Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[CH:20][C:21]([C:24](Cl)=[O:25])=[N:22][CH:23]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[O:14]=[C:12]1[NH:11][C:10](=[O:15])/[C:9](=[CH:8]/[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:24](=[O:25])[C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:27])([F:16])[F:28])=[CH:23][N:22]=3)[N:7]=2)/[S:13]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cn1
Reactant: Nc1nccc(/C=C2\SC(=O)NC2=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C1NC(=O)/C(=C/c2ccnc(NC(=O)c3ccc(C(F)(F)F)cn3)n2)S1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)-5-(trifluoromethyl)picolinamide was prepared as follows. A 2-dram vial was charged with (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.2 mg, 0.100 mmol), Pyridine (1 mL), 5-(trifluoromethyl)picolinoyl chloride (63 mg, 0.301 mmol, 3 equiv.), triethylamine (60.7 mg, 0.599 mmol, 5.9 equiv.), and the reaction was shaken at RT. After 16 h, the reaction was treated with saturated sodium bicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified using reverse phase HPLC to provide the desired product (4 mg, 39.5 mg theoretical, 10%). LC-MS m/z 396.3 (M+1).
Reaction SMILES: [Br-].[CH2:2]([N+:4]([CH3:13])([CH3:12])[CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=[O:9])[CH3:3]>C(O)C>[CH2:2]([N+:4]([CH3:13])([CH3:12])[CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9])[CH3:3]
Reactant: CC[N+](C)(C)CCCC(=O)OC
Agent: [Br-]
Solvent: CCO
Product: CC[N+](C)(C)CCCC(=O)[O-]
Reaction time: 12 h
Yield: 88.9 %

Procedure:
A solution of N-ethyl-4-methoxy-N,N-dimethyl-4-oxo-1-butanaminium bromide (6a) (6.51 g, 0.025 mol) in ethanol (20 ml) was passed through Amberlite® IRA-410 (OH) ion exchange resin column (190 ml) slowly eluting with ethanol (100 ml). The eluate was evaporated to dryness and the residue was several times azeotropically dried with isopropanol, then dissolved in isopropanol (50 ml) and kept at 0° C. for 12 hours. The mixture was filtered and the filtrate was evaporated. The residue (7.35 g) was mixed with cold ethyl acetate and kept at 0° C. for 12 hours. The mixture was filtered and the precipitate was dried over P2O5 in vacuo to furnish 3.54 g (86%) of 4-[ethyl(dimethyl)ammonio]butanoate. The purity of the material was increased by passing a water solution of 4-[ethyl(dimethyl)ammonio] butanoate through DOWEX® 50WX8 ion exchange resin. The solution was evaporated to dryness; the residue was azeotropically dried with isopropanol followed by drying in vacuo over P2O5 to give 1.27 g (31%) of 4-[ethyl(dimethyl)ammonio]butanoate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH:18](Br)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[O:10][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:9][C:4]=2[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(Br)Br
Reactant: Oc1ccc(Cl)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2ccc(Cl)c(Cl)c2O1
Temperature: 100 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
A mixture of 11.0 g of 3,4-dichloro-1,2-benzenediol, 15.38 g of potassium carbonate, 27 g of ethyl dibromoacetate and 100 ml of dimethylformamide is stirred at 100° C. under argon gas atmosphere for 4 hours. The reaction mixture is evaporated to remove solvent and ethyl acetate and water is added to the residue. The organic layer is separated, washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography to give 10.75 g of ethyl 4,5-dichloro-1,3-benzodioxole-2-carboxylate.
Reaction SMILES: Br.[F:2][C:3]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1.CS(O[CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)(=O)=O>CN(C=O)C>[F:2][C:3]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:4]=1[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:34][CH2:33]3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: Br
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 82.5 °C
Yield: 62 %

