Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH3:2].[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][OH:25])[N:22]=3)[CH2:17][C@@:11]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:12]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+]>>[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][O:25][CH3:2])[N:22]=3)[CH2:17][C@@:11]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:12]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:40])([F:41])[F:39])[CH:29]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Iodomethane, 85 mg, 0.6 mmol was added to suspension of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Compound 3a in Table 3; 250 mg, 0.4 mmol) and sodium hydride (24 mg, 0.6 mmol, 60% in oil). The reaction mixture was stirred at 50° C. for 2 hours then quenched by addition of saturated ammonium chloride. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:2 ethyl acetate/iso-hexanes to yield the title compound (246 mg, 95%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:23])[N:10]=2)=[CH:5][CH:4]=1.CO.[S:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=2)[N:28]=[N:27]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:38][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([C:29]4[N:28]=[N:27][S:26][CH:30]=4)=[CH:36][CH:35]=3)=[CH:4][CH:5]=2)[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CBr)cc2)nc1Cl
Reactant: NCc1ccc(-c2csnn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CNCc3ccc(-c4csnn4)cc3)cc2)nc1Cl
Reaction time: 8 h

Procedure:
To the solution of 6-[4-(bromomethyl)phenyl]-2-chloro-5-phenylnicotinonitrile (2-5) 0.294 g, 0.766 mmol) in THF (5 mL) and MeOH (5 mL) was added 1-[4-(1,2,3-thiadiazol-4-yl)phenyl]methanamine (0.147 g, 0.766 mmol) and DIPEA (0.495 g, 3.831 mmol). The mixture wsa stirred overnight and concentrated. The residue was treated with aqueous Na2CO3 solution (2 M, 10 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (3-6% MeOH in CH2Cl2) to give 2-chloro-5-phenyl-6-[4-({[4-(1,2,3-thiadiazol-4-yl)benzyl]amino}methyl)phenyl]nicotinonitrile (2-6). 1H-NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 8.01 (d, J=8.0, 2H), 7.98 (s, 1H), 7.47 (d, J=8.1, 2H), 7.28-7.38 (m, 7H), 7.16-7.18 (m, 2H), 3.84 (s, 2H), 3.83 (s, 2H). LRMS m/z (M+H) Calcd: 494.0, found: 494.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(C(C)C)CC)(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Cc1ccc(C)c(CCN)c1
Reactant: CCOC(=O)CCCBr
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNCCc1cc(C)ccc1C
Yield: 49.1 %

Procedure:
(2,5-Dimethylphenyl)ethylamine 18 (5.36 gm, 0.036 moles), ethyl 4-bromobutyrate (9.11 gm, 0.046 moles) and diisopropylethylamine (6.07 gm, 0.047 moles) were heated at 110-120° C. overnight, cooled, and partitioned between 100 ml DCM and 100 ml water. The aqueous layer was extracted twice with 50 ml portions of DCM. The combined organic extracts were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with a gradient mixture of methanol and DCM. Ethyl 4-[(2,5-dimethylphenyl)ethylamino]butanoate 19 (4.66 gm, 49% yield) was isolated as a slightly yellow oil after removing the solvent. 1H NMR (CDCl3) δ 7.07, 1H, d; 6.88, 1H, br s; 6.79, 1H, d; 4.10, 2H, q; 2.9, 4H, m; 2.35, 2H, t; 2.29, 3H, s; 2.24, 3H, s; 1.74, 2H, m; 1.24, 3H, t; 0.98, 3H, t.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])/[N:7]=[C:8](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])\[C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([Mg]Cl)[CH:22]=[CH2:23]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])([C:9]([F:10])([F:11])[F:12])[CH2:23][CH:22]=[CH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[Mg]Cl
Reactant: CC(C)(C)OC(=O)/N=C(/c1ccccc1F)C(F)(F)F
Solvent: C1CCOC1
Product: C=CCC(NC(=O)OC(C)(C)C)(c1ccccc1F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of [2,2,2-Trifluoro-1-(2-fluoro-phenyl)-eth-(Z)-ylidene]-carbamic acid tert-butyl ester (16.63 g, 57.1 mmol) in 170 mL THF at −75° was added dropwise allylmagnesium chloride solution 2 mol/L in THF (31.4 ml, 62.8 mmol). The reaction temperature was not allowed to exceed −60° C. After 30 minutes, the reaction was quenched with 10% aqueous NH4Cl and extracted with TBME. The organic phase was washed with brine, dried with MgSO4.H2O and evaporated. The crude product was chromatographed on silica gel with hexane/TBME 95/5 to give 18.52 g of the title compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH3:23])[C:14]([Br:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25]C1C(OC)=C(C(CSC2C=CC=CC=2Br)=CC=1)C(OC)=O>>[Br:24][C:14]1[C:15]([O:22][CH3:23])=[C:16]([C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[Br:25])(=[O:9])=[O:8])=[CH:12][CH:13]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1c(CSc2ccccc2Br)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2Br)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 61, starting from methyl 3-bromo-6-(2-bromophenylthiomethyl)-2-methoxybenzoate (Intermediate 81).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH:22]=1)O)C1C=CC=CC=1>C(#N)C.[PH2](O)=O>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:19]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:22]=2)[C:9]=1[OH:8])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1cccc(C(O)(c2ccccc2)c2cccc(-c3ccccn3)c2)c1OCc1ccccc1
Agent: O=[PH2]O
Solvent: CC#N
Product: CC(C)(C)c1cccc(C(c2ccccc2)c2cccc(-c3ccccn3)c2)c1O
Yield: 19.3 %

