Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20](=O)[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:69]([CH3:73])[N:70]=[CH:71][N:72]=2)=[O:16])[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.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:69]([CH3:73])[N:70]=[CH:71][N:72]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cn1ncnc1SCSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2S(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: Cn1ncnc1SCSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Reaction time: 0.33 h
Yield: 94.1 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(2-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (1.73 g: 1.64 mMol.) in dimethylformamide (15 ml) is added at -20° C. phosphorus trichloride (0.41 ml: 4.08 mMol.), and the mixture is stirred at the same temperature for 20 minutes. The reaction mixture is poured into cold two layers of aqueous sodium hydrogen carbonate and ethyl acetate and stirred. The organic layer is taken, washed with water and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=2:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(2-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.60 g) as dark brown foam. Yield: 94%.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[C:6](Cl)=[N:7][CH:8]=[N:9][C:10]=1[C:11]([F:14])([F:13])[F:12]>CO>[Br:4][C:5]1[C:6]([O:2][CH3:1])=[N:7][CH:8]=[N:9][C:10]=1[C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(F)c1ncnc(Cl)c1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncnc(C(F)(F)F)c1Br
Yield: 91 %

Procedure:
16.7 ml of sodium methoxide (a 28% methanol solution, 86.4 mmoles) was added, at room temperature, to a solution of 21.5 g (82.2 mmoles) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine dissolved in 100 ml of methanol. The mixture was stirred to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein. The residue was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with n-hexane to obtain 19.2 g (yield: 91.0%) of 5-bromo-4-methoxy-6-trifluoromethylpyrimidine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)([CH3:9])[C:6]([OH:8])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[C:29]1[O:33][C:32]([CH3:34])=[N:31][CH:30]=1)[C:22]([NH:24][NH2:25])=[O:23].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.O.[Cl-].[Na+].O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)([CH3:9])[C:6]([NH:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:28]([C:29]2[O:33][C:32]([CH3:34])=[N:31][CH:30]=2)=[C:19]([O:18][CH3:17])[CH:20]=1)=[O:8]
Reactant: CC(CCCCl)(C(=O)O)c1ccc(Cl)cc1
Reactant: COc1cc(C(=O)NN)ccc1-c1cnc(C)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NNC(=O)C(C)(CCCCl)c2ccc(Cl)cc2)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
To a mixture of 5-chloro-2-(4-chlorophenyl)-2-methylpentanoic acid (6.34 g), 3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (5.0 g) and triethylamine (6.78 mL) in DMF (50 mL) was added HATU (9.23 g) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was diluted with ethyl acetate (50 mL), water (150 mL) and saturated brine (50 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine (4×50 mL), and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.19 g). 1H NMR (300 MHz, CDCl3) δ1.54-1.82 (2H, m), 1.66 (3H, s), 2.14-2.23 (2H, m), 2.54 (3H, s), 3.52 (2H, t, J=6.3 Hz), 3.90 (3H, s), 7.35-7.37 (6H, m), 7.48 (1H, s), 7.69 (1H, d, J=8.4 Hz), 7.95 (1H, d, J=4.2 Hz), 9.35 (1H, d, J=4.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:44][CH2:45][C@H:46]([OH:48])[CH3:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH2:37]([O:44][CH2:45][C@H:46]([CH3:47])[O:48][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([NH2:1])=[CH:3][C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:5]2)[CH:12]=[CH:11][CH:10]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2O)n1
Reactant: C[C@@H](O)COCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](COCc1ccccc1)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 46.7 %

