Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:16]([F:17])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:17][C@@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](NC(=O)OCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CNC[C@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of tert-butyl (3R,4R)-3-{[(benzyloxy)carbonyl]amino}-4-fluoropyrrolidine-1-carboxylate (380 mg, 1.2 mmol) in DCM (20 mL) was added TFA (0.34 mL, 3.4 mmol, 3 mol eq). The resulting reaction was stirred at ambient temperature for 2 hr. More TFA (0.34 mL, 3.4 mmol, 3 mol eq) was added and stirring at ambient temperature continued for another 2 hr. The volatiles were removed to give a colorless residue. DCM (30 mL) and aqueous K2CO3 (1 M, 5 mL) were added. The organic layer was separated, extracted with more DCM (30 mL), dried over Na2SO4 and evaporated to give the title compound as a colorless gum (246 mg, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.29-7.43 (m, 5 H) 4.80-5.21 (m, 4 H) 4.07-4.28 (m, 1 H) 3.46 (br. s., 1 H) 2.96-3.30 (m, 2 H) 2.74 (br. s., 1 H). 19F NMR (376 MHz, chloroform-d) δ ppm −72.38 (s, 1F). m/z (APCI+) for C12H15FN2O2 239.2 (M+H)+. Chiral purity was determined as below (using the racemic sample to compare):
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][O:4][C:5](=[O:12])[NH:6][C:7]1[S:11][N:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37].CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C)C=O.O>[S:11]1[C:7]([N:6]([C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:13])[Cl:14])=[O:12])[C@H:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:8][CH:9]=[N:10]1
Reactant: COC(=O)C(O)CC(C)C
Reactant: O=C(Nc1ccns1)OCC(Cl)(Cl)Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1ccns1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
A solution of 2,2,2-trichloroethylisothiazol-5-ylcarbamate (253 mg, 0.918 mmol), triphenylphosphine (266 mg, 1.01 mmol) and methyl 2-hydroxy-4-methylpentanoate (151 mg, 1.03 mmol) in N,N-dimethylformamide (2.0 mL) at 0° C. was treated dropwise with diisopropylazodicarboxylate (200 μL, 1.02 mmol) and stirred at rt for 5 h. The mixture was then poured into water and extracted with a 1:1 mixture of ether and ethyl acetate (3×). The combined organics were washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated. Flash chromatography of the residue on silica gel eluting with a mixture of ethyl acetate and, hexanes (1:3) gave 260 mg of methyl N-isothiazol-5-yl-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate as a faint-yellow oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:19]4[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Reactant: Cc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)cc1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-methylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 78% overall yield. FDMS m/e=364 (M+ of free base). α[D]589 =-11.77 (c=0.34, methanol).
Reaction SMILES: N[C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[FH:17].N([O-])=O.[Na+]>>[Cl:8][C:6]1[CH:7]=[C:2]([F:17])[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=1
Reactant: Nc1cc(Cl)cnc1Oc1ccc(O)cc1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Product: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
122.5 g (0.518 mole) of 4-(3-amino-5-chloropyridin-2-yloxy)phenol are introduced at -8° to 0° C. into a vessel charged with 400 g (20 moles) of hydrogen fluoride. Then 37.3 g (0.540 mole) of sodium nitrite are added in portions over one hour. The mixture is stirred for 2 hours at 0° C. and slowly heated to 55° C. in an autoclave. Excess hydrogen fluoride is removed by distillation and the residue is taken up in 200 ml of methylene chloride and the solution is neutralised with ice-water and ammonia, the organic phase is dried and concentrated by evaporation, affording 112 g of 4-(5-chloro-3-fluoropyridin-2-yloxy)phenol with a melting point of 97°-98° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].Cl[C:13]([O-])=O.[C:16]([O:19][C:20]([O-])=O)([O-])=[O:17]>>[OH:5][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][NH:1][C:16]([O:19][CH2:20][CH3:13])=[O:17]
Reactant: NCCC(O)c1ccccc1
Reactant: O=C([O-])OC(=O)[O-]
Reactant: O=C([O-])Cl
Product: CCOC(=O)NCCC(O)c1ccccc1