Procedure:
A solution of 6 (1.12 g, 2.24 mmol) in acetonitrile (15 mL) and 50% aqueous hypophosphorous acid (10 mL) was kept at reflux for 3 hr. The acetonitrile was removed in vacuo, the residue was diluted with water (80 mL) and extracted with ethyl acetate (150 mL). The organic phase was washed with water (100 mL), saturated sodium bicarbonate (100 mL) and water (2×100 mL), dried over sodium sulfate and filtered. The solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica (50 g) with 2% ethyl acetate in heptane (2 L) and 4% (3 L) to yield pure A3 (0.17 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[S:14](=[O:16])(=[O:15])[CH2:13][CH2:12][C:10]3=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23].O.[Cl-].[NH4+]>C(O)(C)C>[OH:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]4[S:14](=[O:16])(=[O:15])[CH2:13][CH2:12][C:10]4=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1
Reactant: N#Cc1cnc2ccc3c(c2c1Cl)CCS3(=O)=O
Reactant: COc1cc(N)cc(O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc(O)cc(Nc2c(C#N)cnc3ccc4c(c23)CCS4(=O)=O)c1
Yield: 22.8 %

Procedure:
65 mg (0.23 mmol) of 9-chloro-1,2-dihydrothieno[3,2-f]quinoline-8-carbonitrile 3,3-dioxide are refluxed together with 39 mg (1.2 eq., 0.28 mmol) of 3-hydroxy-5-methoxyaniline in 2 ml of isopropanol for 2 hours. After the reaction is complete, the crude product is mixed with water and sat. ammonium chloride solution, extracted 3× with dichloromethane/methanol, washed 1× with sat. sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. Final purification of the compound took place by chromatography. 20 mg (22%) of the desired product were obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[N+]([O-])=O)=[CH:8][CH:7]=1>CS(C)=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:1]=[N:2][NH:3][CH:13]=2)=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])/C=C/c1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc(-c2c[nH]nn2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 30.8 %