Procedure:
A mixture of Intermediate 95a (0.50 g, 2.2 mmol) in dry THF (17 mL) was treated with triphenylphosphine (1.13 g, 4.32 mmol) and (R)-(−)-1-benzyloxy-2-propanol (0.52 mL, 3.24 mmol) then diisopropylazodicarboxylate (0.85 mL, 4.32 mmol) was added dropwise (the reaction mixture became very warm). After stirring at ambient temperature for 1.75 h the mixture was treated with water (0.2 mL) then concentrated in vacuo to a viscous orange oil. The oil was purified by FCC, using 0-7% EtOAc in DCM. The resulting oil was purified further by FCC, using 0-30% EtOAc in cyclohexane. The product was applied to a pre-conditioned (with MeOH)SCX-2 cartridge and eluted with MeOH then 2N NH3 in MeOH. The product containing fractions were combined and concentrated in vacuo to give the title compound as a viscous golden oil (0.39 g, 48%). LCMS (Method 3): Rt 3.77 min, m/z 380.4 [MH+].
Reaction SMILES: Br[C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].C([Mg]Cl)(C)C.O1CCCC1.[CH3:20][C:21]([CH3:27])=[C:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1>C1(C)C=CC=CC=1>[Cl:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[CH:23]1[C:22](=[C:21]([CH3:27])[CH3:20])[CH:26]2[CH:25]=[CH:24]1
Reactant: Clc1cccc(Cl)c1Br
Reactant: CC(C)=C1C=CC=C1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)=C1C2C=CC1c1c(Cl)cccc12
Yield: 87.8 %

Procedure:
A solution of 2-bromo-1,3-dichlorobenzene (22.59 g, 0.1 mol) in dry toluene (100 ml) under a nitrogen atmosphere was reacted at −8 to −15° C. with 2M isopropylmagnesium chloride in tetrahydrofuran (50 ml, 0.1 mol) for 1 hour. Subsequent addition of 6,6-dimethylfulvene (13.03 g, assay 97.8%, 0.12 mol) at 0° C. was followed by heating to reflux temperature for 10 hours. Aqueous work up with saturated aqueous ammonium chloride and ethyl acetate extraction followed by washings with brine and water and drying over sodium sulphate gave the crude material which was purified by chromatography on silica gel in hexane to give the desired product (19.03 g, assay 95.2% by g.l.c., 83.6% yield) as a yellow solid. This reaction is also disclosed in WO 2007/068417.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:26]=[CH:25][C:10]3[NH:11][C:12]([C:14]4[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=4)=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:27]>>[ClH:27].[ClH:27].[N:1]1([CH2:6][C:7]2[CH:26]=[CH:25][C:10]3[NH:11][C:12]([C:14]4[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=4)=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ccc(-c2nc3cc(Cn4ccnc4)ccc3[nH]2)cc1
Agent: Cl
Product: O=C(O)c1ccc(-c2nc3cc(Cn4ccnc4)ccc3[nH]2)cc1
Yield: 59 %

Procedure:
A mixture of 3 parts of ethyl 4-[5-(1H-imidazol-1-ylmethyl)-1H-benzimidazol-2-yl]benzoate and 50 parts of a hydrochloric acid solution 6N was stirred and refluxed for 12 hours. The reaction mixture was evaporated to dry. The residue was taken up in 2 parts of water and 2-propanone. The product was filtered off and dried, yielding 2 parts (59%) of 4-[5-(1H-imidazol-1-ylmethyl)-1H-benzimidazol-2-yl]benzoic acid dihydrochloride. monohydrate; mp. 288.2° C. (compound 259).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[C:16]([Cl:29])[C:15]=1[O:30][CH3:31].CN1C=CN=C1>[Cl-].[Cl-].[Zn+2].C(O)(C)(C)C.ClCCCl>[Cl:29][C:16]1[C:15]([O:30][CH3:31])=[C:14]([NH:13][C:2]2[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)[CH:28]=[CH:27][C:17]=1[CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1Cl)OCC
Agent: Cn1ccnc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1Cl)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (2.1 g, 9.77 mmol) in a 1:1 mixture of DCE and t-butanol (20 mL) was added ZnCl2 (1M, 10 mL) and stirred for half an hour at RT. After cooling at 0° C. diethyl 4-amino-2-chloro-3-methoxybenzylphosphonate (3 g, 9.77 mmol) in a 1:1 mixture of DCE and t-butanol (20 mL) was added followed by N-methylimidazole (800 mg, 9.75 mmol) drop wise while stirring was continued for 24 hrs. The solvents were removed under reduced pressure and the residue was purified by column chromatography (SiO2, ethyl acetate and hexanes (1:1)) to yield the desired compound in 1.5 g (32%) yield. 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.38 (d, 1H), 8.03 (s, 1H), 4.01-4.18 (q, 4H), 3.98 (s, 3H), 3.29 (d, 2H), 1.24 (t, 6H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([NH:17][C:18](=O)[CH2:19][CH3:20])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[CH2:2][CH3:3].[CH2:22](I)[CH2:23][CH3:24]>>[CH2:1]([O:5][CH2:6][CH:7]([N:17]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:19][CH3:20])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH3:3]
Reactant: CCC(=O)NC(CCOc1ccccc1)COC(=O)CC
Reactant: CCCI
Product: CCCOCC(CCOc1ccccc1)N(CCC)CCC