Procedure:
To a mixture of 4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-ol HBr salt (1.0 g, 2.4 mmol) and K2SO3 (2.5 g) in DMF (15 mL) at rt was added tert-butyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate (1.0 g, 3.4 mmol, and the reaction mixture was heated at 80-85° C. for 4 h. This mixture was directly purified by flash column chromatography on silica gel eluting with hexane:EtOAc/600:400, and then 300:700 to obtain the desired product (786 mg, 62%) as a glassy solid material. 1H NMR (CDCl3) δ 8.57 (d, 1H, J=5.0 Hz), 8.20 (dd, 1H, J=9.9, 2.8 Hz), 8.13 (dd, 1H, J=8.8, 1.7 Hz), 7.43 (d, 2H, J=2.2 Hz), 7.33 (t, 1H, J=7.7 Hz), 6.54 (d, 1H, J=5.0 Hz), 4.20 (m, 2H), 4.04 (d, 2H, J=6.6 Hz), 4.00 (s, 3H), 2.77 (m, 2H), 2.19-1.89 (m, 3H), 1.47 (s, 9H), 1.34 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][C:12]([NH:18][C:19]3[N:28]=[C:27]4[C:22]([C:23](=[O:40])[N:24]([C:32]5[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:39])[C:25]5[N:26]4[CH:29]=[CH:30][N:31]=5)=[CH:21][N:20]=3)=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=1[N:24]1[C:23](=[O:40])[C:22]2[CH:21]=[N:20][C:19]([NH:18][C:12]3[CH:13]=[N:14][C:15]4[CH2:16][CH2:17][NH:8][CH2:9][C:10]=4[CH:11]=3)=[N:28][C:27]=2[N:26]2[CH:29]=[CH:30][N:31]=[C:25]12.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCc2ncc(Nc3ncc4c(=O)n(-c5c(F)cccc5Cl)c5nccn5c4n3)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2cnc(Nc3cnc4c(c3)CNCC4)nc2n2ccnc2n1-c1c(F)cccc1Cl

Procedure:
A mixture of Example 277A (54.6 mg, 0.097 mmol) and trifluoroacetic acid (0.075 mL, 0.970 mmol) in CH2Cl2 (3 mL) was stirred overnight. The solids were filtered, rinsed with CH2Cl2, and dried to provide the title compound as a trifluoroacetic acid salt. 1H NMR (400 MHz, CD3OD) δ 3.29-3.26 (m, 2H), 3.68 (t, J=6.4 Hz, 2H), 4.55 (s, 2H), 7.11 (d, J=1.9 Hz, 1H), 7.44-7.35 (m, 1H), 7.56-7.53 (m, 1H), 7.66-7.60 (m, 1H), 7.91 (d, J=1.9 Hz, 1H), 8.38 (bs, 1H), 8.93 (bs, 1H), 9.26 (s, 1H). MS (ESI+) m/z 463.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)[CH2:5][F:6].C(Cl)Cl.[OH-].[Na+]>CO>[NH2:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([I:1])[CH:9]=1)[CH2:5][F:6]
Reactant: O=[N+]([O-])c1cc(I)cc(CF)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(I)cc(CF)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-iodo-5-nitrobenzyl fluoride (9.2 g, 32.7 mmol) described in Step C, in methanol (311 mL) was treated with TiCl3 (311 mL, >10 wt. % in 20-30 wt % HCl) and stirred at room temperature for 20 minutes. The reaction was poured into a separatory funnel containing 95:5 CH2Cl2 :MeOH and the aqueous layer was made basic with 15% aq. NaOH. The layers were separated and the aqueous layer was extracted with 95:5 CH2Cl2 :MeOH. The organic layers were combined, dried (MgSO4), filtered and concentrated to give an orange semi-solid. Purification by flash chromatography (3:1 to 1:1 hexane:methylene chloride) provided 3-amino-5-iodobenzyl fluoride as a tan solid: mp 48.5-50° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:4]([CH3:16])[N:3]=1.[N-:17]=[N+:18]=[N-:19].[Na+].CN(C)C=O>O>[CH3:14][CH:13]([CH3:15])[CH2:12][NH:11][C:6]1[CH:5]=[C:4]([CH3:16])[N:3]2[N:17]=[N:18][N:19]=[C:2]2[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Cl)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NCC(C)C)c([N+](=O)[O-])c2nnnn12
Temperature: 60 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 2-chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine (10.0 g, 41.0 mmol), sodium azide (2.67 g, 41.0 mmol), and anhydrous N,N-dimethylformamide (200 mL) was heated at 60° C. After 5 hours, the dark green solution was allowed to cool to room temperature, poured slowly into water (2 L), and stirred for fifteen minutes. A green precipitate formed, which was filtered and washed with water to yield 9.37 g of N-(2-methylpropyl)-5-methyl-8-nitrotetraazolo[1,5-α]pyridin-7-amine as a light green solid, m.p. 185-187° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)(=[O:23])=[O:22])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1>CO.[Pd]>[ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)(=[O:23])=[O:22])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc(N)c1
Reaction time: 2 h
Yield: 47.7 %

