Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[C:18]([CH:26]=O)=[CH:17]1)[CH3:15].CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH2:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[C:18]([CH2:26][NH:6][CH3:5])=[CH:17]1)[CH3:15]
Reactant: CCn1cc(C=O)c2cc(F)ccc21
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CCn1cc(CNC)c2cc(F)ccc21
Yield: 50 %

Procedure:
According to the procedure of Preparation 11 (c), except substituting 1-ethyl-5-fluoro-1H-indole-3-carboxaldehyde (0.2 g, 1.9 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.1 g, 50%) was prepared as a viscous oil: MS (ES) m/e 207 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[NH:27][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([NH2:26])[CH:20]=4)[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH:29]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][N:2]([CH3:28])[C:3]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[NH:27][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([NH:26][C:36](=[O:37])[C:35]5[CH:39]=[CH:40][C:32]([CH:29]6[CH2:31][CH2:30]6)=[CH:33][CH:34]=5)[CH:20]=4)[C:13]=3[CH:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CN(C)C(=O)N1CC=C(c2cc3c(-c4ccc(F)c(N)c4)ncnc3[nH]2)CC1
Reactant: O=C(Cl)c1ccc(C2CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CN(C)C(=O)N1CC=C(c2cc3c(-c4ccc(F)c(NC(=O)c5ccc(C6CC6)cc5)c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Intermediate 10 (80 mg, 0.210 mmol), 4-cyclopropyl-benzoyl chloride (J. Med. Chem., 52(14), 4329-4337; 2009) (76 mg, 0.421 mmol), and DMAP (2.6 mg, 0.021 mmol) in pyridine (2 ml) was stirred at r.t. overnight. The mixture was evaporated to dryness, then sat. aqueous NaHCO3 was added, and the mixture was extracted with DCM. The organic layer was dried, filtered, and evaporated to dryness. The residue was purified by flash chromatography (silica gel, EtOAc/MeOH/NH3 gradient) to obtain Example 20.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.C(N(CC)CC)C.[Br:25][C:26]1[N:31]=[CH:30][C:29]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:28][CH:27]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[Br:25][C:26]1[N:31]=[CH:30][C:29]([CH:32]=[CH:33][C:34]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:35])=[CH:28][CH:27]=1
Reactant: O=C(O)C=Cc1ccc(Br)nc1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(Br)nc2)cc(F)c1NS(C)(=O)=O
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (63 mg, 0.219 mmol) was suspended in THF and treated with triethylamine (25 mg, 0.241 mmol) and then the resulting mixture was stirred for 10 mins. 3-(6-bromo-pyridin-3-yl)-acrylic acid (50 mg, 0.219 mmol) was added to the reaction mixture followed by DMTMM (66 mg, 0.241 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO3 (×2), and brine, and then dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (EtOAc/n-Hexane) to yield the title compound (71 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:41])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([C:26]4[S:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=4)[OH:25])[CH3:22])=[C:17]([CH2:33][O:34]CC[Si](C)(C)C)[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:41])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([C:26]4[S:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=4)[OH:25])[CH3:22])=[C:17]([CH2:33][OH:34])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1COCC[Si](C)(C)C)CC(O)c1ccc(C#N)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)CC(O)c1ccc(C#N)s1
Yield: 101.3 %

Procedure:
A solution of 170 mg of N-(4-chlorobenzyl)-2-{[[2-(5-cyanothien-2-yl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 4 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is extracted with 4 portions of CH2Cl2, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 5% MeOH in CH2Cl2 provides 146 mg of the title compound as a white solid. Recrystallization from acetonitrile affords white needles.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH:19][C:20]([O:22]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:3]1=[O:32].CN(C)C=O.[NH2:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH2:43][CH2:42]2.C(N(CC)CC)C>O>[CH2:44]1[C:45]2[C:41](=[CH:40][C:39]([NH:38][C:20]([NH:19][C@@H:4]3[N:5]=[C:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:2]([CH3:1])[C:3]3=[O:32])=[O:22])=[CH:47][CH:46]=2)[CH2:42][CH2:43]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CN1C(=O)[C@H](NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)[C@H](NC(=O)Nc2ccc3c(c2)CCC3)N=C(c2ccccc2)c2ccccc21
Reaction time: 4 h

