Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])(=O)(=O)C.[N:6]1[C:15]2[CH:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:32][C:33]#[N:34]>CCN(C(C)C)C(C)C>[N:34]1[C:13]([CH2:14][N:16]([CH:14]2[C:15]3[N:6]=[CH:7][CH:8]=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]2)[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:12][CH:11]=[CH:32][C:33]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:15][N:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: CC#N
Agent: CS(=O)(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: NCCCCN(Cc1cccc(-c2ccccn2)n1)C1CCCc2cccnc21

Procedure:
Using the general alkylation procedure A: Reaction of the mesylate from above and 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione in dry CH3CN and DIPEA gave the desired amine as a yellow oil. Deprotection with hydrazine following General Procedure E gave COMPOUND 361 as a colorless oil. 1H NMR (CDCl3) δ 1.42-1.58 (m, 4H), 1.63-1.72 (m, 1H), 1.86-2.04 (m, 2H), 2.14-2.19 (m, 1H), 2.08-2.19 (m, 2H), 2.60 (t, 2H, J=6.9 Hz), 2.65-2.90 (m, 4H), 3.83 (d, 1H, J=15.6 Hz), 3.99 (d, 1H, J=13.2 Hz), 4.18 (dd, 1H, J=9, 6 Hz), 7.03 (dd, 1H, J=7.8, 4.8 Hz), 7.25-7.33 (m, 2H), 7.74-7.82 (m, 3H), 8.15 (d, 1H, J=8.1 Hz), 8.34 (d, 1H, J=8.1 Hz), 8.51 (d, 1H, J=3.6 Hz), 8.66 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 21.83, 26.64, 26.79, 29.72, 31.82, 42.40, 53.27, 58.48, 61.50, 119.30, 121.54, 121.86, 123.30, 123.82, 134.59, 136.81, 137.24, 137.52, 147.58, 149.56, 155.27, 156.91, 158.64, 162.20. ES-MS m/z 388 (M+H). Anal. Calcd. for C24H29N5.1.3CH2Cl2: C, 61.03; H, 6.40; N, 14.06. Found: C, 61.25; H, 6.36; N, 13.98.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[N:8]=1)(=O)=O.[Cl:25][C:26]1[C:27](B(O)O)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:25][C:26]1[C:27]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[N:8]=2)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: O=S(=O)(Oc1ccc(F)c(NCc2cccc(F)c2)n1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1cccc(CNc2nc(-c3cc(F)ncc3Cl)ccc2F)c1
Temperature: 120 °C
Yield: 57.2 %

Procedure:
5-fluoro-6-(3-fluorobenzylamino)pyridine-2-yl trifluoromethanesulfonate (0.0811 g, 0.220 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (0.116 g, 0.661 mmol), and sodium carbonate (0.286 mL, 0.573 mmol, 2M in H2O) were dissolved in DME (2 mL). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf) CH2Cl2 adduct (0.036 g, 0.044 mmol). The reaction mixture was then heated in the microwave at 120° C. for 10 min. The reaction mixture was then filtered through a pad of Celite. The filtrate was concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 5 EtOAc/95 hexanes to 60 EtOAc/40 hexanes yielded 0.044 g (57%) of 5′-chloro-2′,5-difluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine. LCMS (m/z): 350.0 (MH+), retention time=1.16 min.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][CH3:15])=[C:4]([CH3:16])[CH:3]=1.ClCC1C2C(=CC=CC=2)C=CC=1C.C(Br)CC.CCOCC>C1(C)C=CC=CC=1>[CH2:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH:3][C:4]=1[CH3:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1c(C)cc(Br)c2ccccc12
Agent: Cc1ccc2ccccc2c1CCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCBr
Product: CCCCc1c(C)ccc2ccccc12

