Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=3)[N:10]([CH:20]([CH3:22])[CH3:21])[CH:9]=2)=[CH:6][C:5]([C:23]#[N:24])=[N:4]1)[CH3:2].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([C:7]3[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:23]#[N:24])[CH:6]=3)=[CH:9][N:10]2[CH:20]([CH3:21])[CH3:22])=[CH:15][CH:14]=1
Reactant: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc([N+](=O)[O-])ccc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc(N)ccc12
Reaction time: 0.25 h
Yield: 109.3 %

Procedure:
Stir a solution of 1-Ethyl-5-(1-isopropyl-6-nitro-1H-indol-3-yl)-1H-pyrazole-3-carbonitrile (0.127 g, 0.393 mmol) and tin(II) chloride dihydrate (0.887 g, 3.93 mmol) in DMF (2.5 mL) at 70° C. for 1 h. After this time, Pour the reaction carefully into a stirring solution of saturated aqueous sodium bicarbonate (50 mL), diluted with ethyl acetate (50 mL) and stir for 15 min. Filter the resulting mixture through diatomaceous earth. Separate the organic layer of the filtrate and wash with water (3×50 mL) then brine (50 mL). Dry the resulting solution over sodium sulfate, filtered and concentrate the filtrate under reduced pressure to afford 5-(6-Amino-1-isopropyl-1H-indol-3-yl)-1-ethyl-1H-pyrazole-3-carbonitrile (0.126 g, quant.) as a yellow foam. Use the foam without further purification.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([OH:34])[C:28]=4[C:35]=3[CH3:36])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>CCCCCC.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29]([O:34][CH2:3][C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=5)[C:28]=4[C:35]=3[CH3:36])[CH2:22][CH2:23]2)=[CH:16][CH:17]=1
Reactant: ClCc1ccccn1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(OCc3ccccn3)C(C)(C)O4)CC2)cc1
Yield: 86 %

Procedure:
Using 2-chloromethylpyridine hydrochloride and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 74. Yield 86%. mp. 120–121° C. (hexane-ethyl acetate). 1H-NMR (CDCl3) δ: 1.37 (3H, s), 1.59 (3H, s), 2.09 (3H, s), 2.25 (3H, s), 2.28 (3H, s), 3.05–3.28 (8H, m), 3.79 (3H, s), 4.67 (2H, s), 4.75 (1H, s), 6.86 (2H, d, J=9.2 Hz), 6.97 (2H, d, J=9.2 Hz), 7.15–7.21 (1H, m), 7.48 (1H, d, J=7.6 Hz), 7.68 (1H, t, J=7.6 Hz), 8.52 (1H, d, J=4.4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Br)c(-c2cccnc2)c1
Temperature: 120 °C
Yield: 69.8 %

Procedure:
A solution of Pd(Ph3P)4 (1.410 g, 1.220 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (3.94 ml, 24.41 mmol), pyridin-3-ylboronic acid (3.00 g, 24.41 mmol), and potassium carbonate (13.49 g, 98 mmol) in 32 mL dioxane and 16 mL water was heated to 120° C. overnight. LC/MS showed incomplete conversion, so an additional portion of pyridin-3-ylboronic acid (3.00 g, 24.41 mmol) and potassium carbonate (13.49 g, 98 mmol) were added and the reaction mixture was heated to 120° C. for 3 hours. LC/MS showed no further conversion, so the reaction mixture was poured into water and was extracted with DCM. The organics were then concentrated. Purification of the crude residue by column chromatography (0-100% EtOAc/heptane) gave 3-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (5.150 g, 17.05 mmol, 69.8% yield) as a yellow solid. m/z (ESI) 303.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[N:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:35]#[N:36].C(O)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=2)[C:35]#[N:36])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=2[N:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:4][CH:3]=1
Reactant: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
(5-Bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amine (2.33 g) is dissolved in N,N-dimethylformamide (16.8 ml) and thereto is added sodium hydride (60%) (273 mg) under ice-cooling. Twenty minutes thereafter, thereto is added 3-bromomethyl-5-trifluoromethyl-benzonitrile (2.08 g) and the mixture is stirred at room temperature for 1 hour and 15 minutes. To the reaction solution are added acetic acid to consume the excess sodium hydride, and thereto are added ethyl acetate and water, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-({(5-bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-methyl)-5-trifluoromethyl-benzonitrile (2.81 g). MS (m/z): 626/628 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[OH:8].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[C:19]=1F>>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[O:8][C:19]1[C:20]([C:24]#[N:25])=[CH:21][CH:22]=[CH:23][C:18]=1[F:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(F)c1
Reactant: N#Cc1cccc(F)c1F
Product: N#Cc1cccc(F)c1Oc1ccc(N)cc1F

