Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([NH:14][C:15]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:20]=2[Cl:27])=[O:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)=[O:37]>CN(C)C=O>[Cl:27][C:20]1[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=1[C:18]([NH:17][C:15](=[O:16])[NH:14][C:4]1[CH:3]=[C:2]([NH:1][C:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[O:37])[CH:7]=[CH:6][C:5]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[O:28]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: COC(=O)C=Cc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(NC(=O)Oc2ccc(Cl)cc2)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Yield: 9 %

Procedure:
100 mg (0.24 mmol) of methyl 3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)-ureido]phenyl}acrylate (example 54 b) were reacted in 2 ml of dimethylformamide with potassium carbonate and 4-chlorophenyl chloroformate. The precipitate resulting after 4 hours was filtered off with suction. Preparative HPLC (column: Waters Xterra™MS C18, 5 μm, 30×100 mm, mobile phases: A: H2O+0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10% A/90% B) resulted in 12 mg (9%) of the desired product.
Reaction SMILES: [CH:1]1[C:16]2[C:17]3[C:4]([C:5](=O)[O:6][C:7](=[O:18])[C:8]=3[CH:9]=[C:10]3[C:15]=2[O:14][CH2:13][CH2:12][O:11]3)=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].O>N1C=CC=CC=1>[OH:22][N:21]1[C:5](=[O:6])[C:4]2=[CH:3][CH:2]=[CH:1][C:16]3[C:17]2=[C:8]([CH:9]=[C:10]2[C:15]=3[O:14][CH2:13][CH2:12][O:11]2)[C:7]1=[O:18]
Reactant: O=C1OC(=O)c2cc3c(c4cccc1c24)OCCO3
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2cccc3c4c(cc(c23)C(=O)N1O)OCCO4
Yield: 97 %

Procedure:
To a solution of 70 mg (0.27 mmol) of 9H,10H-5,8,11-trioxabenzo[de]anthracene-4,6-dione (from Example R3) in 4 mL pyridine was added 80 mg (1.16 mmol) of hydroxylamine hydrochloride and the reaction mixture refluxed for 1.5 hours and poured into 20 mL water while hot. The precipitate was isolated after 24 hours, washed with water, 1% HCl, water, and dried to yield 71 mg of the title compound, mp 344-347° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].CC(C[AlH]CC(C)C)C.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](OC)=[O:27])=[CH:21][CH:20]=1)#[N:18]>C1COCC1.CCOC(C)=O>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH:5][C:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=1)=[O:27]
Reactant: CC(C)(C)CCN
Reactant: COC(=O)Cc1ccc(C#N)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)CCNC(=O)Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
Dissolve 3,3-dimethylbutylamine (0.8 mL, 6.4 mmol) in anhydrous THF (2 mL) under nitrogen. Cool the solution at 0° C. and add DIBAL-H (6.2 mL, 6.2 mmol, 1M solution in toluene). Allow the mixture to warm up to room temperature and stir for 2 h. Add this complex to a solution of methyl (4-cyanophenyl)acetate (192 mg, 1.1 mmol) in THF (4 mL) and stir at room temperature overnight. Dilute with EtOAc and quench with 5% KHSO4. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:3) to obtain the desired intermediate (160 mg, 60%). MS (ES+) m/z: 245 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1C=CC=CC=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.BrCCCCC(C)(C)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: C1=COCCC1
Agent: CC(C)(CO)CCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCCCBr)COC1CCCCO1
Yield: 83 %

Procedure:
According to the procedure for the preparation of 207d, (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818) 206c (521.0 g, 2.49 mol) was reacted with 3,4-dihydro-2H-pyran (278.0 g, 3.30 mol) and p-toluenesulfonic acid hydrate (3.13 g, 16 mmol) in CH2Cl2 (2.2 L) to yield 207c (603.0 g, 83%) as a pale-yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 4.55 (t, 1 H, J=3.3), 3.84 (m, 1 H), 3.50 (m, 1 H), 3.47 (d, 1 H, J=9.0), 3.42 (t, 2 H, J=6.7), 2.99 (d, 1 H, J=9.0), 1.88 (m, 2 H), 1.75-1.33 (m, 10 H), 0.91 (s, 3 H), 0.90 (s, 3 H). 13C NMR (CDCl3): δ 99.37, 76.58, 62.17, 38.56, 34.43, 34.19, 33.90, 30.88, 25.79, 24.80, 24.71, 22.89, 19.67. HRMS (LSIMS, nba): Calcd for C13H25BrO2 (MH+): 293.1116, found: 293.1128.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:13]([CH:16]=[C:17](SC)[S:18][CH3:19])([O-:15])=[O:14]>>[N+:13]([CH:16]=[C:17]([S:18][CH3:19])[NH:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:15])=[O:14]
Reactant: NCCSCc1ncccc1O
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CSC(=C[N+](=O)[O-])NCCSCc1ncccc1O

