Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C@:11]([F:15])([CH:13]=[CH2:14])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[C:32]([O:33][CH3:34])=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([F:35])[CH:24]=4)=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[CH:1]1([N:6]2[CH2:12][C@:11]([F:15])([CH:13]=[CH2:14])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[C:32]([O:33][CH3:34])=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:35])[CH:24]=4)=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)OC)cc3OC)ncc2N(C)C1=O
Agent: Cl
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3OC)ncc2N(C)C1=O
Temperature: 95 °C
Reaction time: 3.5 h

Procedure:
A mixture of (R)-methyl 4-(9-cyclopentyl-7-fluoro-5-methyl-6-oxo-7-vinyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoate (400 mg, 0.821 mmol) was suspended in conc. HCl (1.0 mL) and it was stirred at 95° C. for 3-4 hrs. At this time the reaction was cooled to room temperature and filtered to reveal the product as a tan solid (295 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.82 (m, 4H) 1.98-2.02 (m, 4H) 3.29 (s, 3H) 3.51 (br. s., 2H) 3.94 (s, 3H) 4.88 (t, J=8.08 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.43, 12.63, 10.86 Hz, 1H) 7.41-7.57 (m, 1H) 7.82 (s, 1H) 8.12 (s, 1H) 8.31 (d, J=8.08 Hz, 1H). [M+H] calc'd for C23H25F2N5O4, 474. found 474.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:51]4[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCN(C)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-methylpiperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H53Cl2N6O3 [(M+H)+] 747.3551, observed 747.3554.
Reaction SMILES: CC(C)(CCCC)C=CC([CH:7]1[CH:14]2[CH:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][CH:8]1[CH3:16])=O.[BH4-].[Na+]>>[CH3:16][CH:8]1[CH2:9][CH:10]2[O:11][C:12](=[O:15])[CH2:13][CH:14]2[CH2:7]1
Reactant: CCCCC(C)(C)C=CC(=O)C1C(C)CC2OC(=O)CC21
Agent: [BH4-]
Agent: [Na+]
Product: CC1CC2CC(=O)OC2C1

Procedure:
The crude, optically active (3aR,4S,-5R,6aS)-[S*,R*(E)]-4-(4,4-dimethyl-1-oxo-2-octenyl)hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one (11.1 g) was reduced with sodium borohydride (1.1 g) as described in Example V. After workup 10.45 g (93%) of optically active [3aR-[3aalpha,4alpha(1S*,2E),5beta,6aalpha]]-4-[1-(hydroxy)-4,4-dimethyl)-2-octenyl]hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one was obtained as a viscous, amber colored oil. The product gave a single spot on TLC and was used as is in Examples XVI through XXIV of the synthesis.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([F:12])=[C:4]([F:13])[C:3]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20].[Li]CCCC.[CH:26](N1CCOCC1)=[O:27].Cl>C1COCC1>[F:13][C:4]1[C:5]([F:12])=[C:6]2[O:10][C:9]([CH3:11])=[CH:8][C:7]2=[C:2]([CH:26]=[O:27])[C:3]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: COCCOCOc1c(F)c(F)c2oc(C)cc2c1Br
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCOc1c(F)c(F)c2oc(C)cc2c1C=O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
27.2 g (77.5 mmol) of 4-bromo-6,7-difluoro-5-(2-methoxyethoxymethoxy)-2-methylbenzofuran are initially introduced at −75° C. in 500 ml of THF, and 52.0 ml (85.2 mmol) of n-BuLi (15% soln. in hexane) are added. After 2 h at this temperature, 15.5 ml (155 mmol) of N-formylmorpholine are metered in, and the batch is stirred at this temperature for 2 h. The reaction soln. is slowly warmed to −10° C. and hydrolysed using dil. HCl. The batch is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:MTBE=2:1→n-heptane:MTBE=1:1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][CH:25]([CH2:30][CH:31]3[O:33][CH2:32]3)[C:26]([O:28]C)=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH:24][CH:25]([CH2:30][C:31]([OH:33])([S:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH3:32])[C:26]([OH:28])=[O:27])(=[O:22])=[O:23])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1cccs1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(C)(O)Sc3cccs3)C(=O)O)cc2)cc1

