Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].[CH3:5]OCOC.[CH3:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][CH3:19]>ClCCCl>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:5][Cl:2])=[CH:14][C:13]=1[S:18][CH3:19]
Reactant: COCOC
Reactant: CSc1ccccc1SC
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCCl
Product: CSc1ccc(CCl)cc1SC
Temperature: 25 °C
Yield: 55.3 %

Procedure:
46 g (0.343 mol) of AlCl3 are suspended in 200 ml of 1,2-dichloroethane and, at 0° C., 9.1 g (0.12 mol) of formaldehyde dimethylacetal are added. Then 17.0 g (0.1 mol) of 1,2-bis-(methylthio)benzene are added dropwise and the suspension is heated to room temperature. When the starting material can no longer be detected by GC analysis, the solution is poured into ice/water and the organic phase is separated off and dried over magnesium sulfate. When the solvent has been distilled off, 12.1 g (55%) of 1,2-bis(methylthio)-4-chloromethyl-benzene are obtained in the form of a yellow oil. The 1H-NMR spectrum (CDCl3) of the compound is consistent with the suggested structure: 7.17-7.13, s and d, 3 aromatic H; 4.52, s, 2H; 2.44, s, CH3S and 2.43, s, CH3S.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CN(C)C(=O)N1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN(C)C(=Nc1ccccc1N1CCOCC1)N1CCOCC1

Procedure:
Reaction of 4-dimethylcarbamoylmorpholine (3.8 g) in benzene (25 ml) with 4-(2-aminophenyl)morpholine (3.5 g) in the presence of phosphorus oxychloride (2.1 ml) for 40 hours at 80°-85° C. gave N,N-dimethyl-N'-(2-morpholinophenyl)morpholine-4-carboxamidine (m.p. 126°-128° C.) which was recrystallised from hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: OB(O)c1ccccc1
Product: Brc1ccc2ncc(-c3ccccc3)n2c1

Procedure:
The title compound, off-white solid (0.4 g, 68%), MS (ISP) m/z=273.4 [(M+H)+], mp 77° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available phenylboronic acid (0.29 g, 2.38 mmol).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:20][CH2:21][CH2:22][CH:4]2[NH:3]1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].Br[CH2:33][CH2:34][O:35][CH2:36][CH2:37]Br>CC#N>[N:19]1([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]3[N:5]4[CH2:20][CH2:21][CH2:22][CH:4]4[NH:3][S:2](=[O:1])(=[O:23])[C:7]=3[CH:8]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: BrCCOCCBr
Reactant: Nc1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=S1(=O)NC2CCCN2c2ccc(Oc3cccc(N4CCOCC4)c3)cc21

Procedure:
A mixture of 300 mg (0.90 mmol) of {3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl}amine, 192 mg of Na2CO3 (1.81 mmol), 5 mg of NaI, 126 μl of 2-bromoethyl ether (0.905 mmol) in 6 ml of CH3CN is refluxed overnight. The suspension is filtered; the filtrate is evaporated, taken up in CH2Cl2 and washed with saturated NaCl solution. After evaporation in vacuo, the expected product is purified by chromatography on silica (CH2Cl2/acetone 96/4).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[C:9]([O:11][C:12](=O)C=2C(C)C)=[O:10])=[CH:5][CH:4]=1.CO.O1C[CH2:25][CH2:24][CH2:23]1.C[Si](C=[N+]=[N-])(C)C.CCCCCC.C1(C)C=CC=CC=1.[C:47]([O:50][CH2:51]C)(=[O:49])[CH3:48]>>[OH:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7]/[C:8](=[C:48](\[CH:24]([CH3:25])[CH3:23])/[C:47]([O:50][CH3:51])=[O:49])/[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(C)C1=C(Cc2ccc(CO)cc2)C(=O)OC1=O
Reactant: C1CCOC1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)/C(Cc1ccc(CO)cc1)=C(\C(=O)OC)C(C)C
Yield: 81 %

Procedure:
To a solution of 2-[4-(hydroxymethyl)benzyl]-3-isopropylmaleic anhydride (101 mg, 0.388 mmol) in a mixed solvent of methanol (1.0 mL) and tetrahydrofuran (1.0 mL) was added a 2.0 M trimethylsilyl diazomethane-hexane solution (1.0 mL, 2.0 mmol) with stirring under ice cooling. The reaction mixture was stirred at room temperature for 2 h and directly concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (toluene-ethyl acetate 4:1→3:1) to give 96 mg of dimethyl 2-[4-(hydroxymethyl)benzyl]-3-isopropylmaleate as oil (yield: 81%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[OH:10].C1(C)C=CC=CC=1.C(OCC)(=O)C>CCCCCCC.[O-2].[Mn+2]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=[O:10]
Reactant: COc1cccc(C(O)c2ccc(F)cc2F)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)c2ccc(F)cc2F)c1
Yield: 58.3 %