Procedure:
The entitled compound was obtained in the same method as in Example 221 (step 1) or in accordance with the method or by combining it with an ordinary method but using tert-butyl (3-fluoro-4-hydroxy-phenyl)-carbamate obtained in Example 196 (step 1) and 1,2-difluoro-3-cyano-benzene.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Br:1][C:2]1[C:3]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CCNCCO
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Temperature: 140 °C

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and 2-(ethylamino)ethanol to afford a white solid. (The RM was heated 18 h at 140° C.). HPLC (Condition 4) tR=5.92 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=450.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36]([OH:38])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:40][C:41](=[NH:43])[CH3:42].N1(O)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]=[C:21]1[C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]1[CH2:11][C@@H:10]([C:36]2[O:38][N:43]=[C:41]([CH3:42])[N:40]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13]1)=[O:20]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: CC(=N)NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nc(C)no3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 114.1 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (265 mg), N-hydroxy acetamidine (56 mg), 1H-benzotriazol-1-ol (95 mg) and N,N-diisopropylethylamine (259 μl)) were dissolved in DMF (10 ml), WSC.HCl (144 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in toluene (15 ml), and the mixture was refluxed under heating for 15 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (324 mg). The obtained tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate was dissolved in 4M hydrogen chloride-ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure. The residue was dissolved in methanol (3 ml), 4M Hydrogen chloride-ethyl acetate (1 ml) was added and the mixture was stirred for 5 min. The solvent was evaporated under reduced pressure to give the object product (74 mg).
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:12]1>O1CCOCC1>[ClH:9].[CH3:10][N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[CH:19]=[C:20]([NH:24][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:15][CH2:16]1
Reactant: CN1CCC(Oc2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Product: CN1CCC(Oc2cccc(NC(=O)c3ccccc3)c2)CC1
Product: Cl
Temperature: 110 °C

Procedure:
Add benzoyl chloride (0.062 mL, 0.534 mmol) to a solution of 3-(1-methyl-piperidin-4-yloxy)-phenylamine (preparation 28, 102 mg, 0.494 mmol) in dioxane (3.5 mL) in a sealed tube and heat at 110° C. for 2 hr. Purification by SCX column, eluting with ammonia (2.0 N in methanol) gives the title compound as the free base (137 mg, 91%). Dissolve the residue in diethyl ether and treat with ethereal hydrogen chloride (1.0 M). Triturate the resulting gum with ether to give the title compound as the hydrochloride salt (139 mg, off-white solid). Mass spectrum (free base, ion spray): m/z=311.2 (M+1), 1H NMR (free base, CDCl3): 7.97 (bs, N—H), 7.85-7.82 (m, 2H), 7.52 (tt, J=1.3 Hz, 7.3 Hz, 1H), 7.49-7.42 (m, 3H), 7.22 (t, J=8.1 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.69 (dd, J=2.1 Hz, 8.3 Hz, 1H), 4.38-4.30 (bm, 1H), 2.72-2.62 (bm, 2H), 2.35-2.23 (bm, 5H), 2.04-1.96 (bm, 2H), 1.89-1.79 (bm, 2H). Analysis calculated for C19H23ClN2O2.0.6H2O: C, 63.80; H, 6.82; N, 7.83. Found C, 63.67; H, 6.62; N, 7.83.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](I)[CH:12]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Clc1cccc(I)c1
Product: Clc1cccc(-n2ccc3ccccc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-chloro-3-iodobenzene: ESMS m/e: 227.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][C:6]2[NH:7][C:8]([C:10]3[C:14]([NH2:15])=[CH:13][NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1.[F:20][C:21]1C=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1N=C=O.CCN(CC)CC.[CH3:38][N:39]([CH:41]=[O:42])C>CCO>[F:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:27])[C:38]=1[NH:39][C:41]([NH:15][C:14]1[C:10]([C:8]2[NH:7][C:6]3[CH:16]=[C:17]([O:18][CH3:19])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:9]=2)=[N:11][NH:12][CH:13]=1)=[O:42]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1OC
Reactant: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)Nc3c(F)cccc3F)[nH]c2cc1OC
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.19 mmol), 2,4 difluorophenyl isocyanate (31.4 mg, 0.20 mmol) and Et3N (0.027 ml) suspended in a mixture of DMF and EtOH (5 ml) was stirred at 70° C. for 1 h and then reduced in vacuo. The residue was purified by prep HPLC to give 1-(2,6-difluoro-phenyl)-3-[3-(5,6-dimethoxy-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-urea as a white solid (11 mg) (LC/MS: Rt 2.10, [M+H]+ 415).
Reaction SMILES: [CH:1](=[N:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16]Cl)[CH2:14][S:15][C@H:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:32].[Na+]>CC(C)=O>[CH:1](=[N:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][I:32])[CH2:14][S:15][C@H:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N=Cc4ccccc4)C(=O)N23)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3C(N=Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
30 g (65.65 mM) of p-methoxybenzyl 7-benzylideneamino-3-chloromethyl-3-cephem-4-carboxylate was dissolved in 500 ml of acetone. Then, 29.5 g (197 mM) of sodium iodide was added thereto, and the mixture was stirred at room temperature for 1 hour. From the reaction solution thus obtained, the solvent was distilled off under reduced pressure. To the residue, 500 ml of ethyl acetate was added. The mixture was washed with a saturated sodium thiosulfate aqueous solution and then with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 27 g (yield: 75%) of p-methoxybenzyl 7-benzylideneamino-3-iodomethyl-3-cephem-4-carboxylate.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]3[N:10]=[C:11]([N+:13]([O-])=O)[CH:12]=[C:6]3[CH2:5]2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]3[N:10]=[C:11]([NH2:13])[CH:12]=[C:6]3[CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCN(C1CC1)C2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc2n(n1)CCN(C1CC1)C2
Yield: 78.3 %