Procedure:
Sodium azide (4.28 g, 65.8 mmol) was added to a solution (E)-1-fluoro-4-(2-nitro-vinyl)-benzene (1.00 g, 5.98 mmol) in DMSO (50 mL), the solution was stirred at room temperature for 14 hours and the reaction mixture was poured onto water. The aqueous phase was extracted with AcOEt. The organic phase was washed with saturated solution of NaHCO3, brine, dried over MgSO4, filtered and evaporated to yield 300 mg (1.84 mmol, 31%) of 4-(4-fluoro-phenyl)-1H-[1,2,3]triazole.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:7][C:8]#[CH:9].[C:17]([NH:21][C:22]1[C:31]([CH:32]=[O:33])=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:34]3[C:39]([C:40]([N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[O:41])=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:47])[CH:28]=2)[N:23]=1)([CH3:20])([CH3:19])[CH3:18]>C1COCC1.[Cl-].[NH4+]>[C:17]([NH:21][C:22]1[C:31]([CH:32]([OH:33])[C:9]#[C:8][CH2:7][CH2:6][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:34]3[C:35]([CH3:47])=[CH:36][CH:37]=[CH:38][C:39]=3[C:40]([N:42]3[CH2:43][CH2:44][CH2:45][CH2:46]3)=[O:41])[CH:28]=2)[N:23]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: C#CCCOC1CCCCO1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(NC(C)(C)C)c(C=O)cc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(NC(C)(C)C)c(C(O)C#CCCOC3CCCCO3)cc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M) (0.624 mL, 1.559 mmol) was added to a solution of 2-(3-butynyloxy)tetrahydro-2H-pyran (0.244 mL, 1.559 mmol) in THF (10 mL) at −78° C. The solution was stirred 1 h at this temperature before warming to 0° C. for 30 min at which time it was slowly added by syringe to a solution of 2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinoline-3-carbaldehyde (0.324 g, 0.780 mmol) in THF (10 mL) cooled to −78° C. The resulting dark solution was stirred 10 min at this temperature before warming to 0° C. for 20 min. The reaction mixture was diluted with saturated ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give (2-(2-(tert-butylamino)-3-(1-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)pent-2-ynyl)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone as an orange oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]2[C:24]([C:27]([CH3:33])([O:29][CH2:30][CH2:31][OH:32])[CH3:28])=[CH:25][N:26]=[C:10]12.Cl[C:35](OC1C=CC([N+]([O-])=O)=CC=1)=[O:36].[NH:47]1[CH2:52][CH2:51][CH:50]([N:53]2[CH2:62][C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[NH:55][C:54]2=[O:63])[CH2:49][CH2:48]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]2[C:24]([C:27]([O:29][CH2:30][CH2:31][OH:32])([CH3:33])[CH3:28])=[CH:25][N:26]=[C:10]2[C@H:9]([NH:8][C:35]([N:47]2[CH2:48][CH2:49][CH:50]([N:53]3[CH2:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[NH:55][C:54]3=[O:63])[CH2:51][CH2:52]2)=[O:36])[CH2:15][CH2:14]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: CC(C)(OCCO)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(OCCO)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
Triethylamine (5.0 μL, 0.037 mmol) was added to a solution of 2-{1-[(6S,9R)-9-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl]-1-methylethoxy}ethanol (15.0 mg, 0.041 mmol) and 4-nitrophenyl chloroformate (9.0 mg, 0.045 mmol) in tetrahydrofuran (1 mL) at 0° C. After 15 min, 3-piperidin-4-yl-3,4-dihydroquinazolin-2(1H)-one (9.0 mg, 0.041 mmol) and triethylamine (17 μL, 0.12 mmol) were added and the mixture was allowed to warm to ambient temperature. After 1 h, saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane (3×). The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (8.5 mg). MS 623.3163 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:18])[N:4](C)[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19][C:20]([F:40])([F:39])[O:21]C1C=CC(N2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:1][C:2]1[C:3](=[O:18])[NH:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]([O:21][C:20]([F:40])([F:39])[F:19])=[CH:7][CH:6]=2
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Reactant: O=C1C(=O)N(c2ccc(OC(F)(F)F)cc2)c2ccccc21
Product: CCOC(=O)c1c(O)c(=O)[nH]c2ccc(OC(F)(F)F)cc12

Procedure:
Intermediate 23 was prepared as a white powder following the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 4-trifluoromethoxy-phenylindoline-2,3-dione. 1H NMR (400 MHz, chloroform-d) δ ppm 11.90 (1 H, br. s.), 11.28 (1 H, br. s.), 8.22 (1 H, br. s.), 7.36-7.53 (1 H, m), 7.43 (1 H, br. s.), 4.61 (2 H, d, J=7.1 Hz), 1.54 (3 H, t, J=6.9 Hz). LC-MS (ESI) m/z 317.9 (M+H), RT=2.00 min (Method B).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:8]=1
Reactant: Cc1ccccc1[C@H]1[C@@H]2CNC[C@H]2CC[C@@H]1O[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)C1
Product: Cc1ccccc1[C@H]1[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2CC[C@@H]1O[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from (3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)octahydro-1H-isoindole (step L) and cyclopentane-1,3-dione according to the procedure of Example 7. 1H-NMR (CDCl3): rotamers δ: 7.64 (1 H, s), 7.18 (2 H, s), 7.04-6.97 (4 H, m), 4.74, 4.53 (1 H, s), 4.42 (1 H, m), 3.68, 3.43 (1 H, m), 3.50 (1 H, m), 3.06 (1 H, m), 2.93 (2 H, m), 2.86, 2.76 (1 H, m), 2.57 (1 H, m), 2.40 (2 H, m), 2.28 (3 H, s), 2.20 (1 H, m), 2.17 (1 H, m), 2.10-1.94 (3 H, m), 1.58 (1 H, m), 1.40 (1 H, m), 1.28 (3 H, d, J=6.0 Hz). MS: (MH)+ 552.43
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2[C:10]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:20].[H-].[Na+].[CH3:27][CH2:28][N:29]([CH2:32][CH2:33]Cl)[CH2:30][CH3:31].Cl.[C:36](=[O:39])(O)[O-:37].[Na+]>CN(C)C=O.C(N(CC)CC)C>[F:17][C:16]([F:19])([F:18])[C:36]([OH:37])=[O:39].[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2[C:10]([C:16]([F:18])([F:17])[F:19])=[CH:11][C:12]([C:14]([NH2:15])=[O:37])=[CH:13][C:8]=2[N:7]([CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:6]1=[O:20]
Reactant: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2Cc1ccccc1Cl
Reactant: CCN(CC)CCCl
Reactant: O=C([O-])O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(=O)n(Cc2ccccc2Cl)c2c(C(F)(F)F)cc(C(N)=O)cc21
Product: O=C(O)C(F)(F)F
Temperature: 50 °C
Yield: 60 %