Procedure:
A solution of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-nitro-1-benzenesulfonamide hydrochloride (0.4 g) in methanol (250 ml) was charged with a catalytic amount of 10% palladium on carbon (0.085 g). The reaction was placed under an atmosphere of hydrogen (50 psi; 3.44×105 Pa) and shaken on a Parr apparatus for 2 hours. The reaction mixture was filtered and the solvent removed in vacuo. The solid product was recrystallized from 2-propanol to provide 0.18 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-amino-1-benzenesulfonamide hydrochloride as an off white crystalline solid, m.p. 110.2° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.70 (very broad s, 2H), 8.22 (d, J=8.2 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.43 (t, J=5.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 6.95 (t, J=1.9 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.73 (dd, J=8.0, 1.5 Hz, 1H), 5.63 (broad s, 2H), 4.56 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.7 Hz, 2H), 2.77 (q, J=6.3 Hz, 2H), 1.83 (m, 4H), 1.60-1.40 (m, 4H), 0.97 (t, J=7.3 Hz, 3H); IR (KBr) 3313, 3135, 2957, 2870, 2782, 1671, 1599, 1485, 1454, 1313, 1155, 1084, 754, 686 cm−1; MS (EI) m/e 466.2150 (466.2151 calcd for C24H30N6O2S). Anal calcd for C24H30N6O2S*HCl*0.25H2O: C, 56.79; H, 6.26; N, 16.56; Cl, 6.98. Found: C, 56.87; H, 6.22; N, 16.19; Cl, 7.22.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:49][C:50]1[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=1[C:52]([O:54][CH3:55])=[O:53]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:49][C:50]2[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=2[C:52]([O:54][CH3:55])=[O:53])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Product: CCCCc1nn(Cc2ccccc2C(=O)OC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 72 %

Procedure:
By the procedure of Example 3, Step A, 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) was alkylated with methyl 2-(bromomethyl)benzoate [R. M. Scrowston and D. C. Shaw, J. Chem. Soc. Perkin Trans. I, 749 (1976)] to give a 72% yield of the titled compound as a foam, homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 766 (M+1)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:17][C:18]([C@@:20]1([NH:30]C(OC(C)(C)C)=O)[C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:21]1[CH3:29])=[O:19])([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>C(#N)C>[C:13]([O:17][C:18]([C@@:20]1([NH2:30])[C@@H:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:21]1[CH3:29])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: C[C@@H]1[C@H](c2ccccc2)[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1[C@H](c2ccccc2)[C@]1(N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Under argon atmosphere, p-toluenesulfonic acid monohydrate (3.5 g, 18 mmol) was added to a solution of (1S,2R,3R)-1-t-butoxycarbonylamino-2-methyl-3-phenyl-cyclopropanecarboxylic acid t-butyl ester (3.2 g, 9.1 mmol) obtained in Preparation Example 5-2 in acetonitrile (30 mL) at 0° C., and the mixture was stirred at room temperature for 16 hours. The obtained solution was cooled to 0° C., and 1N aqueous sodium hydroxide solution (20 mL) was added. The aqueous layer was extracted twice with ethyl acetate (15 mL) and dried over magnesium sulfate. Then, the residue was filtrated and the solvent was evaporated to give a crude product of the title compound (1.8 g, yield 99%) as a crude product of a pale-yellow oil. The obtained product was used in the next step without purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.S(Cl)([Cl:12])=O.[OH-].[Na+]>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Cl:12]
Reactant: OCc1cccc(I)c1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: ClCc1cccc(I)c1

