the precipitated oil was extracted with ether (2×400 ml). The combined extracts were dried over magnesium sulphate and concentrated in vacuo to give 2-methoxy-1-(5-bromopyrid-3-yl)cyclohexanol (30.6 g). The cyclohexanol was added in small portions to stirred sulphuric acid (114 ml). The reaction exothermed to 50° C., but no external cooling was applied. When the addition was completed after 20 minutes the red/brown solution was stirred at room temperature for 4 hours. The reaction mixture was poured onto ice/water (11) and basified to pH8 with sodium carbonate. The product was extracted with ether (2×300 ml). The ether extracts were combined, dried with magnesium sulphate and evaporated to give a pale orange oil. The oil was purified by flash chromatography over silica gel eluting with hexane/ethyl acetate 6.4 to give 2-(5-bromopyrid-3-yl)cyclohexanone (15.1 g) m.p. 67°-9° C. NMR(CDCl3). 1.6-2.1(m,4H); 2.1-2.4(m,2H); 2.4-2.6 (m,2H); 3.6-3.66(dd,1H); 7.6(s,1H); 8.18(s,1H); 8.38(s,1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[CH2:7][C:6]=2[C:5]([C:13]#[N:14])=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[N:15]=[N:16][NH:17][N:14]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CN1Cc2c(C#N)ccc(N)c2C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nn[nH]n3)ccc(N)c2C1=O
Temperature: 120 °C
Yield: 38.9 %

Procedure:
A mixture of 7-Amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (Compound 181B, 25.0 mg, 0.134 mmol), sodium azide (104 mg, 1.60 mmol) and ammonium chloride (85.7 mg, 1.60 mmol) in DMF (6 mL) were mixed and heated in microwave at 120° C. for 9 hours. The crude mixture was filtered and directly purified by MDP to obtain the title compound (12.0 mg, 39% yield). MS (ES+): m/z 231.23 (100) [MH+]; HPLC: tR=0.59 min (UPLC, analytical).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][C:13]1[N:18]=[C:17]([NH:19][NH2:20])[CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:10]([O:9][C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:20][NH:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:12])[N:18]=1)=[O:8])[CH3:11]
Reactant: Cc1cccc(NN)n1
Reactant: CCOC(=O)C1CCCC1=O
Solvent: CCO
Product: CCOC(=O)C1CCCC1=NNc1cccc(C)n1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A solution of ethyl 2-oxocyclopentanecarboxylate (6.34 g, 5.88 mL) and (6-methyl-pyridin-2-yl)-hydrazine (5 g) in ethanol (100 mL) was heated to 80° C. under an atmosphere of nitrogen for about 19 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo to provide a crude material (7.72 g), which was directly taken to the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][NH:30][CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Cl:34][C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41](Cl)=[O:42])=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][N:30]([C:41](=[O:42])[CH2:40][O:39][C:38]2[CH:44]=[CH:45][C:35]([Cl:34])=[CH:36][CH:37]=2)[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)COc2ccc(Cl)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [4′-(6-ethoxy-pyridin-3-yl)-2′-ethylaminomethyl-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester and 4-chlorophenoxyacetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:21]3[C:22]4[N:13]([CH2:14][C:15](=[O:23])[NH:16][C:17]=4[CH:18]=[CH:19][CH:20]=3)[C:12]2=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:21]3[C:22]4[N:13]([CH2:14][C:15](=[O:23])[N:16]([CH3:25])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[C:12]2=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)n2c(=O)n3c4c(cccc42)NC(=O)C3)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(=O)n3c4c(cccc42)N(C)C(=O)C3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-[(4-methylphenyl)sulfonyl]-4H-imidazo[1,5,4-de]quinoxaline-2,5(1H,6H)-dione from Step D (1.16 g, 3.38 mmol) in DMF (40 mL) was added potassium carbonate (467 mg, 3.38 mmol) and the resulting mixture was stirred at ambient temperature for 10 min. Iodomethane (480 mg, 3.38 mmol) was added dropwise and the reaction mixture was stirred for 18 h, then poured into H2O (50 mL). The resulting precipitate was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=358 (M+1).
Reaction SMILES: [C:1]([C:8]1[S:12][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:9]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C(OCC)C.C(OCC)(=O)C>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)c1ccc(-c2cccs2)s1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCc1ccc(-c2cccs2)s1
Reaction time: 1 h