Procedure:
Combine (2,4-difluoro-phenyl)-(3-methoxy-phenyl)-methanol (Compound 7) (89.2 g, 357 mmol), manganese oxide (96 g, 1.1 mol), and toluene (500 mL) and heat to reflux, under a nitrogen atmosphere for 2 hours. TLC (30% ethyl acetate in heptane) shows that the reaction is complete. Filter reaction mixture through celite® and concentrate. Purify by column chromatography using a graded solvent mixture of 10% dichloromethane in heptane to 50% dichloromethane in heptane to give an oil. Cool overnight to solidify, and triturate with pentane to give the title compound as a white solid (51.7 g, 58% Yield). NMR is consistent with the final, desired compound. mp=50° C.-52° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.Cl.O[C:17]1[C:26]2C(=NC=C(I)C=2)N(C)C(=O)[C:18]=1[C:30]([O:32]C)=[O:31].C(O)(C(F)(F)F)=[O:35]>>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:26](=[O:35])[CH2:17][CH2:18][C:30]([OH:32])=[O:31]
Reactant: Cn1c(=O)cc(O)c2cc(I)cnc21
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1c(O)c2cc(I)cnc2n(C)c1=O
Agent: Cl
Product: Cn1c(=O)c(C(=O)CCC(=O)O)c(O)c2cc(I)cnc21
Temperature: 80 °C
Yield: 96 %

Procedure:
4-Hydroxy-6-iodo-1-methyl-1,8-naphthyridin-2(1H)-one. Concentrated aqueous HCl (10 mL) was added to a solution of methyl 4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (Method 2) (1.00 g, 2.78 mmol) in TFA (10 mL). The mixture was heated at 80° C. for 18 hours. The solvent was removed, and the residue rinsed with water and diethyl ether. The product was dried in a vacuum oven at 50° C. to afford the title compound in 96% yield. 1H-NMR (300 MHz, DMSO-d6) δ ppm 11.84 (1H, s), 8.82 (1H, d, J=2.3 Hz), 8.43 (1H, d, J=2.3 Hz), 5.89 (1H, s), 3.39 (3H, s). MS m/z: 303 (M+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:3]=12.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([N:25]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=4[NH:5][CH:6]=3)=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2c(c1Cl)CCCCCC2
Reactant: NNc1ccccc1
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccccc1)CCCCCC3

Procedure:
Reaction of ethyl 5,6,7,8,9,10-hexahydro-4-chlorocycloocta[b]pyridine-3-carboxylate with phenylhydrazine according to the procedure analogous to that described in example 1 yields 2,3,6,7,8,9,10,11-octahydro-2-phenylcylcoocta[b]pyrazolo[3,4-d]pyridin-3(5H)-one, m.p. 310°-312°.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[C:29](#[N:32])[CH:30]=[CH2:31]>C(O)(C)C>[C:29]([CH2:30][CH2:31][N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17]1)#[N:32]
Reactant: C=CC#N
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Product: N#CCCN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 95 °C

Procedure:
A solution of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (15 g, 0.049 mole) and acrylonitrile (5.2 g, 0.098 mole) in isopropanol (50 ml) was stirred at reflux (95° C.) for twenty hours. The reaction mixture was cooled then concentrated to an oil (17 g, 96%) of which 3.5 g was distilled to an oil of 3-(2-cyanoethyl)-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzezepine (2.6 g, 235°-237° C./0.1 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1>>[CH3:25][C:21]1[CH:20]=[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:24]=[CH:23][N:22]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Cc1cc(CCl)ccn1
Agent: Cl
Product: Cc1cc(Cn2cc(C#Cc3ccnc(Cl)c3)nc2C)ccn1

