Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([O:34][CH2:35][C@@H:36]1[CH2:38][O:37]1)[CH:28]=[CH:27]2>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:38][C@H:36]([OH:37])[CH2:35][O:34][C:29]5[CH:28]=[CH:27][C:26]6[C:31](=[CH:32][CH:33]=[C:24]([Br:23])[CH:25]=6)[CH:30]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc(OC[C@@H]3CO3)ccc2c1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc4cc(Br)ccc4c3)CC1)O2

Procedure:
Compound 217 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-{[(6-bromo-2-naphthyl)oxy]methyl}oxirane and conditions outlined in procedure Y. M.p.=104-105° C.; 400 MHz 1H NMR (CDCl3) δ: 7.94-7.85 (m, 3H), 7.70-7.56 (m, 3H), 7.54-7.47 (m, 1H), 7.23-7.17 (m, 1H), 7.12 (d, J=2.6 Hz, 1H), 4.26-4.18 (m, 1H), 4.17-4.08 (m, 2H), 3.04-2.94 (m, 1H), 2.96 (s, 2H), 2.90-2.78 (m, 2H), 2.76-2.66 (m, 2H), 2.56 (t, J=11.4 Hz, 1H), 2.24-2.12 (m, 2H), 2.00-1.85 (m, 2H); LCMS: 660 [M+H].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: NCCCO
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzonitrile (1.0 g; 6.02 mmol), 0.502 ml (6.62 mmol) of 3-amino-propan-1-ol and 1.15 ml (6.62 mmol) of diisopropylethylamine in 5 ml THF is stirred at rt for 1 hr (temperature raises somewhat at the beginning). After concentration in vacuo the residue is dissolved in 50 ml of ethyl acetate, washed with 50 ml of 4% aqueous sodium hydrogen carbonate and brine, dried and concentrated. 1.32 g of pure title compound as a solid are thus obtained (99% yield).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=12.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][C:3]1[N:4]2[C:5]([S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=32)=[N:1][N:2]=1
Reactant: c1ccc2c(c1)sc1nncn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1nnc2sc3ccccc3n12
Temperature: 25 °C

Procedure:
s-Triazolo(3,4-b)benzothiazole (6.4 grams; 0.0366 mole) was slurried with 200 milliliters of carbon tetrachloride, with stirring, at room temperature, and then heated. N-Bromosuccinimide (6.8 grams; 0.0366 mole plus 5 percent) was added and the solution refluxed and a pinch of azobisisobutylnitrile added to initiate the reaction. Subsequently the reaction mixture was filtered to separate blackish crystals, which were washed with carbon tetrachloride. The carbon tetrachloride was removed by evaporation, to yield a purple solid. This was chromatographed on a column packed with silica gel and eluted with ethyl acetate. The second portion was analyzed by elemental analysis and NMR, which confirmed its identity as the expected 3-bromo-s-triazolo(3,4-b)benzothiazole, m.p., 166°-7° C.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[N:52]1([CH2:56][CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C>CN(C)C=O>[N:52]1([CH2:56][CH:57]2[CH2:62][CH2:61][N:60]([C:8]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:28][C:27]=4[F:48])[CH:22]=[CH:21][N:20]=3)=[O:7])[CH2:59][CH2:58]2)[CH2:55][CH2:54][CH2:53]1
Reactant: C1CN(CC2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCC(CN2CCC2)CC1
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(azetidin-1-ylmethyl)piperidine dihydrochloride (69 mg) and triethylamine (0.085 ml) at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the titled compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (42.0 mg, 92%).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].[Cl:10][C:11]1[CH:12]=[C:13]([CH:24](O)[CH3:25])[C:14]2[O:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[C:15]=2[C:22]=1[CH3:23].CN(C)C=O>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:24]([Cl:3])[CH3:25])[C:14]2[O:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[C:15]=2[C:22]=1[CH3:23]
Reactant: Cc1c(Cl)cc(C(C)O)c2c1C(=O)NCCO2
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(C)Cl)c2c1C(=O)NCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A mixture of cyanuric chloride (15 mg, 0.079 mmol), 7-chloro-9-(1-hydroxyethyl)-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (14 mg, 0.053 mmol) and N,N-dimethylformamide (20 μL) in methylene chloride (0.4 mL) was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired compound (10 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:4]=1[CH:5]=[O:6].[C:12]([O:16]C)(=[O:15])[CH:13]=[CH2:14]>>[CH:5]([C:4]1[CH:7]=[C:8]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH:14]=[CH:13][C:12]([OH:16])=[O:15])=[O:6]
Reactant: COc1ccc(I)cc1C=O
Reactant: C=CC(=O)OC
Product: COc1ccc(C=CC(=O)O)cc1C=O