Procedure:
Example 34 is prepared from 2-thiophenethiol and 1d using the procedure described for compound 20.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:11][C:10]2[C:5](=[N:6][C:7]([CH2:12][NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].C(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:20])[O:11][C:10]2[C:5](=[N:6][C:7]([CH2:12][N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:30]([O:29][CH3:28])[CH:31]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: CC1(C)C=Cc2nc(CNc3ccccc3)ccc2O1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N(Cc2ccc3c(n2)C=CC(C)(C)O3)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 25a (60 mg, 0.226 mmol) in DCM (3 mL) was added triethylamine (0.06 mL, 0.452 mmol) and 3,4-dimethoxybenzoyl chloride (54 mg, 0.271 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was washed with dH2O (×2) and sat. NaHCO3 (×2), dried over MgSO4 and concentrated in vacuo. Purification by column: silica gel: 3:1 DCM/EtOAc gave a quantitative yield of a light yellow oil. 1H NMR (CDCl3): δ 7.26-7.17 (m, 3H), 7.17-7.08 (m, 3H), 7.06-6.97 (m, 2H), 6.95 (t, J=5.0 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.53-6.40 (m, 1H), 5.92-5.79 (m, 1H), 5.16 (s, 2H), 3.83 (s, 3H), 3.66 (s, 3H), 1.46 ppm (s, 6H). 13C NMR (CDCl3): δ 169.9, 150.3, 149.0, 148.6, 147.9, 144.7, 140.6, 135.1, 129.0, 127.8, 127.2, 126.3, 124.0, 123.6, 123.0, 122.3, 112.6, 109.9, 77.4, 77.0, 77.0, 76.7, 55.8, 55.7, 55.6, 28.2 ppm. HRMS (ESI) m/z calcd for C26H27N2O4 [(M+H)+] 431.1971. found: 431.1951.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:38]=[C:39]1[NH:43][C:42](=[O:44])[CH:41]([CH2:45][C:46]2[CH:60]=[CH:59][C:49]([O:50][C:51]3[CH:58]=[CH:57][C:54]([CH:55]=O)=[CH:53][CH:52]=3)=[CH:48][CH:47]=2)[S:40]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:31][O:30][C:28]1[CH:27]=[C:6]([CH:7]=[CH:55][C:54]2[CH:53]=[CH:52][C:51]([O:50][C:49]3[CH:59]=[CH:60][C:46]([CH2:45][CH:41]4[S:40][C:39](=[O:38])[NH:43][C:42]4=[O:44])=[CH:47][CH:48]=3)=[CH:58][CH:57]=2)[CH:5]=[C:4]([O:3][CH3:2])[CH:29]=1
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1
Reactant: O=Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(C=Cc2ccc(Oc3ccc(CC4SC(=O)NC4=O)cc3)cc2)cc(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3,5-dimethoxybenzyltriphenylphosphonium bromide (0.82 g, 2.0 mmol) in THF (10 mL) at 0° C. was added solid potassium tert-butoxide (224 mg, 2.0 mmol). The resultant red solution was stirred for 15 min at 0° C. then cooled to −78° C. Solid 53 (0.3 mg, 0.90 mmol) was added and the reaction was allowed to warm to room temperature. After 30 min 10% citric acid (50 mL) was added and the mixture was partitioned between water (50 mL) and ethyl acetate (75 mL). The organic layer was washed with water (50 mL) and brine (50 mL) then dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using hexanes-ethyl acetate (7:3) to yield 55 as a slightly opaque film (25 mg, 6%) after concentration and drying under high vacuum. 1H NMR (400 MHz, DMSO-d6): δ 12.04 (b s, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.61 (d, J=12.4 Hz, 1H), 6.53 (d, J=12.0 Hz, 1H), 6.39 (d, J=2.4 Hz, 1H), 6.36 (t, J=2.4 Hz, 1H), 4.90 (dd, J=9.2 and 4.4 Hz, 1H), 3.62 (s, 6H), 3.36 (dd, J=14.0 and 4.4 Hz, 1H), 3.11 (dd, J=14.4, 8.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)c(Cl)cc43)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)c(Cl)cc43)cc2o1
Temperature: 120 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of 6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (460 mg, 1.08 mmol), (1R,2R)-2-aminocyclohexanol (245 mg, 2.13 mmol) and DIEA (366 mg, 2.84 mmol) in DMA (10 mL) was stirred at 120° C. for 1 h. The reaction mixture was cooled to rt, poured into water (30 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give (1R,2R)-2-((6-((5-bromo-6-chloro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a light yellow solid (470 mg, 82.3%). 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.41 (s, 1H), 7.14 (s, 1H), 5.48 (s, 2H), 4.68 (d, J=4.2 Hz, 1H), 3.33 (br s, 2H), 1.91 (br s, 2H), 1.63 (br s, 2H), 1.25 (br s, 4H). LCMS (ESI) m/z 477 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC(C)C)=O.[NH3:23].C([O-])(O)=O.[Na+]>C1COCC1.CN1CCCC1=O>[C:4]([O:3][C:1]([N:8]1[CH2:11][CH:10]([C:12](=[O:14])[NH2:23])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(N)=O)C1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To 1.0 g (4.97 mmol) boc-azetidine-3-carboxylic acid in 10 mL anhydrous THF was added 0.55 mL of 1-methyl-2-pyrrolidinone. The reaction mixture was cooled to −20° C., then 0.62 mL (4.72 mmol) isobutyl chloroformate was added and the reaction was stirred for 5 minutes. 1.51 mL (24.85 mmol) aqueous ammonia (28% w/w) was added and the mixture was stirred at −20° C. for 2 hours. 5 mL aqueous NaHCO3 (1 M) was added and the mixture was allowed to reach room temperature over 1 hour. The mixture was extracted with DCM (3×10 mL), the organic layers were combined, washed with aqueous NaHCO3 (1 M), aqueous citric acid (1 M) and dried over Na2SO4. After filtration and evaporation of the solvent the product was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[CH3:32][CH2:33][C:34](Cl)=[S:35].[OH-].[Na+]>CC(C)=O>[CH3:32][CH2:33][C:34]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[S:35]
Reactant: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CCC(=S)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(C(CCNC(N)=O)Sc3nnn[nH]3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20°) solution of 10.4 g. (0.026 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 220 ml. of 3% sodium bicarbonate and 220 ml. of acetone is added dropwise a solution of 3.66 g. (0.029 mol.) of methylthioacetyl chloride in 52 ml. of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml. of ethyl acetate is added and the slurry if acidified with 3N hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: N.[Na].[C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH3:4].Cl[CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16]>O.[Na].C(O)(=O)C.CCOCC>[CH3:16][C:15]([CH3:17])=[CH:14][CH2:13][CH2:4][C:3](=[O:5])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)=CCCl
Agent: N
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)CCC=C(C)C
Reaction time: 0.17 h
Yield: 38.4 %