Procedure:
A solution of 3-iodobenzyl alcohol (600 mg, 2.56 mmol) in DCM (3 ml) was treated with thionyl chloride (3 ml, 41.3 mmol) and stirred at ambient temperature for 18 h, before addition of further thionyl chloride (1 ml, 13.7 mmol) and heating to reflux for 12 h. The cooled solution was basified with 50% NaOH, diluted with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated to afford a clear syrup which crystallises on standing to give 3-iodobenzyl chloride as a white solid (650 mg, quant.).
Reaction SMILES: C(OC([NH:8][CH:9]1[C:46](=[O:47])[N:11]2[C:12]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.O>C(#N)C>[NH2:8][CH:9]1[C:46](=[O:47])[N:11]2[C:12]([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:14][S:15][C@H:10]12
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12
Solvent: CC#N
Solvent: O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OCc4ccccc4)c(=O)c3=O)CS[C@H]12

Procedure:
Diphenylmethyl 7-(t-butoxycarbonylamino)-3-(2-benzyloxy-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate was deprotected with a solution of pTSOH.H2O in acetonitrile as described in the preceding experiment to provide the title compound which was directly used in the next step.
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:25]1([C:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37](=[O:42])[CH2:36]3)=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN(C=O)C>[C:1]([N:28]1[CH2:29][CH2:30][N:25]([C:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37](=[O:42])[CH2:36]3)=[O:32])[CH2:26][CH2:27]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: O=C(O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Cc2cc(C(=O)N3CCN(C(=O)c4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a solution of 3.2 g of benzoic acid and 4 ml of triethylamine in 50 ml of DMF was added dropwise a solution of 3.87 g of isobutyl chloroformate in 2 ml of DMF. After stirring the mixture for 30 minutes at room temperature, a solution of 8.8 g of 5-(1-piperazinylcarbonyl)oxindol in 3 ml of DMF was added dropwise thereto, and the mixture was stirred for 30 minutes at room temperature and then for 1 hour at 50° to 60° C. The reaction mixture was poured into a large amount of a saturated saline solution, extracted with chloroform, washed with water and dried. The solvent was distilled off, and the residue was recrystallized from methanol to give 1.9 g of 5-(4-benzoyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:4].[Cl:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=1[C:34]1[CH:38]=[C:37]([CH2:39]O)[O:36][N:35]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][CH2:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:39][C:37]2[O:36][N:35]=[C:34]([C:27]3[C:28]([F:33])=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[Cl:25])[CH:38]=2)=[CH:13][CH:12]=1)=[O:4]
Reactant: OCc1cc(-c2c(F)ccc(F)c2Cl)no1
Reactant: COC(=O)C1=C(c2ccc(O)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a sol. of compound B2 (10.0 g, 30 mmol) and [3-(2-chloro-3,6-difluoro-phenyl)-isoxazol-5-yl]-methanol (8.84 g, 30 mmol) in toluene (60 mL) were added ADDP (15.1 g, 60 mmol) and PBu3 (90%, 30.0 mL; 108 mmol). The mixture was stirred for 2 h at 80° C., and was allowed to cool to rt. The solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4→EtOAc) yielded the title compound (8.64 g, 51%). LC-MS: tR=1.15 min; ES+: 561.25.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:20]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.C(N(CC)CC)C>[C:20]1([CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:34]=[CH:35][C:36]([NH:39][C:15]([C:10]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=5)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:16])=[CH:37][CH:38]=3)[CH2:31][CH2:32]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 0.08 h
Yield: 104.6 %