Procedure:
(R)-1,3-Dihydro-1-methyl-3-(p-nitrophenyloxycarbonyl)amino-5-phenyl-2H-1,4-benzodiazepin-2-one (200 mg. 0.46 mmole) was dissolved in 2 ml of freshly degassed, dry N,N-dimethylformamide (DMF) and treated with 1 ml of DMF containing 74 mg (0.50 mmole) of 5-aminoindane and 97.4 μl of triethylamine. The resulting solution was stirred under nitrogen for four hours. The reaction mixture was poured into 75 ml of water and extracted with ethyl acetate (3×40 ml). The combined organic extracts were washed with 1N sodium hydroxide solution (4×100 ml), 10% citric acid solution (2×100 ml), and brine. The organic extracts were then dried and the residue was plug-filtered through a six inch silica gel column. The eluate was concentrated and the residue was crystallized from a methylene chloride-ether mixture to give the title compound: mp 156°-158° C. NMR: Structure is consistent with the spectrum.
Reaction SMILES: [C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)[C@H]1CCC=C[C@H]1c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CCC=C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 900 mg (4.45 mmol) of 1(R)-phenyl-2(S)-carboxy cyclohex-5-ene (See U.S. Pat. No. 5,750,549, Example 158, Step B) in a 4:1 solution of MeOH/THF was added trimethylsilyldiazomethane until a yellow color persisted. After stirring at room temperature for 3 hour the reaction was concentrated in vacuo and the residue was purified by flash chromatography eluting with 0-15% EtOAc in hexanes to afford the ester (300 mg) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.19-7.30 (m, 5H), 5.98-6.01 (m, 1H), 5.76-5.79 (m, 1H),3.89 (s, 1H),3.50 (s, 3H), 2.95-2.98 (m, 1H), 2.16-2.32 (m, 2H),1.80-1.87 (m, 2H) ppm.
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[Br-:11].C(OC([NH:19][CH2:20][CH2:21][CH2:22][P+:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br-:11].[NH3+:19][CH2:20][CH2:21][CH2:22][P+:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Br-:11]
Reactant: CC(C)(C)OC(=O)NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: [Br-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [NH3+]CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
The solution of TFA/CH2Cl2 (1:1, 50 ml) containing triisoproylsilane (0.2 ml) was added to (3-((tert-butoxycarbonyl)amino) propyl)triphenylphosphonium bromide (6.15 g, 14.6 mmol). The mixture was stirred for 2 hours. After removal of the solvent, the compound was dried over vacuum and directly used in next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]([CH3:11])[CH2:9][O:10][C:6]=2[C:5]([CH:12]2[C@H:17]([O:18]CC3C=CC=CC=3)[C@@H:16]([O:26]CC3C=CC=CC=3)[C@H:15]([O:34]CC3C=CC=CC=3)[C@@H:14]([CH2:42][O:43]CC3C=CC=CC=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:7]2[CH:8]([CH3:11])[CH2:9][O:10][C:6]=2[C:5]([CH:12]2[CH:17]([OH:18])[CH:16]([OH:26])[CH:15]([OH:34])[CH:14]([CH2:42][OH:43])[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([O:58][CH2:59][CH3:60])=[CH:56][CH:57]=1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)C(C)CO3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc(C3OC(CO)C(O)C(O)C3O)c3c(c2Cl)C(C)CO3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.6 %