Procedure:
reacting said α-(2-aminoethyl)benzenemethanol with a chloroformate or dicarbonate to form an N-(3-hydroxy-3-phenylpropyl)urethane;
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][NH:12][CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22](Br)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][N:12]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: BrCCc1ccccc1
Reactant: COc1cccc(C2=CCCNC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cccc(C2=CCCN(CCc3ccccc3)C2)c1

Procedure:
A mixture of 5 g of 3-(3-methoxyphenyl)-1,2,5,6-tetrahydropyridine hydrochloride, 100 ml of acetone, 7 g of sodium carbonate and 3.5 ml of phenethyl bromide was refluxed for 16 hours and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. The elution with a 7-3 cyclohexane-ethyl acetate mixture yielded 6.2 g of 3-(3-methoxyphenyl)-1-phenethyl-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]3[O:12][CH2:13][CH2:14][O:15][C:10]=3[CH:9]=2)[O:5][C:4](=[O:18])[CH:3]=1.[CH:19](=O)[CH2:20][CH:21]([CH3:23])[CH3:22].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N1CCCCC1>C(O)(=O)C.C(O)C>[CH2:25]([S:32][CH:19]([C:3]1[C:4](=[O:18])[O:5][C:6]([C:8]2[CH:17]=[CH:16][C:11]3[O:12][CH2:13][CH2:14][O:15][C:10]=3[CH:9]=2)=[CH:7][C:2]=1[OH:1])[CH2:20][CH:21]([CH3:23])[CH3:22])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)CC=O
Reactant: SCc1ccccc1
Reactant: O=c1cc(O)cc(-c2ccc3c(c2)OCCO3)o1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)CC(SCc1ccccc1)c1c(O)cc(-c2ccc3c(c2)OCCO3)oc1=O