Procedure:
A mixture of 1.4 g of ferric nitrate in 1200 ml of liquid ammonia was formed at -60° C. and was then stirred for 5 minutes after which 2 g of sodium were added thereto at -60° C. The mixture was stirred for 10 minutes and 104 g of sodium were added at -55°±5° C. over 21/2 hours. The mixture was stirred at -55° C. for one hour. 300 g of ethyl acetylacetate were added thereto over 30 minutes at less than -30° C. 1000 ml of ether at -20° C. were added to the mixture which was then stirred for 5 minutes. 289 g of 1-chloro-3-methyl-2-butene were added over 30 minutes at less than -25° C. and the mixture stood at room temperature for 17 hours. 1000 ml of ether were progressively added at less than +15° C. followed by a solution of 250 ml of acetic acid in 1000 ml of water. The decanted aqueous phase was extracted with ether and the combined organic phases were washed with 2 N hydrochloric acid, then with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was rectified under reduced pressure to obtain 175.5 g of ethyl 7-methyl-3-oxo-6-octenoate with a boiling point of 98° to 107° C. at 3 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:14][C:15](=O)[CH3:16].Cl>C(O)(=O)C.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH:15]([CH3:16])[CH3:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Brc1ccc(C2CCNCC2)nc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCC(c2ccc(Br)cn2)CC1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
5-Bromo-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl (6.7 g, 18.9 mmol) was dissolved in 2% acetic acid in MeOH (40 ml). Propanone (8 mL, 113 mmol) and Na(CN)BH3 (3.6 g, 57 mmol) were added. The reaction mixture was stirred at RT over night. LC-MS showed only product. The reaction mixture was added 1N HCl filtered and evaporated in vacuo. The compound was dissolved in water pH was adjusted to PH=12 extracted with DCM (3×200 mL). The DCM phase was dried with Na2CO3 filtered and evaporation gave 4.4 g (82%) white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[N+:26]([C:29]1[CH:34]=[C:33]([S:35]([C:38]([F:41])([F:40])[F:39])(=[O:37])=[O:36])[CH:32]=[CH:31][C:30]=1Cl)([O-:28])=[O:27]>>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:15][C:14]1[CH:22]=[CH:23][C:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:30]3[CH:31]=[CH:32][C:33]([S:35]([C:38]([F:40])([F:41])[F:39])(=[O:37])=[O:36])=[CH:34][C:29]=3[N+:26]([O-:28])=[O:27])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[CH:12][CH:13]=1)[CH3:21]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)COc1ccc(S(=O)(=O)c2ccc(Oc3ccc(S(=O)(=O)C(F)(F)F)cc3[N+](=O)[O-])cc2)cc1