Procedure:
1-(2-Chlorobenzyl)-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (280.6 mg) was dissolved in N,N-dimethylformamide (50 ml), and to the solution was added sodium hydride (41.5 mg). The reaction mixture was stirred under ice-cooling for 10 minutes. 2-Chlorotriethylamine hydrochloride (178.5 mg) and triethylamine (0.167 ml) were added, and the mixture was stirred at 70° C. for 18 hours. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was dissolved in 2-methyl-2-propanol (30 ml) and heated at 50° C. To the solution was added powdered potassium hydroxide (1.119 g), and the mixture was stirred for 1 hour. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was purified by HPLC using condition 1 to give the title compound (280.9 mg, 60%).
Reaction SMILES: [Cl:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:31]NC.C=O.C(O)(C)(C)C>C(Cl)Cl>[Cl:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:31])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Cl)[C@H]2S(=O)(=O)C1
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C=C1C(C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Cl)[C@H]2S1(=O)=O
Temperature: 95 °C
Yield: 37.7 %

Procedure:
Benzhydryl 7α-chloro-3-methyl-3-cephem-4-carboxylate 1,1-dioxide (9.3 g, 0.0215 mol) was dissolved in methylene chloride (35 ml), dimethylamine hydrochloride (4.9 g, 0.0645 mol), formaldehyde solution (2.25 g, 0.075 mol) and t-butyl alcohol (300 ml) were added and the mixture was heated to reflux at 95° C. for 4 hours. After removing the solvent under reduced pressure the residue was redissolved in methylene chloride, washed successively with water, dried over sodium sulfate and concentrated. The product was purified over a silica column using hexane-ethyl acetate mixture as the eluant to yield benzhydryl 7α-chloro-2-methylene-3-methyl-3-cephem-4-carboxylate 1,1-dioxide (3.6 g, 40%) as a white foam. IR (Nujol) ν max 1723, 1800 cm-1.
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]1[S:12][C:11]([CH2:13][CH2:14][O:15][CH2:16][C:17]([NH2:19])=O)=[CH:10][CH:9]=1.CO>O1CCCC1>[CH3:7][C:8]1[S:12][C:11]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH2:19])=[CH:10][CH:9]=1
Reactant: Cc1ccc(CCOCC(N)=O)s1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CCOCCN)s1

Procedure:
Borane-tetrahydrofuran solution (1.0 M in THF, 21.7 ml) was added dropwise to a stirred solution of the product from step b) (1.25 g) in dry tetrahydrofuran (100 ml). The reaction was heated at reflux under an inert atmosphere for 5 hours. The reaction was cooled and methanol (10 ml) added cautiously. The solvents were removed in vacuo and the residue dissolved in methanol (100 ml) to which was added concentrated hydrochloric acid (sg. 1.18, 0.45 ml). This solution was heated at reflux for 15 min then the solvent removed in vacuo. The residue was purified by flash chromatography (dichloromethane: 5% methanol as eluant) to give the subtitle compound as a white solid (0.916 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:23](OCC)=[O:24].[O-]CC.[Na+].Cl>C(O)C>[OH:24][CH:23]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 71.7 %

Procedure:
N-[3-(2-Oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (0.957 g, 3.25 mmol) and ethyl formate (0.78 mL, 9.75 mmol) were dissolved in anhydrous ethanol (6.50 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (6.07 mL, 16.26 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (0.752 g, 2.33 mmol, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]Br.C(O)(=O)C>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[Br:13]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1c(Br)cc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Amino-3-nitro-benzaldehyde (2.1 g) was dissolved in 25 ml of dichloromethane. Bromine (2 ml) and acetic acid (1 ml) were added and the mixture was stirred for 2 h at room temperature. The mixture was diluted with ethyl acetate and washed with aq. NaHSO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.