Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O>[F:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:13]2/[C:12](=[O:17])[CH2:16][CH2:15][CH2:14]/2)=[CH:6][CH:5]=1
Reactant: O=C1CCCC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1CCC/C1=C\c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A solution of KOH (1.5 g, 26.7 mMol) in water (27 mL) was added to 4-fluoro-benzaldehyde Compound 3a (7.45 g, 60.0 mMol) and cyclopentanone Compound 1a (5.0 g, 59.4 mMol). The mixture was heated to 65° C. and stirred for 24 hrs at 65° C. The reaction mixture was allowed to cool to ambient temperature, acidified to pH 3 using 1N HCl and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over Na2SO4, then filtered and concentrated. The resulting residue was purified on a silica gel column (using 5% EtOAc/Hexane) to give (2E)-2-(4-fluoro-benzylidene)-cyclopentanone Compound 3b (2.60 g, 13.7 mMol).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]=3)=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1
Reactant: CN1CCC(=O)CC1
Reactant: COc1ccc2[nH]ccc2n1
Product: COc1ccc2[nH]cc(C3=CCN(C)CC3)c2n1
Yield: 83.7 %

Procedure:
Beginning with 0.80 gm (5.4 mMol) of 5-methoxypyrrolo-[3,2-b]pyridine and 1.2 mL (10.1 mMol) 1-methyl-4-piperidone, 1.1 gm (84%) of the title compound were recovered as a yellow solid essentially by the procedure described in Example 5. An analytical sample was recrystallized from methanol.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][CH2:12]3)[CH2:6][CH2:5]2)[N:20]=1
Reactant: O[C@H]1CC[C@H](N2CCNCC2)CC1
Reactant: Cc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccnc(N2CCN([C@H]3CC[C@H](O)CC3)CC2)n1

Procedure:
The compound 10a (4.3 g, 23.3 mmol) is placed in 100 ml of toluene in the presence of 2-chloro-4-methylpyrimidine (3 g, 23.3 mmol) and of triethylamine (4.9 ml, 35.1 mmol) and then this mixture is heated at reflux for 16 h.
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH2:8][CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:10][SiH:11]([Cl:13])[Cl:12]>>[C:1]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[Si:11]([Cl:13])([Cl:12])[Cl:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl[SiH](Cl)Cl
Reactant: CC(C)(C)C1=CCCC1
Product: CC(C)(C)C1CCCC1[Si](Cl)(Cl)Cl
Yield: 60 %

Procedure:
A one-liter autoclave equipped with a stirrer was charged in a nitrogen atmosphere with 50 grams (0.40 mol) of 1-tert-butylcyclopentene, 108 grams (0.80 mol) of trichlorosilane and 20 grams (82 mmol) of 1,1'-azobis(cyclohexane-1-carbonitrle) and the mixture was reacted at a temperature of 130° C. for 3 days. The resulting reaction mixture was purified by distillation thereby obtaining 62 grams (0.24 mol) of 2-tert-butylcyclopentyltrichlorosilane. The structure of the resulting product was identified by 1H-NMR.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:16].[OH-].[Na+]>S(=O)(=O)(O)O>[Br:5][C:6]1[CH:15]=[CH:14][C:13]([N+:1]([O-:4])=[O:2])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCCc2c(Br)cccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCCc2c(Br)ccc([N+](=O)[O-])c21
Reaction time: 0.75 h
Yield: 336.6 %

Procedure:
To prepare this compound, 90% fuming nitric acid (0.115 gram, 0.165 mmol) was added to a solution of 5-bromo-3,4-dihydro-2H-naphthalen-1-one (0.34 g, 1.50 mmol) in 3 mL concentrated sulfuric acid at 0° C. After 45 minutes, the mixture was poured into ice, and 6 N aqueous sodium hydroxide (9 mL) was added very slowly. That mixture was extracted twice with EtOAc (40 mL each), and the two extracts were combined. The combined EtOAc extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was subjected to flash chromatography (40% EtOAc/hexanes) and recrystallization (EtOAc/hexanes) to afford 0.15 g (38%) of 5-bromo-3,4-dihydro-8-nitro-2H-naphthalen-1-one. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J=8.2, 1H), 7.25 (d, J=8.2, 1H), 3.07 (t, J=6.2, 2H), 2.74 (t, J=6.7, 2H), 2.18-2.25 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:21][C:14]=3[O:13][CH2:12][CH2:11]2)[C:3]=1[CH:4]=[O:5].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:50])=[CH:45][N:44]=2)[C:28]1=[O:57].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[C:22]([C:20]1[CH:19]=[CH:18][C:15]2[C:16](=[O:17])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:2]([C:31]4[CH:30]=[C:29]([NH:42][C:43]5[CH:48]=[CH:47][C:46]([C:49]([N:51]6[CH2:56][CH2:55][O:54][CH2:53][CH2:52]6)=[O:50])=[CH:45][N:44]=5)[C:28](=[O:57])[N:27]([CH3:26])[CH:32]=4)[C:3]=3[CH:4]=[O:5])[CH2:11][CH2:12][O:13][C:14]=2[CH:21]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(C)(C)c1ccc2c(c1)OCCN(c1cccc(Br)c1C=O)C2=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: O
Product: Cn1cc(-c2cccc(N3CCOc4cc(C(C)(C)C)ccc4C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 97.9 %