Procedure:
In order to implement this procedure, 2-methoxy-5-iodobenzaldehyde (V) was used as starting material, which, through a Heck-type reaction with methyl acrylate followed by in situ hydrolysis of the ester gave 3-formyl-4-methoxycinnamic acid (VI). Alternatively, the coupling reaction may be carried out with acrylic acid, therefore avoiding the hydrolysis step. The 3-formyl-4-methoxycinnamic acid (VI) was reacted with 3 equivalents of Deoxo-Fluor® solution in toluene or tetrahydrofuran, preferably Deoxo-Fluor® 50% in toluene. Dichloromethane the is the preferred reaction solvent between 0° and a reflux temperature, preferably 250. Upon completion of the reaction (determined by thin-layer chromatography) the mixture is diluted with dichloromethane and percolated through a silica gel bed under an inert atmosphere to remove the by-products from the fluorination reaction, giving a solution of 3-difluoromethyl-4-methoxy cinnamyl fluoride (VII).
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][C@@H:8]([CH2:19][CH2:20][CH3:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[C@H:8]([CH2:19][CH2:20][CH3:21])[CH2:7][C:6]([OH:22])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](CC(=O)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A stirred solution of (2R)-2-propyl-succinic acid 1-benzyl ester 4-tert-butyl ester (4.56 g, 14.88 mmol) in anhydrous DCM (20 mL), at 0° C., was treated with a solution of trifluoroacetic acid (10 mL) in anhydrous DCM (10 mL). The reaction mixture was allowed to warm to ambient temperature over 3 h before being concentrated under reduced pressure. The residue was dissolved in dry DCM, before concentrating again. This process was repeated several times in order to remove excess trifluoroacetic acid to leave the sub-title compound (3.70 g, 99%) as a gum: 1H NMR (400 MHz, CDCl3) δ 0.82-0.99 (3H, m), 1.21-1.76 (4H, m), 2.45-2.60 (1H, m), 2.76-3.00 (2H, m), 5.10-5.21 (2H, m), 7.28-7.43 (5H, m), 7.83-8.18 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([OH:16])=[C:11]4[S:17][CH:18]([CH3:20])[CH2:19][C:9]([C:10]=34)=[C:8]2[CH2:21][CH2:22][OH:23])=[CH:4][CH:3]=1.[C:26]1([C:32]2[CH:33]=[CH:34][C:35]([CH2:38]Cl)=[N:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CCOC(C)=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH2:38][C:35]4[CH:34]=[CH:33][C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:37][N:36]=4)=[C:11]4[S:17][CH:18]([CH3:20])[CH2:19][C:9]([C:10]=34)=[C:8]2[CH2:21][CH2:22][OH:23])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(-c2ccccc2)cn1
Reactant: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(O)c(c23)S1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(OCc4ccc(-c5ccccc5)cn4)c(c23)S1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of product from Step 5 (150 mg, 0.39 mmol), 5-phenyl-2-picolyl chloride (95 mg, 0.47 mmol) and Cs2CO3 (152 mg, 0.47 mmol) in CH3CN (5 mL) was stirred at r.t. for 20 hours, then at 60° C. for 1.5 hours. The mixture was diluted with EtOAc (25 mL), washed 3× with H2O, dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel, eluting with a 1:1 mixture of EtOAc and hexane, to afford the title product as an oil which solidified.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCc1cccc(-c2ccc(CN)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCc1cccc(-c2ccc(CNCc3ncc[nH]3)cc2)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.1 %

Procedure:
An anhydrous methanol solution (0.50 ml) containing the compound (30.1 mg) obtained in Example 36-5 and 2-imidazole carboxaldehyde (10.1 mg) was added with trimethyl orthoformate (0.029 ml), and the whole was stirred at room temperature for 14 hours. Sodium borohydride (17.0 mg) was added thereto and the whole was stirred for 30 minutes. The solvent was distilled off. The residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried with anhydrous sodium sulfate, and the solvent was distilled off, thereby obtaining the subject compound (30.4 mg).
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[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A heterogeneous mixture of 4-nitrophenol (5 g), methyl 2-bromoisobutyrate (5.6 mL) and K2CO3 (7.5 g) in acetone (60 mL) was refluxed overnight. The reaction mixture was then diluted with water (150 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were evaporated to give methyl 2-(4-nitrophenoxy)isobutyrate (49).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:12]([CH3:16])([CH2:13]2)[CH2:11][CH2:10][C:9](=[O:17])[CH:8]=3)=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[Br:23]Br>C(Cl)Cl.CCOC(C)=O>[Br:23][C:8]1[C:9](=[O:17])[CH2:10][CH2:11][C:12]2([CH3:16])[C:7]=1[C:6]1[C:14](=[CH:15][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:13]2
Reactant: COc1ccc2c(c1)CC1(C)CCC(=O)C=C21
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(c1)CC1(C)CCC(=O)C(Br)=C21
Temperature: 25 °C
Reaction time: 22 h
Yield: 46.5 %