Procedure:
1-Bromo-4-butyl-3-methylnaphthalene-- A solution of 1-chloromethyl-2-methylnaphthalene (32.3 g) in dry toluene (150 ml) was dropwise added to a Grignard reagent, from n-propylbromide (27.1 g), Mg(5.3 g), and dry ether (150 ml). The ether was evaporated, and the resulting solution was refluxed for 2 hrs. The reaction mixture was cooled and poured into an ice-cooled aqueous ammonium chloride. The organic layer was taken, and aqueous layer was extracted with ether. Combined organic solution was washed with 10% HCl, 10% NaOH, and water and dried. The solvent was evaporated, and the residue was distilled to give an oil (8.8 g) of 1-butyl-2-methylnaphthalene, bp2 82°-86° C. The oil (8.8 g) was brominated by a similar manner given in Example 9 to afford an oil (8.0 g, 65.1%) of bp2 124°-128° C.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([OH:11])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:12][C:8]=1[C:9]([NH:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)=[O:11])[CH:2]=[C:3]([CH3:4])[CH3:5]
Reactant: NCCc1ccncc1
Reactant: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)O)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCOc1ccc(OCC=C(C)C)c(C(=O)NCCc2ccncc2)c1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
2,5-diprenyloxybenzoic acid(1.99 g) was dissolved in chloroform(38 ml) and triethylamine(1.91 ml), and then diphenylphosphinic chloride(1.31 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.85 g) added thereto, was stirred for 1 hour at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.11 g of the aimed compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:36])[C:8]2[CH:9]=[C:10]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:12][C:7]=2[N:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:5][C:4]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:3]1.C1COCC1.[Li+].[OH-]>C(Cl)Cl.O.C(O)(=O)C>[O:36]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:17][CH2:18][C:19]([OH:21])=[O:20])[C:11]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:12][C:7]=2[N:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:5][C:4]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(S(C)(=O)=O)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(S(C)(=O)=O)c(OCC(=O)O)cc2S(=O)(=O)C1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-mesyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 20; 46 mg, 0.085 mmol) was added THF (5 ml), water (1 ml) and LiOH (10 mg, 0.4 mmol). The reaction was stirred for 1 hour and then excess acetic acid was added to quench the reaction. Water and DCM were added and the aqueous phase was extracted three times with DCM. The combined organic phases were dried and concentrated to give the title compound 40 mg (91%). NMR 0.7–0.85 (m, 6H), 1.0–1.7 (m, 8H), 3.2 (m, 2H), 3.3 (s, 3H), 3.8 (s, 2H), 4.9 (s, 2H), 5.0 (brs, 1H), 7.05–7.15 (m, 3H), 7.3–7.4 (t, 2H), 7.5 (s; 1H), 7.6 (s, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[NH:32][C:33](=O)[O:34]C1C=CC=CC=1.NC1C=NC=CN=1>>[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[NH:32][C:33]([N:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=3)[CH:10]=2)[CH2:4][CH2:3]1)=[O:34]
Reactant: O=C(Nc1cnccn1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Agent: Nc1cnccn1
Product: O=C(Nc1cnccn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1