Procedure:
2-(propionylamino)-4-phenoxy-1-butanol propionate, described in Example 5, with propyliodide, followed by reduction gives 1-propoxy-N,N-dipropyl-4-phenoxy-2-butanamine,
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[C:1]1([CH2:7][C:8]([O:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: [Na]
Product: COc1ccc(COC(=O)Cc2ccccc2)cc1

Procedure:
Phenylacetic acid, sodium salt, is reacted with 4-methoxybenzyl bromide to obtain 4-methoxybenzyl phenylacetate;
Reaction SMILES: [CH3:1][C:2]([N:5]1[N:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6]1)([CH3:4])[CH3:3].O1CCCC1.C([Li])CCC.[CH3:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[CH:30]2>CCCCCC.C1(C)C=CC=CC=1.C(O)C>[CH3:4][C:2]([N:5]1[N:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:32]2[CH:31]=[CH:30][C:29]3[C:34](=[CH:35][CH:36]=[C:27]([CH3:26])[CH:28]=3)[NH:33]2)=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)n1nnc(-c2ccccc2)n1
Reactant: Cc1ccc2ncccc2c1
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C=CC(c1ccccc1-c1nnn(C(C)(C)C)n1)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 g (490 mmol) of 2-(1,1-dimethylethyl)-5-phenyl-2H-tetrazole and 500 ml of anhydrous tetrahydrofuran are introduced into a 2-liter three-necked round-bottomed flask under a nitrogen atmosphere. 215 ml (580 mmol) of 2.5M n-butyllithium solution in hexane are added dropwise to the mixture. The mixture is heated at the reflux temperature for 45 minutes, followed by addition of 49 g (410 mmol) of 6-methylquinoline dissolved in 300 ml of toluene. The reaction medium is left for 2 hours at the reflux temperature and is then cooled to room temperature. Next, 300 ml of ethanol are added and the solvent is evaporated off under reduced pressure. The residue is taken up in 500 ml of water and is filtered, washed with 200 ml of isopropanol and dried under vacuum.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]([C:14]2[C:33]([CH:34]3[CH2:36][CH2:35]3)=[CH:32][C:17]3[C:18]([C:28]([NH:30][CH3:31])=[O:29])=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[O:20][C:16]=3[CH:15]=2)[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[F:37].C([O-])(=O)C.[K+].[B:43]1(B2OC(C)(C)C(C)(C)O2)[O:47]C(C)(C)C(C)(C)[O:44]1>O1CCOCC1.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:34]1([C:33]2[C:14]([N:9]([C:5]3[CH:4]=[C:3]([F:37])[C:2]([B:43]([OH:47])[OH:44])=[C:7]([F:8])[CH:6]=3)[S:10]([CH3:13])(=[O:11])=[O:12])=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:18]([C:28](=[O:29])[NH:30][CH3:31])[C:17]=3[CH:32]=2)[CH2:36][CH2:35]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(B(O)O)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 19.4 %