Procedure:
By the procedure of Example 4(i), 3-hydroxy-2-[(2-aminoethyl)thiomethyl]pyridine (from the dihydrobromide (4.2 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) to give 1-nitro-2-methylthio- 2-[2-((3-hydroxy-2-pyridyl)methylthio)ethylamino]ethylene which, on reaction with methylamine by the process of Example 3(ii) gives 1-nitro-2-methylamino-2-[2-((3-hydroxy-2-pyridyl)methylthio)ethylamino] ethylene.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[C:21]([CH:30]2[CH2:32][O:31]2)=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=1)[C:25]#[N:26]>>[F:19][C:20]1[C:21]([CH:30]([OH:31])[CH2:32][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:18]=[CH:17][C:12]4[C:13](=[O:16])[O:14][CH2:15][C:11]=4[CH:10]=3)[CH2:2][CH2:3]2)=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=1)[C:25]#[N:26]
Reactant: COc1cc(C2CO2)c(F)cc1C#N
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Product: COc1cc(C(O)CN2CCN(CCc3ccc4c(c3)COC4=O)CC2)c(F)cc1C#N

Procedure:
5-fluoro-4-(1-hydroxy-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one and 5-fluoro-2-(methyloxy)-4-oxiran-2-ylbenzonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([O-])(O)=[O:19].[Na+].O=C(Cl)OC(Cl)(Cl)Cl>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:18]=[O:19])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C([O-])O
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Temperature: 0 °C
Yield: 90 %

Procedure:
To a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (4) (WO 2000043384) (1.00 g, 4.36 mmol) in DCM (90 mL) was added a saturated aq solution of NaHCO3 (60 mL). The mixture was stirred vigorously, cooled to 0° C. and diphosgene (2.1 mL, 17.4 mmol) was added in a single portion. After stirring for 1 hr at RT, the layers were separated and the organics dried and evaporated to give a brown oil. The oil was triturated with iso-hexane (5.0 mL) and the solid filtered. The filtrate was concentrated in vacuo to give 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole (19) as a light brown oil (1.00 g, 3.92 mmol, 90%). m/z 288 (in MeOH) (M+H+MeOH)+ (ES+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24])[C:20]([CH2:27][O:28][CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][C:38](=[O:40])[CH3:39])([CH3:24])[CH3:25])[C:20]([CH2:27][O:28][CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
2-(7-Benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethylamine (1.88 g, 4.65 mmol), triethylamine (1.3 mL, 9.3 mmol), and dichloromethane (50 mL) were combined and cooled to 0° C. Acetyl chloride (0.36 mL, 5.11 mmol) was added and the reaction was stirred for 30 minutes. The cooling bath was removed and the reaction was stirred for an additional 3.5 hours. Water was added and the layers were separated. The organic fraction was sequentially washed with brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide a tan solid. The solid was purified by flash column chromatography on silica gel (eluting with a gradient of 6-7.5% methanol in dichloromethane) to yield 1.71 g of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as a cream colored solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-nitrophenol (1 g, 7.12 mmol, 1.00 equip, 99%), tert-butyl 2-bromoacetate (1.68 g, 8.53 mmol, 1.00 equip), potassium carbonate (1.49 g, 10.60 mmol, 1.50 equip, 99%), and tetrahydrofuran (50 mL). The resulting solution was stirred for 4 h at 70° C. in an oil bath. The resulting solution was diluted with water (150 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined. The resulting mixture was washed with water (1×100 mL) and brine (1×100 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20) to yield tert-butyl 2-(4-nitrophenoxy)acetate as a yellow solid.
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:11]1([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:10]>FC(F)(F)C(O)=O>[C:9]([C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:10]
Reactant: CC(C)(C)OC(=O)CC1(C#N)CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#CC1(CC(=O)O)CCCCC1