Procedure:
Using procedure as in example 10, a reaction of ethyl [4-(4-hydroxyphenylsulfonyl)phenoxy]acetate (100 mg, 0.297 mmol), NaH (13 mg, 1.1 equiv.) and 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (86 mg, 1 equiv.) afforded{4-[4-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-benzenesulfonyl]-phenoxy}-acetic acid ethyl ester. 1HNMR (300 MHz, DMSO-d6) δ 8.79 (d, J=2.3 Hz, 1H), 8.29 (dd, J=2.3 & 9.0 Hz, 1H), 8.07 (d, J=8.9 Hz, 2H), 7.92 (d, J=8.9 Hz, 2H), 7.52 (d, J=8.9 Hz, 2H), 7.47 (d, J=9.0 Hz, 1H), 7.14 (d, J=8.9 Hz, 2H), 4.91 (s, 2H, CH2), 4.15 (q, J=7.2 Hz, 2H, OCH2CH3), 1.19 (t, J=7.2 Hz, 3H, OCH2CH3). MS-EI m/z 589 [M+].
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:36][C:37]2[CH:46]=[CH:45][C:40]([C:41]([NH:43]O)=[NH:42])=[CH:39][CH:38]=2)[CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]2=[O:35])(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:41]3[N:42]=[C:1]([CH3:2])[O:4][N:43]=3)=[CH:45][CH:46]=2)[CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]2=[O:35])(=[O:25])=[O:26])=[CH:20][CH:19]=1
Reactant: CC(=O)O
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(CN(C3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
To a solution of acetic acid (63 μl, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (1/1 to 4/1) yielded 0.43 g (91%) 4-chloro-N-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=474.9 (MH+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])[NH:7][C:6]=2[CH:20]=1.F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC1C=CC2N=C(C(N)C)N(C3C=CC=CN=3)C=2C=1>CCOC(C)=O.CN(C)C(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:8]([CH:10]([NH2:12])[CH3:11])=[N:7][C:6]=2[CH:20]=1
Reactant: Fc1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2[nH]1
Agent: CC(N)c1nc2ccc(F)cc2n1-c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(N)c1nc2cc(F)ccc2n1-c1ccccn1
Temperature: 150 °C
Reaction time: 0.23 h
Yield: 31.6 %

Procedure:
To a microwave vial was added (S)-tert-butyl 1-(6-fluoro-1H-benzo[d]imidazol-2-yl)ethylcarbamate (Prepared in Example 16, 0.5126 g, 1.835 mmol), N,N-Dimethylacetamide (4.08 mL), 2-fluoropyridine (0.189 mL, 2.202 mmol), and cesium carbonate (1.196 g, 3.67 mmol). The mixture was heated for 40 min in the microwave reactor (Temperature: 150° C. Pressure: 92˜94 psi, Power: 8˜10 W). At this time, the mixture was poured into EtOAc (100 mL), filtered and then concentrated on the high vacuum to remove most of the DMA. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 20% gradient of EtOAc in hexane over 14 min, then 20% EtOAc in hexane for 14 min, then 20 to 50% gradient of EtOAc in hexane over 14 min, and then 50% EtOAc in hexane for 14 min as eluent to give a mixture of four isomer of two regioisomers and two stereoisomer of each regioisomer, 1-(6-fluoro-1-(pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)ethanamine and 1-(5-fluoro-1-(pyridin-2-yl)-1H-benzo[d]imidazol-2-yl)ethanamine (0.1486 g, 0.580 mmol, 31.6% yield) as a yellow syrup: LC-MS (ESI) m/z 257.0 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[I:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(Cc1ccccc1)c1cccc(I)c1

Procedure:
m-Iodobenzoic acid (1 g, 0.004 mol) was dissolved in MeCN (20 ml), Cs2CO3 (2.63 g, 2 eq) and benzyl bromide (0.528 ml, 1.1 eq) added. The mixture was heated at reflux overnight. The mixture was concentrated, taken up in EtOAc, washed with water, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc in hexane) to give 1.6 g of M16-3.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=1.C([Li])CCC.[CH:32](=[O:34])[CH3:33]>O1CCCC1>[OH:34][CH:32]([C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=1)[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(I)cn2CCN2CCCC2)CC1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1cn(CCN2CCCC2)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
Combine tert-butyl 4-(4-iodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (40.00 g, 82.63 mmol) and tetrahydrofuran (600 mL). Cool to −70° C. under nitrogen. Add 2.5 M n-butyllithium in hexanes (67.76 mL, 2.1 eq) dropwise. Add acetaldehyde (23.22 mL, 5.0 eq) and stir for 15 minutes. Quench over aqueous saturated ammonium chloride (75 mL). Separate the layers. Wash the aqueous phase with methyl tert-butyl ether. Wash the organics with water and aqueous saturated sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Dissolve in ethanol. Add 85% aqueous phosphoric acid dropwise to achieve a suspension. Stir the mixture overnight at room temperature. Filter and dry the resulting off-white solid under vacuum to give tert-butyl 4-(4-(1-hydroxyethyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate; phosphoric acid (28.00 g, 69%). MS (ES) m/z=393 [M]+.