Procedure:
2-Bromo-6-(8-tert-butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)benzaldehyde (109 mg, 0.27 mmol), 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (179 mg, 1.5 eq), XPHOS (8 mg, 0.06 eq), and potassium phosphate (115 mg, 2 eq) were taken up in n-butanol (2 mL) and water (0.5 mL) and a stream of argon was bubbled through the mixture for 10 minutes. Then the catalyst Pd(dba)2 (5 mg, 0.03 eq) was added and the reaction was placed under argon and stirred at 100° C. for 40 minutes. By TLC analysis the reaction was complete, so it was cooled to room temperature and diluted with ethyl acetate (150 mL) and water (50 mL). The layers were partitioned and then separated and the organic layer was further washed with water (3×50 mL) and then finally washed with brine (1×50 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated. Purification by Preparative Thin Layer Chromatography on silica gel eluting with 7% methanol in dichloromethane gave the title compound as an off-white powder (168 mg) (M+H)+=636.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH2:18]([C:12]1[CH:13]=[CH:14][C:15]([C:7]([C@@H:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]2[C:10]([OH:9])=[O:11])=[O:8])=[CH:16][CH:17]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCc1ccccc1
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCc1ccc(C(=O)[C@@H]2CCCC[C@H]2C(=O)O)cc1
Temperature: 0 °C

Procedure:
Trans-1,2-cyclohexanedicarboxylic anhydride (6.76 g , 0.044 mole) was heated with 1-phenylheptane (100 ml) and anhydrous aluminum chloride (12.86 g, 0.096 moles) at 100° C. for 1 hour. The reaction mixture was then poured into a mixture of ice water (500 ml) and concentrated hydrochloric acid (50 ml). The product was extracted with ether (2×200 ml) and the extracts dried over magnesium sulfate and filtered. The ether was removed under reduced pressure and the remaining solution chromatographed on silica (hexane and then hexane:ether:acetic acid at 70:30:1) to yield trans-2-(4-heptylbenzoyl) cyclohexane-1-carboxylic acid (7.36 g), m.p. 91°-94° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1C=CC=CC=1.BrCC#[N:27].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C.[Pd].C(C(C)=O)C>[C:2]([CH2:1][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)#[N:27]
Reactant: N#CCBr
Reactant: COC(=O)/C=C/c1ccc(OCc2ccccc2)c2[nH]ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OCC#N)c2[nH]ccc12

Procedure:
A suspension of 7-benzyloxy-4-(2(E)-methoxycarbonylethenyl)indole (0.50 g, 1.63 mmol) in methanol (40 ml) and ethyl acetate (10 ml) was hydrogenated at 60 p.s.i. over 10% palladium on charcoal (0.10 g) for 3 hours. The catalyst was filtered off and the filtrate was evaporated. A stirred solution of the residue and bromoacetonitrile (0.12 ml, 1.72 mmol) in methyl ethyl ketone was heated under reflux with solid anhydrous potassium carbonate (0.48 g, 3.4 mmol) for 3.5 hours, poured onto ice-hydrochloric acid and extracted with dichloromethane. The extract was dried and evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:3) to give a pale solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:26]=[N:25][C:24]([NH2:23])=[N:29][CH:28]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-methyl-pyridine (example E.85) (0.20 g, 0.509 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.124 g, 0.56 mmol) according to the general procedure VI. Obtained as an off-white solid (0.100 g, 48%). MS (ISP) 407.2 [(M+H)+], 409.1 [(M+2+H)+] and 411 [(M+4+H)+]; mp 188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][C:13]#N)[N:6]3[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([F:22])[C:20]=4[CH:21]=[C:5]3[C:4]=2[N:3]=1.CC(C[AlH]CC(C)C)C.[OH2:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][CH:13]=[O:32])[N:6]3[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([F:22])[C:20]=4[CH:21]=[C:5]3[C:4]=2[N:3]=1
Reactant: N#CCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: O
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=CCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: -78 °C
Yield: 66 %