Procedure:
The title compound was prepared by Method C using 4-hydroxy-6-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2H-pyran-2-one (1.00 g, 4.06 mmol), ethanol (15 mL), isovaleraldehyde (0.35 g, 4.06 mmol), benzylmercaptan (1.0 g, 8.12 mmol), piperidine (0.5 mL), acetic acid (0.5 mL). 1H NMR (400 MHz, DMSO-d6) δ0.78 (t, 6H), 1.36 (m, 1H), 1.5 (m, 1H), 2.06 (m, 1H), 4.2 (m, 1H), 4.31 (brm, 6H), 6.56 (s, 1H), 7.03 (d, 2H), 7.36-7.25 (m, 6H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[O:40][CH2:39][CH2:38][O:37]4)=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.[ClH:42]>CO.O1CCOCC1>[ClH:42].[O:37]1[CH2:38][CH2:39][O:40][CH:36]1[CH2:35][C:32]1[CH:31]=[CH:30][C:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][O:21][C:17]3[CH:16]=[C:15]([CH:8]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH2:7])[CH:20]=[CH:19][CH:18]=3)[CH:24]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2cccc(-c3ccc(CC4OCCO4)cc3)c2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(c1ccccc1)c1cccc(OCc2cccc(-c3ccc(CC4OCCO4)cc3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl((3-((4′-((1,3-dioxolan-2-yl)methyl)-[1,1′-biphenyl]-3-yl)methoxy)phenyl)(phenyl)methyl)carbamate (1.44 g, 2.6 mmol) in methanol (6.5 mL), was added hydrogen chloride in dioxan (6.5 mL). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated to afford a mixture of the title compound and the corresponding dimethyl acetal. The material was used in the next step without further purification.
Reaction SMILES: [I:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:37]1([P:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[I-:1].[C:13]1([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:11][C:9]([C:8]2[N:7]3[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[C@H:6]3[S:5][CH2:4][C:3]=2[CH2:2][P+:43]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:10])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Product: [I-]
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A solution of diphenylmethyl 3-iodomethyl-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (30 g.,) Rf 0.6 in ethyl acetate (500 ml.) was stirred in the dark at room temperature and treated, over 45 minutes, with a solution of triphenylphosphine (24.9 g., ca. 2 equivs.) in ethyl acetate (150 ml.). The mixture was stirred for a further 60 minutes at 0°, and the precipitated solid collected by filtration. The solid was washed with ethyl acetate and dried in vacuo to give the phosphonium iodide (31.7 g., 74.5%), Rf 0.0, m.p. 142°-146° (decomp.), [α]D + 10° (tetrahydrofuran), λmax 269 nm (ε 9,400) and 276 nm (ε 8,600) νmax (CHBr3) 3350 (NH), 1780 (β-lactam), 1710 (CO2R), 1680 and 1505 (CONH), and 1445 (P-C(aryl)) cm-1, τ (CDCl 3) 4.39 (C(7) -H,dd,J4.5 and 9 Hz), 5.19 (C(6) --H, d, J 4.5 Hz) 4.75 and 4.85 (CH2 -P, four major signals of two AB-q JP-H 16 Hz), 6.05 and 6.68 (C(2) -- CH2 two dd, JH--H 18 Hz, JP-H 3-4 Hz). [Found: C, 59.3; H, 4.5; I, 13.4; N, 2.6; P, 3.4; S, 7.3. C45H38IN2O4PS2 (892.8) requires C, 60.5; H, 4.3; I, 14.2; N, 3.1; P, 3.5; S, 7.2%].
Reaction SMILES: [CH3:1][Sn:2]([CH3:15])([CH3:14])[C:3]1[CH:12]=[N:11][C:10]2[NH:9][C:8](=[O:13])[CH2:7][O:6][C:5]=2[CH:4]=1.[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:19].S(O)(O)(=O)=O.COS(OC)(=O)=O>C1COCC1>[CH3:19][N:9]1[C:8](=[O:13])[CH2:7][O:6][C:5]2[CH:4]=[C:3]([Sn:2]([CH3:15])([CH3:14])[CH3:1])[CH:12]=[N:11][C:10]1=2
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: C[Sn](C)(C)c1cnc2c(c1)OCC(=O)N2
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: CN1C(=O)COc2cc([Sn](C)(C)C)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 680 mg of 7-trimethylstannyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (0.0022 mole) in 10 ml of THF is added 2.4 ml of LiN(TMS)2 (0.0024 mole) in THF. The homogenous solution is maintained under nitrogen at room temperature for 20 min , 300 mg (0.0024 mole) of dimethylsulfate sulfate is added and the reaction mixture allowed to stir overnight. The reaction mixture is then quenched with 10 ml of sat. ammonium chloride and extracted with 3×50 ml ethyl acetate. The ethyl acetate is then washed with 3×10 ml sat. ammonium chloride, dried over sodium sulfate and concentrated to obtain off white product whish is used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:10]1[CH2:11][C:12]2=[O:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:19]1([CH:18]2[CH:11]3[C:12](=[O:17])[CH:13]4[CH2:15][CH2:16][CH:10]3[CH:9]([CH2:14]4)[NH:8]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC1CC2CCC1CC2=O
Reactant: O=Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C2CCC3C(C2)NC(c2ccccc2)C13
Yield: 90.8 %