Procedure:
A mixture of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride (0.185 mole) in DCM (1500 ml) and triethylamine (50 ml) was stirred on an ice-bath for 5 minutes. 4-[4-(Phenylmethyl)-1-piperazinyl]-benzenamine (0.37 mole) in DCM (500 ml) was added dropwise. The mixture was stirred for 3 hours. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 99.8 g of N-[4-[4-(phenylmethyl)-1-piperazinyl]phenyl]-4′-(trifluoro-methyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 5, melting point 180° C.).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:28]([NH2:30])[CH3:29])[CH:20]=[CH:21][C:22]=1[O:23][C:24]([F:27])([F:26])[F:25]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:19]3[CH:20]=[CH:21][C:22]([O:23][C:24]([F:25])([F:26])[F:27])=[C:17]([Cl:16])[CH:18]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CC(N)c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1ccc(OC(F)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (513 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (666 mg, 2.39 mmol, Step-1 of Intermediate-1) and 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanamine hydrochloride (600 mg, 2.17 mmol, Amine-83, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=O)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][OH:18]>C(O)C.O>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15](=[N:17][OH:18])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Reactant: NO
Solvent: O
Solvent: CCO
Product: ON=C1C2CCC1CN(Cc1ccccc1)C2
Yield: 68 %

Procedure:
To a solution of the title compound of Step A (6.6 g, 30.7 mmol) in ethanol (80 ml) was added hydroxylamine (3.6 ml of a 50% Wt solution in water, 42.9 mmol) and the resulting mixture heated at reflux for 4 h. The cooled reaction mixture was evaporated and the residue triturated with hexanes, filtered and dried to afford the title compound 4.8 g (68%) as a white solid. 1H NMR (CDCl3): 1.76 (m, 2H), 1.97 (m, 2H), 2.40 (d, J 10.1 Hz, 2H), 2.56 (s, 1H), 2.84 (dd, J 10.3 and 3.7 Hz, 1H), 2.91 (dd, J 10.1 and 3.0 Hz, 1H), 3.35 (s, 1H), 3.57 (s, 2H), 7.29 (m, 1H), 7.35 (m, 4H), 8.49 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH3:21])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].OO.C(=O)([O-])[O-:25].[K+].[K+].O>CS(C)=O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:25])[CH:8]=3)=[CH:10][C:11]([CH3:21])=[N:12]2)=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(-c2ccnc(C#N)c2)n(-c2ccc(F)cc2)n1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(-c2ccnc(C(N)=O)c2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 628.7 %

Procedure:
To a solution of 2-cyano-4-[1-(4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 32; 1.0 g, 0.0036 mol) in 25 mL of DMSO was added hydrogen peroxide (0.43 mL, 0.0036 mol) and potassium carbonate (0.072 g, 0.00051 mol) at zero degrees C. The reaction mixture was warmed up to room temperature over 1 hour. Water was added and the mixture was stirred for 0.5 hours. The resulting precipitate was collected by filtration to give 0.95 g (89% yield) of product as a pale yellow solid: mp: 168-170° C.; Anal. Calc'd. for C16H13FN4O: C, 64.86; H, 4.42; N, 18.91. Found: C, 64.48; H, 4.27; N, 18.80.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]=[CH:6]1)#[N:2].[H][H]>CO.[Pt]=O>[C:1]([CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6]1)#[N:2]
Reactant: [H][H]
Reactant: N#CCCn1cnc([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CO
Product: N#CCCn1cnc(N)c1
Yield: 84.8 %

Procedure:
1-(2-Cyanoethyl)-4-nitroimidazole (3.32 g, 20 mmol) was dissolved in methanol (100 ml), and platinum oxide (50 mg) was added to the solution. The mixture was stirred for 12 hours in a hydrogen atmosphere. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (chloroform:methanol=10:1 to 5:1) to obtain 2.31 g of the title compound (oil).