Procedure:
Following the procedure in Example 1, Step 6, 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (150 mg, 0.40 mmol, from Example 1, Step 5) and phenyl pyrazin-2-ylcarbamate (261 mg, 1.2 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from aminopyrazine) were used to provide the title compound (24 mg). MS (APCI 10V) AP+ 456.2, 376.2, 335.2, AP− 454.2, 435.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.43-2.50 (m, 2H) 2.56-2.62 (m, 2H) 3.54-3.61 (m, 2H) 3.64-3.70 (m, 2H) 6.46 (s, 1H) 6.98-7.05 (m, 2H) 7.10-7.17 (m, 2H) 7.40 (td, J=7.72, 0.67 Hz, 1H) 8.06-8.11 (m, 1H) 8.16 (d, J=2.68 Hz, 1H) 8.28 (dd, J=2.68, 1.54 Hz, 1H) 8.43 (ddd, J=2.56, 1.71, 0.85 Hz, 1H) 9.04 (d, J=1.56 Hz, 1H).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7].C(OC(N1CCC(NC(=O)C2C=C(OC)C=C(O)C=2)CC1)=O)(C)(C)C.Cl.O1CCOCC1.[CH2:52]([O:54][C:55]1[CH:56]=[C:57]([CH:60]=[C:61]([O:64][CH2:65][CH3:66])[C:62]=1[F:63])[CH:58]=O)[CH3:53].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>CCO.C(O)(=O)C>[CH2:52]([O:54][C:55]1[CH:56]=[C:57]([CH:60]=[C:61]([O:64][CH2:65][CH3:66])[C:62]=1[F:63])[CH2:58][N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[C:5]2[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:3]([OH:2])[CH:4]=2)[CH2:14][CH2:13]1)[CH3:53]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: COc1cc(O)cc(C(=O)NC2CCNCC2)c1
Agent: COc1cc(O)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 3-hydroxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride [prepared from 4-(3-hydroxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (example 168a) by Boc cleavage using HCl/dioxane in EtOH at rt in analogy to the procedure described in example 250b)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 447.2 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:33][CH3:34])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]2[CH2:25][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][C:22]2=[O:32])[CH:9]=1)([CH3:3])[CH3:2].CI.[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[K+].O>C1COCC1.C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:33][CH3:34])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[CH2:20][N:21]2[CH2:25][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]([CH3:37])[C:22]2=[O:32])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C[C@@H](c2ccccc2)NC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C[C@@H](c2ccccc2)N(C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-phenylimidazolidin-2-one (12.6 mg, 0.0269 mmol) in THF (1.5 mL) was added MeI (10 μL, 0.162 mmol), followed by KHMDS (162 μL of a 0.5 M solution in toluene, 0.081 mmol). The reaction was stirred at room temperature for 10 minutes, and then poured into water (10 mL). The mixture was extracted with EtOAc (30 mL) and the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 50% EtOAc/hexanes afforded (4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-4-phenylimidazolidin-2-one. Rf=0.26 (40% EtOAc/hexanes). LCMS=483.2 (M+1)+. 1H NMR (CDCl3, 500 MHz, atropisomers observed; doubling of peaks.) δ 7.68-7.53 (m, 2H), 7.21-7.36 (m, 7H), 6.87-6.94 (m, 2H), 4.08-4.56 (m, 3H), 3.72 & 3.71 (2 singlets, 3H), 3.34-3.38 (m, 1H), 2.77-2.89 (m, 2H), 2.67 & 2.63 (2 singlets, 3H), 1.18-1.26 (m, 6H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:30])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:10]([C:17]#[N:18])=[N:11]2.CO.O1CCCC1.[OH-].[Li+]>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([C:17]#[N:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1)=[C:8]2[CH3:30]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C#N)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2)c(C#N)nc2c(Cl)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [8-chloro-2-cyano-3-(4-methanesulfonylbenzyl)-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.056 g), methanol (1.5 mL), tetrahydrofuran (1.5 mL), water (2.0 mL) and lithium hydroxide (0.60 g) was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water gave title compound as a white solid, 0.015 g.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([CH:10]=1)[C:8]#[N:9].[OH:16][C:17]1[CH:25]=[CH:24][C:23]2[N:22]3[CH2:26][CH2:27][CH:28]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:21]3=[CH:20][C:19]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CS>CN(C=O)C.C(O)(C(F)(F)F)=O.O>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:2][O:16][C:17]1[CH:25]=[CH:24][C:23]2[N:22]3[CH2:26][CH2:27][CH:28]([CH2:29][C:30]([OH:32])=[O:31])[C:21]3=[CH:20][C:19]=2[CH:18]=1)#[N:9]
Reactant: N#Cc1cc(CCl)ccc1C1CCCC1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Agent: N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)ccc1C1CCCC1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
5-(Chloromethyl)-2-cyclopentylbenzonitrile (38.2 mg, 0.174 mmol), tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (50 mg, 0.174 mmol), and K2CO3 (36.1 mg, 0.261 mmol) were dissolved in DMF and heated to 60° C. for 16 h. The reaction mixture was filtered through Celite® and purified by HPLC. The intermediate was isolated and dissolved in TFA (0.2M) and added D/L-cysteine. After 15 min, the mixture was poured into water and extracted with DCM. The organic extract was concentrated to give the title compound. LCMS m/z=415.6 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.55-1.67 (m, 2H), 1.70-1.78 (m, 2H), 1.80-1.88 (m, 2H), 2.11-2.20 (m, 2H), 2.26-2.36 (m, 1H), 2.66 (dd, J=16.5, 8.6 Hz, 1H), 2.86-2.97 (m, 2H), 3.42 (quintet, J=8.6 Hz, 1H), 3.75 (quintet, J=7.3 Hz, 1H), 3.97-4.05 (m, 1H), 4.10-4.17 (m, 1H), 5.06 (s, 2H), 6.12 (s, 1H), 6.85 (dd, J=8.0, 2.0 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.69 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of methyl 6-methylnicotinate (30 g, 198 mmol) in dry THF (150 mL) was added dropwise into a suspension of LiAlH4 (11 g, 289 mmol) in THF (200 mL) at 0 to −5° C. The grey suspension was stirred at RT for 1 h. The reaction mixture was cooled to −5 to 0° C. and water (11 mL) was added dropwise under nitrogen followed by slow addition of 15% NaOH (11 mL) and water (33 mL). The reaction was warmed to RT and stirred for 30 min. at RT. The resulting suspension was filtered and the filtrate was concentrated under vacuum to give (6-methylpyridin-3-yl)methanol as a yellow oil (23 g).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([NH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1)(=[O:32])[CH3:31]
Reactant: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Temperature: 25 °C
Yield: 61 %