Procedure:
A three neck 3 L flask, fitted with a well isolated soxhlet (300 mL) filled with molecular sieves (3 Å), was charged with 5-amino-bicyclo[2.2.2]octan-2-one trifluoro-acetic acid salt (Preparation 76, 85.0 g, 336 mmol, 1.0 eq), benzaldehyde (37.5 mL, 369 mmol, 1.1 eq) and DCM (1.25 L). The suspension was heated to reflux. The clear reaction mixture was concentrated to a tan solid. The latter was suspended in a mixture of diethyl ether (600 mL) and EtOH (50 mL). The solids were collected by filtration (P3) and thoroughly washed with ethyl acetate and diethyl ether. The filter cake was dried in vacuo to yield title compound as an off-white solid (104 g, 305 mmol, 91%, 97.3% pure (HPLC)).
Reaction SMILES: [CH2:1]([C:3](=[CH:8][CH3:9])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:2].[C:10](OC(=O)C)(=[O:12])[CH3:11]>ClCCl>[C:10]([NH:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC=C(C=CCN)CC
Solvent: ClCCl
Product: CC=C(C=CCNC(C)=O)CC
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A mixture of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide (500 mg), hydrazine monohydrate (147 mg), and ethanol (5 ml) was refluxed for 40 minutes under nitrogen atmosphere. After cooling, the precipitate was filtered and washed with ethanol. Evaporation of the filtrate gave a crystalline residue which was dissolved in 1N sodium hydroxide solution and extracted with dichloromethane. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to give 4-ethyl-2,4-hexadien-1-ylamine (205 mg) as an oil. This oil was used in the next reaction without further purification. To a solution of crude 4-ethyl-2,4-hexadien-1-ylamine (205 mg) in dichloromethane (2 ml) at 0° C. was added dropwise acetic anhydride (335 mg). After one hour, the reaction mixture was evaporated to dryness. The residue was chromatographed on silica gel (2% methanol in dichloromethane) to give 1-acetylamino-4-ethyl-2,4-hexadiene (122 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9](=O)[C:8]2[CH:7]=[C:6](/[CH:13]=[CH:14]/[C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:27]C1(C)CCC(=O)C2C=C(/C=C/C3C=CC(C(O)=O)=CC=3)C=CC1=2.[CH2:51]([SH:55])[CH2:52][CH2:53][SH:54]>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][CH:9]([CH:27]2[S:55][CH2:51][CH2:52][CH2:53][S:54]2)[C:8]2[CH:7]=[C:6](/[CH:13]=[CH:14]/[C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: SCCCS
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: CC1(C)CCC(=O)c2cc(/C=C/c3ccc(C(=O)O)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(C2SCCCS2)CCC3(C)C)cc1
Reaction time: 4 h

Procedure:
To a cold solution (0 ° C.) of 140 mg (0.40 mmol) of ethyl (E)4-[2-(5,5-dimethyl-5,6,-dihydro-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate (Compound A2), in 6.0 mL of methylene chloride was added dropwise 130 mg (0.12 mL, 1.2 mmol) of 1,3-propanedithiol and 0.17g (0.15 mL, 102 mmol) of borontrifluoride diethyl etherate. The reaction stirred between 0 ° C. and room temperature for 4 h. The mixture was diluted with aqueous sat. potassium carbonate, and extracted with ether (2x). The organic phase was washed with brine, dried over MgSO4 and then concentrated in vacuo. The crude product was purified by flash chromatography (silica, 10 % ethyl acetate in hexane) to afford the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1.[C:13](OC(=O)C)(=O)[CH3:14]>>[CH3:13][C:14]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N:12]=1
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc2nc(C)oc(=O)c2c1
Yield: 77 %

Procedure:
A solution of 5-methoxyanthranilic acid (7.8 g, 46.5 mmol) was refluxed in acetic anhydride (60 mL) for 2 h 15 before being cooled and concentrated under reduced pressure. The crude residue was then concentrated twice in the presence of toluene before being filtered and washed with ether to yield to the title compound (6.8 g, 77% yield) as a beige solid; LC/MS: m/z 192 [M+H]+, Rt 1.69 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5](=[O:18])[CH2:6][CH:7]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH2:9].C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:19])[C:4](=[N+:29]=[N-:30])[C:5](=[O:18])[CH2:6][CH:7]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:8]=[CH2:9]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=CC(CC(=O)CC(=O)OC)OCc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(CC(=O)C(=[N+]=[N-])C(=O)OC)OCc1ccccc1
Yield: 98.6 %