Procedure:
A solution of 2-(2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)acetonitrile (300 mg, 0.78 mmol) in DCM (6 mL) was stirred at −78° C. for 10 minutes. Then DIBAL-H (1 ml, 1 mmol) was added slowly to the reaction mixture at −78° C. Then the mixture was heated at −78° C. for 2 hours. The mixture was diluted with water (30 mL) and extracted with EA (20 mL×3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by column (PE:EA=3:1) to afford the desired product of 2-(2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)acetaldehyde (200 mg, yield: 66%). 1H-NMR (CDCl3, 400 MHz) δ 9.63 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.34 (d, J=9.8 Hz, 1H), 7.11˜7.13 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.75 (t, J=8.0 Hz, 1H), 3.42 (s, 1H), 3.03 (d, J=8.4 Hz, 1H), 2.61˜2.70 (m, 2H). MS (M+H)+: 315/317.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:24]([CH2:27][CH2:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:31][CH:30]=1)([O-])=[O:25].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:25][N:24]=[C:27]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:41][CH:42]=3)[CH:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C#Cc1cccnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 8 h

Procedure:
Under stirring at room temperature, to a solution of di-tert-butyl(3-ethinyl pyridin-2-yl)imidodicarbonate described in Preparation Example 3-1-1 (12 g), 2-(4-(2-nitro-ethyl)-benzyloxy)pyridine described in Preparation Example 1-3-4 (19.4 g), 4-dimethyl aminopyridine (230 mg), tetrahydrofuran (200 mL) was added di-tert-butyl dicarbonate (28.8 g) divided into four portions over 8 hours. After the additions were finished, stirring was carried out at room temperature for an additional 22 hours. Silica gel was added to the reaction solution and the solvent was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:1 then 2:1) to obtain the title compound (11.8 g, containing approximately 70% of the target compound).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1Br.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: Cc1cc(Br)c(Br)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
A mixture of 1,2-dibromo-4-methyl-5-nitrobenzene (84.3 g, 286 mmol), 2,4-difluorophenol (37.2 g, 286 mmol), and K2CO3 (43.5 g, 315 mmol) were heated to 100° C. for 45 hours. The reaction mixture was cooled to room temperature and then stored in a 5° C. refrigerator overnight. The reaction mixture was poured into 1200 mL of ice water all at once. The resulting damp solid was collected, partially ground up, and stirred in 900 mL H2O for 45 minutes. The solid was collected by filtration and rinsed with 700 mL of water portion-wise. The resulting solid was dried under high vacuum overnight to yield 93.5 g of a brown solid (95% yield). 1H NMR (400 mHz, CDCl3) δ 8.38 (s, 1H), 7.18 (m, 1H), 7.03 (m, 1H), 6.97 (m, 1H), 6.52 (s, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cccnc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1-Benzyl-piperidin-4-yl)-(3-nitro-pyridin-2-yl)-amine (from Step A) in 10 mL of THF was added 2.4 g of SnCl2 and 1 mL of concentrated HCl at room temperature, stirred at room temperature for 2 hours. The reaction was diluted with 40 mL of EtOAc and washed with 30 mL of saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×15 mL EtOAc. The combined organic phases were washed with 15 mL of brine, dried over MgSO4 and concentrated under reduced pressure to give 603 mg of yellow soid.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:11]=[N:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO.O>[CH2:14]([O:13][N:12]=[CH:11][C:5]1([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1(C=NOCc2ccccc2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1(C=NOCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 1-(benzyloxyimino-methyl)-cyclohexanecarboxylic acid methyl ester (1.75 g, 6.36 mmol) and sodium hydroxide (0.76 g, 19.1 mmol) in THF (10 mL), methanol (10 mL) and water (5 mL) was stirred at room temperature for 40 h. The reaction mixture was acidified to pH 4 with 3N aqueous HCl and was extracted with EtOAc (50 mL×2). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a yellow oil. (1.59 g, 96%). MH+262.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([S:18][C:19]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[N:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([OH:32])=[O:31])=[C:15]([S:18][C:19]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[N:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccnn3-c3ccccn3)CS[C@H]12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Sc3ccnn3-c3ccccn3)CS[C@H]12
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirring suspension of (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (100 mg, 0.16 mmol) and anisole (0.6 mL) in dichloromethane (1.2 mL) at 0° C. was added trifluoroacetic acid (1.2 mL). After 30 min at 0° C., the solvent was removed with a rotary evaporator. The residue was dissolved in ethyl acetate, and was extracted with saturated aqueous sodium bicarbonate. The aqueous extracts were washed with ether, and were then acidified to pH 4-5 using aqueous HCl. This was extracted with ethyl acetate, and the organic extracts were washed with water and brine, and were dried (sodium sulfate) and concentrated. The resulting oil was triturated with hexane to afford the title compound (60 mg, 75%) as a pale yellow solid. 1H NMR (acetone-d6) δ3.55 (d, 1, J=18), 3.63 (d, 1, J=16), 3.71 (d, 1, J=16), 3.79 (d, 1, J=18), 5.25 (d, 1, J=4), 5.89 (dd, 1, J=4, 9), 6.44 (d, 1, J=2), 7.2-7.4 (m, 6), 7.78 (d, 1, J=2), 7.92 (d, 1, J=10), 8.02 (dt, 1, J=2, 10), 8.18 (d, 1, J=9), 8.48 (dd, 1, J=2, 8).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.7 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (11 g, 57 mmol) and triethylamine (17.3 g, 171 mmol) in tetrahydrofuran (180 ml) was added methanesulfonyl chloride (9.8 g, 85.5 mmol) at 5° C. The mixture was stirred for 3 hours at room temperature, poured into water, and extracted with ethyl acetate. The organic extract was washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford (S)-3-methanesulfonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (16.9 g, quant.) as colorless oil.
Reaction SMILES: F[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]#[N:12])[C:5]2=[CH:4][CH:3]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>CN1CCCC1=O>[N:13]1([C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]#[N:12])[C:5]3=[CH:4][CH:3]=2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCNC1
Reactant: N#Cc1n[nH]c2nc(F)ccc12
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1n[nH]c2nc(N3CCCNCC3)ccc12