Procedure:
Preparation of 5,5′″-Bis(4-n-hexyl)-2,2′:5′,2″:5″,2′″-quaterthiophene (6TTTT6) is now discussed. A mixture of 6.2 g of bithiophene, 8.0 g of hexanoic anhydride, and 0.4 g boron trifluoride etherate is heated to about 100° C. and allowed to cool. The resulting mixture is dissolved in toluene, washed with aqueous sodium bicarbonate (allowing for venting of carbon dioxide gas), dried with magnesium sulfate, filtered, concentrated on a rotary evaporator, and chromatographed on 160 grams of silica gel eluting with hexane/methylene chloride mixtures. The product 5′-hexanoylbithiophene is isolated. The 5′-hexanoylbithiophene (3.9 g sample) is added to a stirred mixture of 3.0 g of aluminum chloride and 3.4 g of lithium aluminum hydride suspended in 300 mL of ethyl ether. After 1 hour, 50 mL ethyl acetate and 15 mL of concentrated hydrochloric acid are cautiously added, and the mixture is filtered, concentrated, and eluted through 30 g of silica gel with hexane. The product 5′-hexylbithiophene is isolated. A measured 2.4 g of this compound is dissolved in 150 mL of tetrahydrofuran. A measured 9.6 mmol of butyllithium as a hexane solution is added with stirring and cooling to −78° C. After 20 minutes, 2.6 g of cupric chloride is added. The mixture is allowed to warm to room temperature. After one day, dilute hydrochloric acid is added to dissolve the copper salts, and the mixture is dissolved in toluene, washed with concentrated hydrochloric acid and dilute aqueous ammonia, dried with magnesium sulfate, filtered, concentrated, and triturated with hexane, methanol, and petroleum ether.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14][N:15]3[N:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14][N:15]3[N:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2ccc(Cn3ncc([N+](=O)[O-])n3)o2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-4-nitro-2H-[1,2,3]triazole (218 mg, 0.78 mmol), iron powder (132 mg, 2.33 mmol) and NH4Cl (210 mg, 3.89 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 0.5 h. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by 1M NaOH (20 mL). The aq. layer was extracted with CH2Cl2 (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.71 min; [M+H]+=251.16.
Reaction SMILES: [CH2:1]([N:13]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CCCC(OCC)=O)CCOC1C=CC(CCC(=O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:1]([N:13]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])=[CH:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(CCOc1ccc(CCC(O)C(F)(F)F)cc1)CCC(=O)OCC
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Product: CCCCCCCCCCCCN(CCOc1ccc(CCC(=O)C(F)(F)F)cc1)CCC(=O)OCC
Yield: 68 %

Procedure:
3[N-Dodecyl-N-2-[4-[3hydroxy4,4,4-trifluorobutyl]phenoxy]ethylamino]propanoic acid, ethyl ester (320 mg, 0.60 mmol) was oxidized as described in the preparation of 4-[N-dodecyl-N-[2-[4-(3oxo-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester (Example 48 ) and afforded the title compound (216 mg, 68%) as a pale yellow oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[C:20]1([CH3:32])[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:29]2[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:32])[CH2:27][CH2:28]2)=[CH:9][N:8]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: Cc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCN(c3ccccc3C)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
A suspension of 7.7 g (0.040 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 6 ml of dimethyl-formamide was treated with 15 g (0.11 mol) of dry potassium carbonate. At the same time a suspension of 10 g (0.040 mol) of 1-o-tolyl-piperazine dihydrochloride was treated with 15 g (0.11 mol) of dry potassium carbonate in 60 ml of dimethylformamide. After stirring at room temperature for 1/2 hr both solutions were combined and stirred for a further 4 hours. The reaction mixture was suction filtered, the residue was chromatographed over silica gel with dichloromethane/ethyl acetate 1:1 as the eluent and recrystallized from ethanol/ethyl acetate. 2.5 g of 2-methyl-5-(4-o-tolyl-piperazin-1-ylmethyl)-pyrimidin-4-ylamine were obtained as beige crystals; m.p. 189°-190°.