Procedure:
In accordance with the process of Example 2, 5-benzyloxy-3-oxo-6-heptenoic acid methyl ester (1.07 g; 4.1 m mol), p-toluenesulfonyl azide (810 mg; 4.1 m mol) and triethylamine (450 mg; 4.5 m mol) were used as starting materials to obtain 1.16 g of 5-benzyloxy-2-diazo-3-oxo-6-heptenoic acid methyl ester as yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:20]5[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=5)[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Yield: 4.3 %

Procedure:
A solution of 1.00 g (3.88 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.47 g (3.88 mmol) of p-fluorobenzonitrile, 0.54 g (3.88 mmol) of K2CO3 and 8 ml of dimethylsulfoxide are stirred at 80° C. for 3 days. The reaction mixture is allowed to cool and is diluted with water producing a brown precipitate which is collected by filtration and dried. The crude product is purified by flash column chromatography (5% methanol in chloroform) to yield 0.06 g (4%) of the title compound as a pink solid: m.p.>275° C.; m/e 358.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[C:26](Cl)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[C:32]([F:33])([F:34])[F:35])[C:26]([NH:21][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:27]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)c(F)c2)ccc1OCCN1CCCC1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 3-(1-methyl-1H-pyrazol-5-yl)-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (0.029 g, 0.10 mmol) in CH2Cl2 (1.5 mL) was added 3-fluoro-4-(trifluoromethyl)benzoyl chloride (0.018 mL, 0.12 mmol) and triethylamine (0.018 mL, 0.13 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.042 g, 88%). LCMS m/z (%)=477 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 10.55 (s, 1H), 8.07-7.95 (m, 3H), 7.88 (dd, J=2.6, 9.0 Hz, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 6.31 (d, J=1.8 Hz, 1H), 4.33-4.29 (m, 2H), 3.69 (s, 3H), 3.58-3.52 (m, 2H), 3.35-3.25 (m, 2H), 2.92-2.81 (m, 2H), 1.95-1.85 (m, 2H), 1.80-1.69 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:27][CH2:28][C:29](O)=[O:30])[C:10]=2[CH:9]=1.[C:32](Cl)(=O)C(Cl)=O.[NH2:38][CH2:39][CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:32])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:27][CH2:28][C:29]([NH:38][CH2:39][CH2:40][C:41]3[NH:45][CH:44]=[N:43][CH:42]=3)=[O:30])[C:10]=2[CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Reactant: NCCc1c[nH]cn1
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(=O)NCCc1cnc[nH]1)C(=O)NC3=O
Yield: 81 %

Procedure:
Reaction of acid (117) prepared as described in example 230 with oxalyl chloride followed by histamine using the procedure described in example 207 gave the amide (128) (81%) as a yellow powder, mp 144–149° C. (dec). 1H NMR δ [(CD3)2SO] 11.12 (br, 1H), 8.52 (d, J=2.6 Hz, 1H), 7.91 (t, J=5.5 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.58 (m, 1H), 7.52–7.42 (m, 4H), 7.32 (dd, J=9.0, 2.6 Hz, 1H), 6.56 (s, 1H), 4.69 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.12 (m, 2H), 2.58 (t, J=6.4 Hz, 2H), 2.39 (t, J=7.4 Hz, 2H). Found: C, 60.73; H, 4.49; N, 11.49. C29H24ClN5O4. 1/2CH2Cl2 requires C, 60.62; H, 4.31; N, 11.98.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]1([CH2:11][C:12](OCC)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.NCC(N)(C)C>C(OCC)(=O)C>[C:5]1([CH2:11][C:12]([NH:3][CH2:2][CH2:1][NH2:4])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: NCCN
Agent: CC(C)(N)CN
Solvent: CCOC(C)=O
Product: NCCNC(=O)Cc1ccccc1

Procedure:
The procedure of Example IX was repeated in all essential details to produce the above compound, except that equivalent amounts of ethylenediamine and ethyl phenylacetate were substituted for 1,2-diamino-2-methylpropane and ethyl acetate, respectively. The product, which was identified by NMR and IR spectroscopy, had a melting point of 37°-38° C.