Procedure:
A solution of 6-(N-(4-bromo-3,5-difluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.093 g, 0.157 mmol), potassium acetate (0.062 g, 0.627 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.013 g, 0.016 mmol), bis(pinacolato)diboron (0.080 g, 0.31 mmol) in 1,4-Dioxane (1.6 ml) was degassed, purged with nitrogen and heated at 90° C. for 4 h. The reaction mixture was diluted with EtOAc and water, filtered through celite, and evaporated. The brown residue was dissolved in 5 mL THF, and 2.5 mL 1M HCl. NaIO4 (0.27 g, 1.25 mmol) was added and the suspension was stirred for 2.5 h and diluted with EtOAc and water. The organic layer was washed with water, brine, dried (Na2SO4), filtered, evaporated and purified by reverse phase chromatography (5-100% CH3CN/H2O (0.1% formic acid)) to afford the title compound (0.017 g, 19%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.91-7.98 (m, 2H), 7.79 (s, 1H), 7.34 (s, 1H), 7.20-7.29 (m, 2H), 6.82-6.92 (m, 2H), 3.38 (s, 3H), 2.95 (s, 3H), 2.01-2.11 (m, 1H), 0.70-1.07 (m, 3H), 0.54 (br. s., 1H). LCMS (m/z, ES+)=559.3 (M+H+).
Reaction SMILES: [OH:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2.[CH2:11]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:25])[C:22](Cl)=[O:23])=[CH:17][CH:16]=1)[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:25])[C:22]([O:1][C:2]23[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]2)[CH2:3]3)=[O:23])=[CH:19][CH:20]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(=O)NC12CC(O)(C1)C2
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Product: CC(=O)NC12CC(OC(=O)C(C)c3ccc(CC(C)C)cc3)(C1)C2

Procedure:
The general procedure of Example 1 Step 3 is repeated starting with N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) and using 2-(4-isobutylphenyl)propanoyl chloride in place of the acetyl chloride to produce 3-acetamidobicyclo[1.1.1]pentan-1-yl 2-(4-isobutylphenyl)propanoate (9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[CH:5][C:4]=1[OH:18].[CH2:19]=[O:20]>[Ti].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=[C:5]([CH:19]=[O:20])[C:4]=1[OH:18]
Reactant: C=O
Reactant: CCCCCCCCCc1ccc(O)c(OC)c1
Agent: [Ti]
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1cc(C=O)c(O)c(OC)c1
Temperature: 218 °C
Reaction time: 0.42 h

Procedure:
A pressure reactor was charged with 500 ml of toluene and heated to 218° C. A slurry of a mixture of 2-methoxy-4-nonylphenol (250.4 g, 1.0 mol), paraformaldehyde (94.5 g, 3.15 mol), titanium cresylate (2 ml) and 50 ml of toluene was added over 5 mins. The container of slurry was washed two times with 2×50 ml of toluene. The reaction mixture was heated (the reactor was heated with a 250° C. hot oil circulating through internal coil) and stirred for 25 mins. and discharged from the reactor. The dark brown mixture was washed with 5% H2SO4 and water. The organic solution was separated and dried over MgSO4. Removal of the solvent left dark color oil as crude product. The purification was achieved through vacuums distillation and chromatography.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.BrCC1C=CC([F:28])=CC=1>>[F:28][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][S:6][C:7]2[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Reactant: Fc1ccc(CBr)cc1
Product: COc1cc(SCc2ccc(F)cc2)cnc1OC

Procedure:
Prepared as described for 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine (Intermediate 8) but using 1-(bromomethyl)-4-fluorobenzene instead of 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][NH2:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][NH:11][C:12](=[O:14])[CH3:13]
Reactant: COCc1ccccc1CN
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COCc1ccccc1CNC(C)=O
Temperature: 60 °C

Procedure:
604 g (4 moles) of o-aminomethylbenzyl methyl ether were dissolved in 1,500 ml of toluene, and 408 g (4 moles) of acetic anhydride were added to the stirred and cooled solution at a rate such that 60° C. was not exceeded. Stirring was continued, the mixture was neutralized with 424 g of 25% strength sodium hydroxide solution, and the aqueous phase was separated off. When the organic phase was evaporated down, 656 g (85% of theory) of the acylated benzyl ether of melting point 67°-68° C. crystallized.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:29]#[N:30])[CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.O>[C:29]([C:25]1([C:22]2[CH:21]=[CH:20][C:19]([CH:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]3[C:6]4[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH3:18])=[CH:24][CH:23]=2)[CH2:28][CH2:27][CH2:26]1)#[N:30]
Reactant: CC(N)c1ccc(C2(C#N)CCC2)cc1
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(NC(=O)Cn1cnc2ccc(F)c(F)c21)c1ccc(C2(C#N)CCC2)cc1