Procedure:
6-Fluoro-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.62 g, 10.0 mmole) was dissolved in 20 mL of N-methylpyrrolidone. Hexahydro-1H-1,4-diazepine (5.0 g, 50.0 mmole) was added and then the reaction mixture was warmed for 2 hours at 80°. It was poured into H2O and then the product was filtered off and recrystallized from MeOH-H2O to give 1.32 g (54.5%) of analytically pure product, mp 196°-197°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH2:13])[C:7]([NH2:12])=[CH:8][C:9]=1[CH2:10][CH3:11])[CH3:2].[N+:14]([C:17]1[C:18]([CH:28]=O)=[N:19][N:20]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:21]=1)([O-:16])=[O:15].S(=O)(O)[O-].[Na+].O>CN(C)C=O>[CH2:1]([O:3][C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]2[NH:12][C:28]([C:18]3[C:17]([N+:14]([O-:16])=[O:15])=[CH:21][N:20]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[N:19]=3)=[N:13][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(N)c(N)cc1CC
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])[nH]c2cc1CC
Temperature: 120 °C
Yield: 52 %

Procedure:
A mixture of 4-ethoxy-5-ethyl-benzene-1,2-diamine [0.18 g, Reference Example 30(s)], 4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carbaldehyde [0.225 g, Reference Example 6(m)] and sodium bisulfite (0.12 g, 1.2 mmol) in dimethylformamide (10 mL) was heated at 120° C. for 1 hour. The mixture was cooled, water (100 mL) was added and the aqueous mixture was extracted with twice ethyl acetate (50 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (ethyl acetate with gradient of 20-0% heptane) to give 5-ethoxy-6-ethyl-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1H-benzoimidazole (200 mg) as a solid. LC-MS (Method E) RT=2.85 minutes, 386 (M+H)+. (b) 2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-1,5,6,7-tetrahydro-1,3-diaza-s-indacene
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH3:12][NH2:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:13][CH3:12])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=CCCc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNCCCc1ccc(Cl)cc1

Procedure:
Intermediate 21 (0.35 g), methylamine (2.07 ml, 2M solution in tetrahydrofuran) were stirred together in tetrahydrofuran (15 ml) for 5 min, before sodium triacetoxyborohydride (1.32 g) was added. The reaction was stirred for 18 h, before water (10 ml) was added, and the tetrahydrofuran was removed in vacuo. The resulting slurry was washed with ethyl acetate (3×50 ml), and then basified to pH 11 using sodium hydroxide (2M). The aqueous was then re-extracted with ethyl acetate (3 ×50 ml). These combined organic extracts were washed with brine (100 ml), dried over magnesium sulphate (1 g), and the solvent removed in vacuo to yield the title compound as a colourless oil (0.13 g).