Procedure:
A mixture of 5-cyclopropyl-2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 135a (2.68 g, 12.9 mmol), Fe (3.6 g, 64.4 mmol) and NH4Cl (4.1 g, 77.4 mmol) in ethanol (30 mL) and water (5 mL) was heated at reflux for 2 h. After the completion of the reaction, the mixture was filtered off. And the solid was washed with ethanol (150 mL). The filtrate was evaporated in vacuo and the residue was extracted with methanol/methylene chloride (1/7). The combined extracts were dried over Na2SO4 and evaporated. The residue was purified on reverse phase Combi-flash to give 135b (1.8 g, 75%). MS: [M+H]+ 179.
Reaction SMILES: [O:1]=[C:2]1[CH2:23][O:22][C:21]2[C:4](=[CH:5][C:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][C:7]=3[CH:20]=2)[NH:3]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:3]1[C:4]2=[CH:5][C:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][C:7]=3[CH:20]=[C:21]2[O:22][CH2:23][C:2]1=[O:1]
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)OCC(=O)N3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(Cc1cccc(F)c1)C(=O)CO3
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of t-butyl 3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 10 ml of DMF were added 250 μl of 1-(bromomethyl)-3-fluorobenzene and 800 mg of cesium carbonate, followed by stirring at 50° C. for 16 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, and water added, followed by extraction with ethyl acetate twice. The combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 609 mg of t-butyl 4-(3-fluorobenzyl)-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Br[C:14]1C=C2C(CCCC2=O)=CC=1>>[Br:1][C:2]1[C:3]2[C:8](=[C:7]([O:12][CH3:14])[CH:6]=[CH:5][CH:4]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCCc2c(Br)cccc21
Reactant: O=C1CCCc2ccc(Br)cc21
Product: COc1cccc2c(Br)cccc12