Procedure:
To a solution of 4-chloro-5-(4-ethoxybenzyl)-3-methyl-7-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (102 mg, 0.124 mmol) in THF/MeOH (4 mL/2 mL) was added 10% Pd/C (50 mg) at rt. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound (24 mg, 42%) as a white solid.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:15]([F:34])=[C:16]([CH:31]=[CH:32][CH:33]=1)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.[NH2:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]([CH3:51])[CH:46]=1>C1COCC1.CCOC(C)=O>[F:34][C:15]1[C:14]([NH:13][C:5]([NH:44][C:45]2[CH:50]=[CH:49][N:48]=[C:47]([CH3:51])[CH:46]=2)=[O:11])=[CH:33][CH:32]=[CH:31][C:16]=1[CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1
Reactant: Cc1cc(N)ccn1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(N)c2F)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)ccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a 0° C. solution of triphosgene (959 mg, 3.24 mmol, 0.35 equiv) in THF (45 mL) was slowly added via cannula a solution of tert-butyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate (2.86 g, 9.25 mmol, 1.0 equiv) and DIPEA (3.2 mL, 18.5 mmol, 2.0 equiv) in THF (25 mL) over approximately 20 minutes. The solution was stirred for an additional 15 min at 0° C., and 4-amino-2-methylpyridine was then added. After stirring at room temperature for 72 h, the reaction was diluted with EtOAc, washed with aq. satd. NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase preparative HPLC provided tert-butyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate (1.77 g, 43%). LCMS m/z (APCI)=444.3 (M+H).
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C:9]1[CH:14]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[N:13]2[C:31](=[O:42])[C@@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C@H:12]2[S:11][CH:10]=1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH:8]([C:9]1[CH:14]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[N:13]2[C:31](=[O:42])[C@@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C@H:12]2[S:11][CH:10]=1)=[O:7]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)=CS[C@H]12
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
In this preparation 31. g. of dried chromium trioxide is added to a mixture of 51 g. of dry pyridine and 800 ml. of dry methylene chloride and stirred at 15° C. under nitrogen for 20 minutes. 26 Grams of benzhydryl 3-hydroxymethyl-7β-(thiophen-2-yl-acetamido)-ceph-2-em-4-carboxylate in 250 ml. of dry methylene chloride is added in one portion. The resulting mixture is stirred for 30 minutes and then filtered through diactomaceous earth. The contents of the reaction flask and the diatomaceous earth are washed with 500 ml. of methylene chloride and combined with the preceding filtrate and then washed with 400 ml. of 5% aqueous potassium hydroxide solution, 500 ml. of 20% aqueous hydrochloric acid and twice with 400 ml. brine. The aqueous washings are back extracted with 500 ml. of methylene chloride and the extracts added to the previously washed methylene chloride filtrate, then dried over sodium sulfate and then stirred for one hour with 30 g. of silica gel. The mixture is filtered and the silica gel washed with 400 ml. 1:1 vol. ethyl acetate/methylene chloride. The combined filtrates are evaporated to dryness under reduced pressure and the resulting residue (26 g.) is recyrstallized from ethyl ether/methylene chloride affording 21.4 g. of benzhydryl 3-formyl-7β-(thiophen-2-yl-acetamido)-ceph-2-em-4-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[CH:27][NH:28][N:29]=[C:23]2[N:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:21]1=[O:34].O>CC(C)=O>[CH3:19][N:20]1[C:25](=[O:26])[C:24]2=[CH:27][N:28]([CH2:2][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=[CH:5][CH:4]=3)[N:29]=[C:23]2[N:22]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:21]1=[O:34]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]nc21
Reactant: ClCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3cccc4ccccc34)nc21
Temperature: 25 °C
Yield: 89.3 %

Procedure:
In accordance with the teaching of German Patent No. 63,381, 1-(chloromethyl)-naphthalene (2.2 g), potassium carbonate (1.6 g) and 5-methyl-7-(2-methylpropyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (2.5 g) were combined in acetone (40 ml) and heated under reflux for 3 hours and then cooled to ambient temperature. Water (200 ml) was added and the precipitated solid was collected by filtration. The solid was triturated with isohexane and then dried in vacuo to give the title compound (3.64 g).
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][CH:12]=1)(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:6][C:7]1[CH:8]=[C:9]([C:13](=[O:19])[CH2:14][CH2:15][C:16]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[O:18])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CCC(=O)O)c1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN1CCN(C(=O)CCC(=O)c2cccc(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Under nitrogen, to a solution of the product of Step 1 (490 mg, 2.52 mmol) in DMF (10 mL), was added 1-methylpiperazine (505 mg, 5.04 mmol), HOBT (1.02 g, 7.6 mmol), HBTU (950 mg, 2.5 mmol), followed with 4-methylmorpholine (770 μL, 7.6 mmol). This mixture was then stirred at rt overnight. The reaction mixture was concentrated and the residue was purified with reverse phase HPLC (5% MeCN/H2O→50% MeCN/H2O), to afford the title compound as white solid (572 mg, 82%). MS (ES+) m/e 277 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[O:15][C:14](=[O:16])[NH:13][CH:12]2[CH2:17][OH:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1.Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[O:15][C:14](=[O:16])[NH:13][CH:12]2[CH2:17][O:18][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C2OC(=O)NC2CO)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC1NC(=O)OC1c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
Compound (H) (200 mg; 0.84 mmols) has been dissolved in anhydrous pyridine (3 ml). The thus obtained solution has been cooled to 0° C. and added with freshly distilled methanesulfonyl chloride (0.06 ml). The solution has been maintained at 0° C. overnight and then diluted with an aqueous solution of hydrochloric acid (stoichiometric amount with respect to pyridine) and ice. After extraction with ethyl acetate, the organic extract has been dried over sodium sulfate and evaporated in vacuo to afford crude (J); yield, 85-90%.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].S(Cl)(Cl)=O.[I-].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Zn+]>O1CCCC1>[CH3:4][O:3][C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11](=[O:13])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH2:9][CH2:10]1)=[O:2]
Reactant: COc1ccccc1[Zn+]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: [I-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCC(C(=O)c2ccccc2OC)CC1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
In an oven dried 1 neck round bottom flask with reflux condenser and stirbar, trans-4-carbomethoxycyclohexane-1-carboxylic acid (1.11 g; 5.4 mmol) was heated to reflux in the presence of 30 mL thionyl chloride. After 3 hours reflux, mixture cooled to 40° C. under nitrogen flow, and excess thionyl chloride was removed at reduced pressure. Residue was taken up in 5 mL of dry tetrahydrofuran and added to a 0° C. mixture of 2-methoxyphenylzinc iodide (11.0 mL; 5.4 mmol), tetrakis(triphenylphospine)palladium (0) (90 mg; 0.08 mmol) in 2.5 mL anhydrous tetrahydrofuran. Mixture was allowed to warm to room temperature over 16 hours. Reaction was quenched with 6 mL 1N HCl and ethyl acetate was taken in. Organics separated and aqueous re-extracted with 20 mL ethyl acetate. Combined organics were washed with sat. NaHCO3, water, brine and dried over MgSO4. Material was purified via flash silica plug (10:1) using 15% ethyl acetate in hexanes isocratic to give 900 mg of title compound. (64% yield)
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1)(C(OC)=O)C(OC)=O)#[N:2].[Li+].[OH-]>CO.O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:5][CH2:4][CH2:3][C:1]#[N:2])=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: COC(=O)C(CCC#N)(C(=O)OC)c1ccc([N+](=O)[O-])cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CCCCc1ccc([N+](=O)[O-])cn1
Yield: 92.9 %