Procedure:
(E)-5-Amino-1-(2-pyridyl)-2-styryl-1H-benzimidazole (199 mg, 0.64 mmol) was dissolved in acetic anhydride (2 ml) and the solution was allowed to maintain at room temperature for 30 min. Then the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (50 ml) and the aqueous mixture was extracted with ethyl acetate (100 ml). The organic extract was washed consecutively with water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. The residual solids were purified by column chromatography (silica gel, 50 g; n-hexane/ethyl acetate (1/2)) and then recrystallized from ethyl acetate to afford 139 mg (61%) of the titled compound as yellow solids. MW: 354.41; mp: 105.4-106.9° C.; 1H-NMR (CDCl3) δ: 8.81-8.74 (1H, m), 7.99 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 7.97 (1H, d, J=15.8 Hz), 7.84 (1H, d, J=1.5 Hz), 7.63 (1H, br.s), 7.58-7.43 (5H, m), 7.41-7.30 (4H, m), 7.12 (1H, d, J=15.8 Hz), 2.21 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.O>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]#[N:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C(N)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
The reaction was carried out under argon. (rac)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1000 mg, 2.03 mmol) was initially charged in dry THF (50 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 726 mg, 3.046 mmol) was added and the mixture was stirred at RT. After 75 min, HPLC control showed complete conversion. Water (20 ml) was then added, the reaction mixture was concentrated and the residue was taken up in ethyl acetate (200 ml). The organic phase was washed with saturated sodium chloride solution (3×50 ml), dried over solid sodium sulfate, filtered and concentrated. The residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 2:3). The title compound was obtained as a colorless solid (890 mg, 92% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16]Cl)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:36].[Na+].[CH:38]([NH:40][C:41]1[N:45]([CH3:46])[N:44]=[CH:43][CH:42]=1)=[O:39].O>CC(C)=O.C(OCC)(=O)C>[I-:36].[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][N+:44]3[N:45]([CH3:46])[C:41]([NH:40][CH:38]=[O:39])=[CH:42][CH:43]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: Cn1nccc1NC=O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(NC=O)cc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Reaction time: 40 h
Yield: 98.3 %

Procedure:
To a mixture of benzhydryl 7β-tert-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylate (15 g) and sodium iodide (4.37 g) in acetone (15 ml) was added 5-formamido 1-methylpyrazole (15 g) at ambient temperature. After being stirred for 40 hours at the same temperature, the mixture was poured into a mixture of water and ethyl acetate. The organic layer was separated and washed with water, aqueous sodium chloride solution, and dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7β-tert-butoxycarbonylamino-3-(3-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (20.95 g).
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]([CH2:12][CH3:13])[C:4]=2[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl.CO>[CH2:12]([N:11]1[C:4]2[CH:3]=[C:2]([N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[F:14])[CH2:26][CH2:25]3)[NH:7][C:6](=[O:8])[C:5]=2[CH:9]=[CH:10]1)[CH3:13]
Reactant: CCn1ccc2c(=O)[nH]c(Cl)cc21
Reactant: Fc1ccccc1N1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: CCn1ccc2c(=O)[nH]c(N3CCN(c4ccccc4F)CC3)cc21
Temperature: 140 °C
Yield: 65.3 %

Procedure:
A mixture of 6-chloro-1-ethyl-1,5-dihydro-pyrrolo[3,2-c]pyridine-4-one (Intermediate G) (16 mg, 0.081 mmol) and 1-(2-fluorophenyl)piperazine (160 mg, 0.888 mmol) was heated at 140° C. in a sealed tube for 5 h. Flash chromatography (20/1 methylene chloride/methanol) afforded 1-ethyl-6-[4-(2-fluoro-phenyl)-piperazin-1-yl]-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one (18 mg, 65%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.28 Hz, 3H) 3.1 (d, J=4.77 Hz, 4H) 3.2 (d, J=4.77 Hz, 4H) 4.0 (q, J=7.19 Hz, 2H) 5.8 (s, 1H) 6.3 (d, J=3.01 Hz, 1H) 6.9 (d, J=3.01 Hz, 1H) 7.1-7.2 (m, 3H) 10.6 (s, 1H). LC-MS calcd. for C19H22FN4O [(M+H)+] 341, obsd. 341.1.
Reaction SMILES: [F:1][C:2]1([F:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1.[C:17]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[F:16][C:2]1([F:1])[C:7](=[O:8])[N:6]([CH3:17])[C:5]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:4]=2[O:3]1
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2OC1(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1C(=O)C(F)(F)Oc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C

Procedure:
To a stirred suspension of 2,2-difluoro-7-nitro-4H-1,4-benzoxazin-3-one (WO 99/40094, 2.16 g, 9.38 mmol) in DMF (10 mL) is added K2CO3 (1.94 g, 14.07 mmol) followed by addition of MeI (0.87 mL, 14.07 mmol). The resulting solution is stirred over night at room temperature. To this reaction mixture is added water (50 mL), and the resulting solution is extracted with EtOAc (50 mL×3). The combined organic phases are washed with water (50 mL) and saline (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give the title compound that is purified by passing through a short silica gel column with EtOAc (1.3 g, 57%), 1H NMR (300 MHz, DMSO) δ 8.25-8.17 (m, 2H), 7.62 (d, 1H), 3.47 (s, 3H).