Procedure:
A third fraction of orange oil (9.06 g, 20.9%) was isolated. TLC showed it to be a nearly 1:1 ratio of 5-bromo-3,4-dihydro-1(2H)-naphthalenone, and 7-bromo-3,4-dihydro-1(2H)-naphthalenone.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[S:5][CH:6]=1.[Li]CCCC.[F:18][C:19]([F:27])([F:26])[C:20](N(OC)C)=[O:21]>C(OCC)C.C1COCC1>[F:18][C:19]([F:27])([F:26])[C:20]([C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[S:5][CH:6]=1)=[O:21]
Reactant: CON(C)C(=O)C(F)(F)F
Reactant: Brc1csc(N2CCOCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1csc(N2CCOCC2)n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a chilled (−78° C.) solution of 4-(4-bromothiazol-2-yl)morpholine (249 mg, 1.00 mmol) in dry diethyl ether (10 mL) was added n-BuLi (480 μL, 2.5 M in hexanes, 1.20 mmol). After 20 minutes, a solution of 2,2,2-trifluoro-N-methoxy-N-methylacetamide (224 μL, 2 mmol) in THF (10 mL) was added over 10 minutes. After 30 minutes, the mixture was warmed to 0° C. After 30 minutes, the mixture was quenched with 10 mL of water, warmed to room temperature, and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was twice purified on SiO2 using ethyl acetate-hexanes (20-100% gradient) to afford 125 mg (47%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:11]([C:18]1[S:22][C:21]([CH2:23][NH2:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:21]1[S:22][C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:19][CH:20]=1)=[O:6]
Reactant: NCc1ccc(Oc2ccccc2)s1
Reactant: O=C(O)c1cccnc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Oc2ccccc2)s1)c1cccnc1Cl
Temperature: 60 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
To a solution of 2-chloro nicotinic acid (1182 mg, 7.50 mmol) in N,N-dimethylformamide (3 mL) were added C-(5-phenoxy-thiophen-2-yl)methylamine described in Preparation Example 24 (1693 mg, 8.25 mmol), benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (3987 mg, 9.0 mmol) and triethylamine (2.5 mL, 18.0 mmol), and the solution was stirred at 60° C. for 2 days. Water was added to the reaction mixture, which was then extracted with ethyl acetate, and then concentrated. The residue was purified by silica gel column chromatography, and the title compound (1181 mg, 3.43 mmol, 46%) was obtained.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:9])[C:5]([OH:8])([CH3:7])[CH3:6].Br[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Br:20])[N:12]=1>O1CCOCC1>[CH3:2][O:3][C:4](=[O:9])[C:5]([O:8][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Br:20])[N:12]=1)([CH3:7])[CH3:6]
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Reactant: COC(=O)C(C)(C)O
Agent: [Na]
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)Oc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
330 mg sodium were suspended in 10 ml 1,4-dioxan. Then 1.7 g 2-Hydroxy-2-methyl-propionic acid methyl ester were added dropwise. The mixture was stirred at 50° C. for thirty minutes and then at 70° C. for thirty minutes until all sodium was dissolved. This solution was then added dropwise to a solution of 2.7 g 2,6-dibromo-3-nitro pyridine in 5 ml 1,4 dioxan at 0° C. The cooling bathe was removed and the mixture stirred at room temperature overnight and then at 70° C. for four hours. The cooled reaction mixture was reduced in vacuo and the residue purified by chromatography on silica gel to obtain 640 mg 2-(6-Bromo-3-nitro-pyridin-2-yloxy)-2-methyl-propionic acid methyl ester as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO)cc1OC1CCCC1
Temperature: 18.5 °C

Procedure:
To a solution of 48.70 g (220 mmoles) or 3-cyclopentyloxy-4-methoxybenzaldehyde in 250 ml of methanol was added portionwise 8.57 g (220 mmoles) of 97% sodium borohydride, within 10 min at 15-22° C. under cooling. After a further 20 min the methanol was removed in vacuo and the residue taken up in 10 ml of water and 300 ml of ether. The ether phase was evaporated to dryness: 48.5 g (99.2%) of liquid benzyl alcohol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.CC(O)=[O:12].OO>O>[CH:5]1[CH:6]=[N+:1]([O-:12])[CH:2]=[C:3]([CH2:7][C:8]#[N:9])[CH:4]=1
Reactant: N#CCc1cccnc1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: N#CCc1ccc[n+]([O-])c1
Reaction time: 72 h

Procedure:
A solution of 3-pyridylacetonitrile (11 g, 93.1 mmol), HOAc (55 mL), and 30% H2O2 (17 mL) was heated at 95° C. overnight, and at room temperature for 72 hours. H2O (50 mL) was added to the reaction mixture and the resulting solution was concentrated. This was repeated with additional H2O (100 mL). Toluene (2×100 mL) was used to remove residual H2O, and the resulting white solid was dried under vacuum overnight affording a waxy white solid: mp 120-125° C.; MS (+) APCI m/z 135 [M+H]+.