Procedure:
To a solution of compound 76 (3.3 g, 10.7 mmol) in CH3OH (100 mL) was added a solution of LiOH (15.4 g, 64.2 mmol) in H2O (100 mL) at room temperature with stirring. The mixture was stirred at room temperature for 2 h. Methanol was removed in vacuo and the residual aqueous solution was washed with EtOAc (two times), then was acidified to pH=2 with 1N HCl. The aqueous phase was extracted with EtOAc. The combined organic extract was dried over Na2SO4, then was stirred at 50° C. for overnight. The solution was concentrated to afford compound 77 (1.9 g, 95%) as a yellow oil.
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2C=CC=[CH:11][CH:10]=2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.[CH3:18][NH2:19].[CH2:20]1[CH2:24]O[CH2:22][CH2:21]1>>[CH3:18][NH:19][CH2:22][C:21]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])=[CH:24][CH:20]=1
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1cc(CBr)ccc1-c1ccccc1
Reactant: CN
Product: CNCc1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
4-Bromomethyl-2-nitrobiphenyl, prpepared as described by D. J. Carini, et al. D. J. Carini, et al. on page 105 in European Application Number 324,377 published Jul. 19, 1989, is reacted with excess methylamine in THF in a manner similar to that described in Example 18A, to give 4'-methylaminomethyl-2-nitrobiphenyl. 4'-Methylaminomethyl-2-nitrobiphenyl is reacted, according to the procedures described in Example 1C, with ethyl 2-butyl-4-chloropyrimidine-5-carboxylate to give ethyl 2-butyl-4-{N-[N-methyl-(2'-nitrobiphenyl-4-yl)methyl]amino)pyrimidine-5-carboxylate. Hydrogenation over palladium on carbon in methanol gives the intermediate ethyl 2-butyl-4-{N-[methyl-(2'-aminobiphenyl-4-yl)methyl]amino}pyrimidine-5-carboxylate. The intermediate is dissolved in methylene chloride containing triethylamine and treated at low temperature with trifluoromethanesulfonyl chloride to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH2:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:3]1=[O:23].[CH3:24][N:25]([CH:27](OC)OC)[CH3:26]>CN(C=O)C>[CH3:24][N:25]([CH3:27])[CH:26]=[CH:8][C:7]1[N:2]([CH3:1])[C:3](=[O:23])[N:4]([CH2:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:5](=[O:12])[C:6]=1[N+:9]([O-:11])=[O:10]
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])c(=O)n(CCCOC2CCCCO2)c(=O)n1C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1c([N+](=O)[O-])c(=O)n(CCCOC2CCCCO2)c(=O)n1C
Temperature: 95 °C
Yield: 73 %

Procedure:
To a solution of 1,6-dimethyl-5-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrimidine-2,4(1H,3H)-dione (980 mg, 3 mmol) in DMF (2 mL) was added DMF-DMA (5 mL). The reaction was heated at 95° C. for 15 h, cooled to RT and concentrated to a residue which was dissolved in EA (20 mL). The mixture was washed with aq. 1N LiCl (3×10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (2:1) to give 6-(2-(dimethylamino)vinyl)-1-methyl-5-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl) pyrimidine-2,4(1H,3H)-dione (840 mg, 73% yield) as a yellow oil. LCMS: MH+ 383 and TR=1.308 min.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[C:12]([C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])=C[C:5]2=[N:4][N:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.I([O-])(=O)(=O)=[O:23].[Na+]>[Ru](=O)=O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13](=[O:23])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]1[CH:5]=[N:4][N:3]=[C:2]1[CH3:1]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3ccccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccccc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 2'-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.