Procedure:
A mixture of 7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (32 mg, 0.14 mmol) and NaHCO3 (60 mg, 0.7 mmol) in CH2Cl2 (0.5 ml) was treated with bromine (0.008 mL, 0.154 mmol), and the resulting mixture was stirred at room temperature for 22 hours. The mixture was diluted with EtOAc (8 ml), washed with dilute aqueous Na2S2O3 (4 mL) and brine (4 ml), dried over MgSO4, filtered, and evaporated under vacuum to a yellow oil (43 mg). This material was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing twice with CH2Cl2, to afford 4-bromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (20 mg) as a gum. The product was contaminated with a trace of 4,6-dibromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one.
Reaction SMILES: Cl[CH:2]([CH3:15])[CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[CH2:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:16]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:2]([CH3:15])[CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:17]
Reactant: CCCCCCCNCC
Reactant: CC(Cl)CC(=O)NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCN(CC)C(C)CC(=O)NCCc1ccccc1

Procedure:
Reflux 5.0 g (21 mmol) of 3-chloro-N-[2-phenylethyl]butanamide, 3.0 gm (21 mmol) N-ethylheptanamine and 3.0 g (21 mmol) of potassium carbonate in 100 mL of methanol. Follow the progress of the reaction by thin layer chromatography on silica gel. At the completion of the reaction remove the solvent in vacuo and add 100 mL of H2O. Extract the aqueous mixture with 3×100 mL of methylene chloride. Dry the organic extracts over anhydrous sodium sulfate. Remove the drying agent and evaporate the solvent to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[CH2:17][CH2:16]1
Reactant: Cc1cnc(N2CCC(=O)CC2)nc1
Reactant: NC1CC1
Product: Cc1cnc(N2CCC(NC3CC3)CC2)nc1

Procedure:
The title compound is prepared from 1-(5-methyl-pyrimidin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 7. LC (method 1): tR=0.55 min; Mass spectrum (ESI+): m/z=233 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:19]=[CH:18][C:17]3[CH2:16][CH2:15][C:14]4[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]=4[C:12]=3[N:11]=2)[N:3]=1.C[N:27](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClC1N=CC2CCC3C=C(OC)C=CC=3C=2N=1>CN(C=O)C>[NH2:1][C:2]1[C:6]([C:7]([NH2:27])=[O:9])=[CH:5][N:4]([C:10]2[N:19]=[CH:18][C:17]3[CH2:16][CH2:15][C:14]4[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]=4[C:12]=3[N:11]=2)[N:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1ccc2c(c1)CCc1cnc(-n3cc(C(=O)O)c(N)n3)nc1-2
Agent: COc1ccc2c(c1)CCc1cnc(Cl)nc1-2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCc1cnc(-n3cc(C(N)=O)c(N)n3)nc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-amino-1-(8-methoxy-5,6-dihydrobenzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid 1 (0.084 g, 0.25 mmol), HBTU (0.113 g, 0.3 mmol) and DIEA (0.18 mL, 1 mmol) in DMF (1 mL) was added amine 2 (0.3 mmol). Resulting reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, solvent was removed on rotavap and residue was purified by preparative HPLC to give 3-amino-1-(8-methoxy-5,6-dihydrobenzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic amide 3.
Reaction SMILES: [CH2:1]([N:3]([CH2:46][CH3:47])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=[O:5])[CH3:2].N1(C(C2C=CC=CC=2S)=O)CCCC[CH2:50][CH2:49]1>>[N:3]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:14]2[C@H:15]([CH3:45])[C@@H:16]3[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]3[C:18]=2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])=[O:5])[CH2:46][CH2:47][CH2:50][CH2:49][CH2:2][CH2:1]1
Reactant: O=C(c1ccccc1S)N1CCCCCC1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccccc3C(=O)N3CCCCCC3)[C@H](C)[C@H]12
Yield: 95 %