Procedure:
To a solution of 2.4 mL (2.4 g, 22 mmol) of anisole in 50 mL of trifluoroacetic acid is added 5.00 g (22.4 mmol) of (1-cyanocyclohexyl)acetic acid, t-butyl ester. The reaction is monitored (TLC) for the loss of starting material and when the reaction is complete it is concentrated under reduced pressure. Water (˜10 mL) is added to the residue and the mixture is adjusted to pH=10-12 with base (NaOH). The basic aqueous layer is extracted with a suitable organic solvent (EtOAc) to remove impurities. The aqueous layer is acidified with acid (HCl) to pH=0-4 and extracted with a suitable solvent (EtOAc). The combined organic extracts of the acidified aqueous layer are dried and concentrated under reduced pressure to afford the product.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.C(N(CC)CC)C.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:30](=[O:31])[CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)Cc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 20 mL of dicloromethane was treated successively with 0.51 mL of triethylamine (1.5 eq.) and 0.33 mL of phenylacetyl chloride (1 eq.), stirred at room temperature for two hours and then diluted with an additional 20 mL of dichloromethane. The organic solution was washed with two 50 mL portions of water and one 50 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 790 mg (100%) of phenylacetic acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (7) as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCl
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C

Procedure:
3.04 g (9.9 mmol) of the compound from Example 4A were dissolved in 100 ml of acetonitrile, and 1.07 g (9.9 mmol) of methyl chloroacetate, 2.73 g (19.8 mmol) of potassium carbonate and a small spatula tip of potassium iodide were added. The reaction mixture was heated under reflux for 1 h and then allowed to cool to RT and filtered. The filtrate was freed from the volatile components on a rotary evaporator and the residue was dried under high vacuum. This gave 3.70 g of the title compound in a purity of about 90%, (89% of theory).
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C(O)(=O)C>C1C=CC=CC=1>[F:9][C:10]([F:18])([F:19])[C:11]1[CH:12]=[C:13]([NH:14][C:2]([CH3:8])=[CH:3][C:4]([O:6][CH3:7])=[O:5])[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C=C(C)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 3.48 g (30 mmol) methyl 3-oxobutanoate in 90 ml benzene are added 4.83 g (30 mmol) 3-(trifluoromethyl)aniline and 1.80 g (30 mmol) acetic acid. The mixture is stirred at reflux for four hours using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 8). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [CH2:1]([CH2:4][C:5](Cl)=[S:6])[CH:2]=[CH2:3].[CH3:8][CH:9]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])[N:12]2[C:23](=[O:26])[CH:24]([NH2:25])[C@H:11]2[S:10]1>ClCCl>[CH3:8][CH:9]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:20])[Cl:21])=[O:16])[N:12]2[C:23](=[O:26])[CH:24]([NH:25][C:5](=[S:6])[CH2:4][CH2:1][CH:2]=[CH2:3])[C@H:11]2[S:10]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: C=CCCC(=S)Cl
Solvent: ClCCl
Product: C=CCCC(=S)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CC(C)S[C@H]12
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suspension of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (0.764 g) in dried dichloromethane (8 ml) were added at -30° C. a solution of triethylamine (0.18 g) in dichloromethane (2 ml) and then a solution of dimethylaniline (0.27 g) in dichloromethane (2 ml). While, allylthioacetic acid (0.528 g) was added to thionyl chloride (5 ml) and the mixture was allowed to stand for 20 minutes at room temperature and 5 minutes at 50° C., after which thionyl chloride was removed under reduced pressure, and the residue was added a small amount of benzene, and then removed under reduced pressure to give allylthioacetyl chloride (0.527 g). A solution of thus obtained allylthioacetyl chloride (0.452 g) in dichloromethane (3 ml) was dropwise added to -30° C. over 5 minutes to the above-mentioned solution of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate, and the mixture was stirred for 1 hour at -20° C. After the reaction, the reaction mixture was in turn washed twice with 5% hydrochloric acid, once with water, twice with a saturated sodium bicarbonate aqueous solution and once with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. After the solvent was distilled off, the residue (0.82 g) was recrystallized from a mixture of ether and isopropyl ether to give 2,2,2-trichloroethyl 2-methyl-7-(2-allylthioacetamido)-3-cephem-4-carboxylate (0.71 g), mp 96° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]2[CH:15]=[N:14][C:13]3[NH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28]C(OC(C)(C)C)=O)[CH:22]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[C:20]1([C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[CH2:27][NH2:28])[C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][C:16]=3[CH:15]=[N:14][C:13]=2[NH:18][N:19]=1.[C:38]([OH:40])([C:37]([F:42])([F:41])[F:36])=[O:39]
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2n[nH]c3ncc4c(c23)CCN(C(=O)OC(C)(C)C)C4)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(-c2n[nH]c3ncc4c(c23)CCNC4)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[3-(tert-butoxycarbonylamino-methyl)-phenyl]-3,6,8,9-tetrahydro-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxylic acid tert-butyl ester (0.07 g, 0.14 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and purified by reverse phase HPLC to give the desired product, 3-(6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-1-yl)-benzylamine as a bis TFA salt and as a white solid (0.046 g, 62%). 1H NMR (400 MHz, DMSO-d6) δ13.98 (s, 1H), 9.27 (brs, 2H), 8.45 (s, 1H), 8.30 (brs, 2H), 7.70 (s, 1H), 7.58 (m, 3H), 4.44 (s, 2H), 4.14 (m, 2H), 3.31 (m, 2H), 3.01 (m, 2H); LC-Mass: m/e 480.73 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[CH:4]=1.[CH3:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15].O>CN(C=O)C>[Br:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][P:12]([CH3:11])(=[O:16])[O:13][CH2:14][CH3:15]
Reactant: CCOP(C)OCC
Reactant: BrCc1cccc(CBr)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(C)(=O)Cc1cccc(CBr)c1
Temperature: 150 °C
Yield: 44 %