Procedure:
N-{1-[4-(1-Cyanocyclobutyl)phenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is synthesized according to example 5 by mixing (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (212 mg, 1.00 mmol) prepared according to scheme 2, 1-[4-(1-aminoethyl)phenyl]cyclobutanecarbonitrile (200 mg, 1.00 mmol) prepared according to scheme 9, Et3N (304 mg, 3.00 mmol, 0.418 mL) and HATU (280 mg, 1.00 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (220 mg, 0.558 mmol, 56%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.39 (d, J=7.03 Hz, 3H) 1.91-2.05 (m, 1 H) 2.16-2.34 (m, 1H) 2.53-2.64 (m, 2H) 2.66-2.78 (m, 2H) 4.87-5.01 (m, 1H) 5.07 (s, 2 H) 7.11-7.31 (m, 1H) 7.33-7.49 (m, 5H) 8.19 (s, 1H) 8.84 (d, J=7.81 Hz, 1H); MS [M+H], calcd: 395.0. found: 395.2.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=O)[CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].CSC.B>>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Agent: B
Solvent: CSC
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2
Yield: 102.1 %

Procedure:
This compound was prepared by General Method 2 from 7-nitro-2H-1,4-benzoxazin-3(4H)-one (2.0 g, 10 mmol) and borane dimethylsulfide (2.0 M in THF, 24 mL, 48 mmol) and purified on silica gel (20:1 CH2Cl2;MeOH) to afford 1.84 g (98%) of 3,4-dihydro-7-nitro-2H-1,4-benzoxazine, an orange solid. Data for 3,4-dihydro-7-nitro-2H-1,4-benzoxazine: Rf 0.76 (11.5:1 CH2Cl2:MeOH); 1H NMR (400 MHz, CDCl3) δ 7.74 (dd, 1H, J=8.7, 2.5), 7.69 (d, 1H, J=2.5), 6.52 (d, 1H, J=8.7), 4.56 (br s, 1H), 4.26 (t, 2H, J=4.4), 3.54 (td, 2H, J=4.4, 2.5)
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].O.[OH-].[Li+].O1CCCC1.CO>O>[C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)c1cccc(C2(C#N)CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)O)c2)CCCCC1
Yield: 90.5 %

Procedure:
Using methyl 3-(1-cyanocyclohexyl)benzoate (1.3 g, 5.3 mmol), lithium hydroxide-monohydrate (0.52 g, 13 mmol), tetrahydrofuran (18 mL), methanol (6.0 mL) and water (6.0 mL) as starting materials and in the same manner as in Reference Example 37, the title compound (1.1 g, 88%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([C:13]#[N:14])[CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([C:13]#[N:14])[CH:12]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2cc(C#N)co2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1coc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-(4-cyano-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. EI-MS m/e (%): 348 (M+, 90), 347 ([M—H]+, 65), 138 (100), 106 (70).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][C:3]=1[CH3:13].O>I>[CH3:13][C:3]1[NH:4][C:5](=[O:12])[C:6]2[C:11]([CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cc1[nH]c(=O)c2ccccc2c1O
Agent: I
Solvent: O
Product: Cc1cc2ccccc2c(=O)[nH]1
Yield: 45.8 %

Procedure:
24.6 g (140 mmol) of 4-hydroxy-3-methyl-2H-isoquinolin-1-one are heated together with 9.13 g (294 mmol) of red phosphorus in 55% hydriodic acid (130 ml) at 160° C. for 7 days. The cooled mixture is poured into water and extracted with dichloromethane. 10.2 g (46% yield) of a white solid are obtained.