Procedure:
Following a procedure similar to that described in Example 18, but using 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and 2-(1-perhydroazepinylcarbonyl)phenylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 95%. This compound was found to be the same as the compound prepared as described in Example 36 and had the same physicochemical properties.
Reaction SMILES: C(OC([NH:8][C:9]([C:11]1[CH:52]=[CH:51][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:26][C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])[C:21](=[O:49])[C:20]2=[O:50])=[CH:13][CH:12]=1)=[NH:10])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH:25]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:26][C:27]([OH:29])=[O:28])[C:21](=[O:49])[C:20]2=[O:50])=[CH:51][CH:52]=1)(=[NH:8])[NH2:10]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(OCCCN2CCN(C(CC(=O)OC(c3ccccc3)c3ccccc3)c3cccnc3)C(=O)C2=O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(OCCCN2CCN(C(CC(=O)O)c3cccnc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
A mixture of 2.3 g of diphenylmethyl 3-[4-[3-(4-tert-butoxycarbonylamidinophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate, 18.5 ml of anisole and 37 ml of trifluoroacetic acid was stirred at room temperature for 3 hours and then distilled under reduced pressure to remove the solvent. The resulting residue was suspended in a mixed solvent of 15 ml of ethyl acetate and 13 ml of water, followed by adding thereto 0.55 g of sodium hydrogencarbonate, and the resulting mixture was stirred at room temperature for 30 minutes. The aqueous layer was separated, adjusted to pH 3.5 with a saturated aqueous sodium hydrogencarbonate solution, and then concentrated to a volume of about 10 ml under reduced pressure. The resulting concentrate was purified by a reversed phase column chromatography (eluent: 25% aqueous acetonitrile solution) to obtain 0.82 g of 3-[4-[3-(4-amidinophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionic acid as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH2:12][O:13][CH3:14])=[CH:6][C:5]=1[O:15][CH2:16][O:17][CH3:18].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]([O:11][CH2:12][O:13][CH3:14])=[CH:6][C:5]=1[O:15][CH2:16][O:17][CH3:18])=[O:19]
Reactant: OB(O)c1ccccc1
Reactant: COCOc1cc(OCOC)c(C(=O)OC)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COCOc1cc(OCOC)c(-c2ccccc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
A Schlenk tube was charged with 5-bromo-2,4-bis-methoxymethoxy-benzoic acid methyl ester (3) (503 mg, 1.5 mmol), phenylboronic acid (272 mg, 2.3 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (82 mg, 0.2 mmol), K3PO4H2O (4.70 g, 34.0 mmol). The reaction tube was evacuated and backfilled with N2 (×3). Toluene (10 mL, anhydrous and sure seal bottle from Aldrich) was added. The reaction was stirred at room temperature for 10 min and heated at 105° C. (preheated oil bath) for 24 h. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (50 mL) and water (70 mL). The aqueous phase was extracted with EtOAc (40 mL×3) and the combined organic layers were washed with water and brine and dried over MgSO4. The purification of the concentrated crude product by column chromatography (25% EtOAc in Hexane) afforded the title product as colorless oil (460 mg, 93%).
Reaction SMILES: [C:1]([C:3]1[C:4](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[O:5][C:6]([CH3:16])([CH3:15])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1)#[N:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O>[N:22]([C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:6]([CH3:16])([CH3:15])[O:5][C:4](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[C:3]=2[C:1]#[N:2])=[CH:9][CH:10]=1)=[N+:23]=[N-:24]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a 200-mL round bottom flask with stirbar was added 2-[3-cyano-4-(4-fluoro-phenyl)-5,5-dimethyl-5H-furan-2-ylidene]-malononitrile (0.20 g, 0.716 mmol) and DMSO (8 mL). The mixture was stirred at room temperature, then sodium azide (0.08 g, 1.23 mmol) was added to it and the reaction continued to react at room temperature. After 2 h, the reaction mixture was completely homogeneous. The product mixture was poured into ice-water (300 mL) and stirred 0.5 h. The yellow precipitate was filtered out through suction filtration. The solid was recrystallized from 1-propanol to give the final product as a yellow solid having a UV spectra as set forth in FIG. 25; (0.19 g, 88% yield). IR (neat): 2924, 2228, 2113, 1567, 1533, 1366, 1279, 1188, 1111, 841 cm−1. 1H NMR (400 MHz, DMSO): δ 7.94 (ddd, J=9.2, 2.8, 2.0 Hz, 2H), 7.40 (ddd, J=9.2, 2.8, 2.0 Hz, 2H), 1.78 (s, 6H); 13C NMR (100 MHz, DMSO): δ 177.1, 176.6, 145.0, 130.6, 123.4, 120.3, 112.3, 111.4, 111.3, 101.6, 100.3, 55.2, 24.9. UV-Vis (CH2Cl2): λmax=384 nm, ε=2.9×104 L·mol−1·cm−1.