Procedure:
To a solution of α,α′-Bisbromo-m-xylene (7.75 g, 29.38 mmol) in DMF (10 mL) was added diethyl methylphosphonite (2.0 g, 14.69 mmol) via syringe. The mixture was heated to 150° C. for 2 minutes in a microwave. The reaction mixture was poured into water and product extracted with ethyl acetate (3×25 mL). The combined organics were washed with water (2×50 mL) and brine (50 mL), and dried over Na2SO4. Reduced volume in vacuo and purified product by flash column eluting 20-100% ethyl acetate in hexanes to give 1.89 g mg (44%) 65 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.24 (t, 3H), 1.33 (d, 3H), 3.08 (d, 2H), 3.97 (dt, 2H), 4.44 (s, 2H), 7.25 (m, 4H). LCMS: m/z for C11H16BrO2P++H observed 291.0 and 293.0 at 2.09 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)(=O)OC.[CH2:20]([O:22][C:23](=[O:39])[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C@@H:31]1[CH:37]=O)[CH3:21]>C1COCC1>[CH2:20]([O:22][C:23](=[O:39])[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[C:35](=[O:36])[CH2:34][CH2:33][CH2:32][C@@H:31]1/[CH:37]=[CH:9]/[C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH3:21]
Reactant: COP(=O)(CC(=O)Cc1cccc(Cl)c1)OC
Reactant: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 35 mg, 0.88 mmol) was added to a solution of [3-(3-chlorophenyl)-2-oxopropyl]-phosphonic acid dimethyl ester (221 mg, 0.80 mmol) in THF (2.0 mL) at 0° C. After 1 h at 0° C., [4-((R)-2-formyl-6-oxo -piperidin-1-yl)-butoxy]-acetic acid ethyl ester (0.88 mmol, crude) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 10 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20%→40% EtOAc/CH2Cl2, gradient) afforded 117 mg (34%) of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-oxo-but-1-enyl]-6-oxo-piperidin-1-yl}-butoxy)-acetic acid ethyl ester.
Reaction SMILES: [Cl-].[OH:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH:30]([C:32]1[N:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1)=O.O1CCCC1.CC(C)([O-])C.[K+]>O>[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:30][C:32]2[N:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)=[CH:28][CH:29]=1
Reactant: OCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=Cc3ccc(CO)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a mixture of [4-(hydroxymethyl)benzyl](triphenyl)phosphonium chloride (1.283 g, 3.064 mmol), tert-butyl 4-(6-formylpyridin-3-yl)piperazine-1-carboxylate (876.3 mg, 3.008 mmol) and anhydrous tetrahydrofuran (10 ml) was added potassium tert-butoxide (383.9 mg, 3.421 mmol), and the mixture was stirred at room temperature for 1 hr. Water (20 ml) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1). The fraction containing the target product was concentrated and the obtained solid was dissolved in ethyl acetate, and extracted twice with 0.2M hydrochloric acid. The aqueous layer was saturated with sodium carbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl 4-(6-{2-[4-(hydroxymethyl)phenyl]vinyl}pyridin-3-yl)piperazine-1-carboxylate (850.2 mg, yield 71.5%, E/Z mixture) as a pale-yellow solid.