Procedure:
The title compound, MS: m/e=323.3 (M+H30), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-chloromethyl-2-methyl-pyridine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([Cl:27])[C:20]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[O:28]1[CH2:31][C:30](=O)[CH2:29]1.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1>C1COCC1>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([Cl:27])[C:20]=2[N:21]2[CH2:26][CH2:25][N:24]([CH:30]3[CH2:31][O:28][CH2:29]3)[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(Cl)c1N1CCNCC1
Reactant: O=C1COC1
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: C1CCOC1
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(Cl)c1N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-amino-N-(5-chloro-4-(piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide (51 mg, 0.13 mmol) (synthesized according to a procedure similar to Example 2) in THF (4 mL) was added oxetan-3-one (14.31 mg, 11.63 μL, 0.1986 mmol) and triacetoxyborohydride (Sodium Ion (1)) (56.12 mg, 0.2648 mmol), and the mixture was stirred at rt for 4 h. The reaction mixture was partitioned between an aqueous saturated solution of NaHCO3 and ethyl acetate. The organic extract was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by fractionlynx to yield 2-amino-N-(5-chloro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 447.2.
Reaction SMILES: C(N1C2[C:7](=[CH:8]C=CC=2)[C:6](=O)[C:5]1=O)CC.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCCCC>>[CH2:5]([N:21]1[C:22]2[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][CH:23]=2)[C:19](=[O:26])[C:20]1=[O:25])[CH2:6][CH2:7][CH3:8]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: CCCCBr
Product: CCCCN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-propylindoline-2,3-dione from commercially available 5-chloro isatin (purchased from Fisher Scientific) and commercially available 1-bromo butane (purchased from Fisher Scientific). 1H NMR δ 7.57 (m, 2H), 6.87 (d, 1H), 3.72 (t, 2H), 1.69 (m, 2H), 1.43 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.O[C@@H]1CCNC1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:30]3[CH2:31][CH2:32][CH:28]([OH:27])[CH2:29]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: OC1CCNC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: O[C@@H]1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(O)C3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with (R)-3-hydroxypyrrolidine. A yellow solid 94 was obtained (0.0385 g, 87%). 1H-NMR (CDCl3, 400 MHz) δ 2.13–2.31 (m, 2H), 3.83 (s, 3H), 3.88–3.95 (m, 4H), 4.74 (m, 1H), 6.79 (s, 1H), 6.92 (d, J=6.6 Hz, 1H), 7.01–7.07 (m, 3H), 7.45–7.53 (m, 3H), 7.86 (s, 1H), 8.14 (d, J=7.0 Hz, 1H); MS (APCI) m/z 447 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][CH2:10][CH2:11][OH:12].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([S:22](Cl)(=[O:24])=[O:23])=[C:17]([CH3:26])[CH:16]=1>>[OH:12][CH2:11][CH2:10][N:9]([CH3:8])[S:22]([C:18]1[C:19]([CH3:21])=[CH:20][C:15]([O:14][CH3:13])=[CH:16][C:17]=1[CH3:26])(=[O:24])=[O:23]
Reactant: CNCCO
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N(C)CCO)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (213 ml, 1,512.5 mmol) was added to a solution of 2-(methylamino)ethanol (53.5 ml, 665.5 mmol) in MC (1,250 ml) and the mixture was cooled to 0° C. A solution of 4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (142 g, 605 mmol) [see AC5, Stage 1] in MC (750 ml) was then slowly added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was then washed with aqueous 0.5 M HCl (800 ml) and water (2×1,000 ml). The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. Purification was carried out by chromatography on silica gel (heptane/ethyl acetate 1:1). The yield was 116.3 g (70%).
Reaction SMILES: [Br:1][C:2]1[O:19][CH:5]2[CH2:6][N:7](CC3C=CC(OC)=CC=3)[C:8](=[O:9])[CH:4]2[CH:3]=1>C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[O:19][CH:5]2[CH2:6][NH:7][C:8](=[O:9])[CH:4]2[CH:3]=1
Reactant: COc1ccc(CN2CC3OC(Br)=CC3C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC2OC(Br)=CC12
Yield: 77.8 %

Procedure:
A solution of 2-bromo-5-(4-methoxy-benzyl)-3a,5,6,6a-tetrahydro-furo[2,3-c]pyrrol-4-one (0.16 g, 0.498 mmol) in TFA (1.8 mL) and anisole (0.2 mL) is stirred at 80° C. for 2.5 hours. The reaction mixture is then diluted with ethyl acetate and neutralised with sat. NaHCO3. The aqueous layer is extracted with ethyl acetate (3×) and the combined organic layers are dried over MgSO4, filtered and concentrated in vacuo. The crude compound is purified by silica gel column chromatography eluting with 1:1 petroleum ether:ethyl acetate followed by 1:4 petroleum ether:ethyl acetate, to afford the title compound (79 mg, 78%).
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH3:37])[CH:32]([NH:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])[C:31]2=[O:47])=[O:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>CN(C)C=O>[CH:13]([O:26][C:27]([C:29]1[N:30]2[CH:33]([S:34][CH2:35][C:36]=1[CH:37]=[CH:6][N:7]([CH3:9])[CH3:8])[CH:32]([NH:38][P:39]([O:41][CH2:42][CH3:43])([O:44][CH2:45][CH3:46])=[O:40])[C:31]2=[O:47])=[O:28])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCOP(=O)(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)CSC12)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CN(C)C)CSC12)OCC
Reaction time: 0.2 h

Procedure:
t-Butoxy-bis-dimethylaminomethane (6 cc) is added to a solution of 2-benzhydryloxycarbonyl-7-diethoxyphosphorylamino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (10 g) in dry N,N-dimethylformamide (100 cc) at 80° C. After 12 minutes at 80° C., the reaction mixture is poured into ethyl acetate (400 cc) and washed with distilled water (5×250 cc). After drying over magnesium sulphate and evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C., 2-benzhydryloxycarbonyl-3-(2-dimethylaminovinyl)-7-diethoxyphosphorylamino-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene (E isomer) (10.5 g) is obtained in the form of an orange crystalline solid. This product is purified by crystallisation from ethyl acetate (30 cc), and 2-benzhydryloxycarbonyl-3-(2-dimethylaminovinyl)-7-diethoxyphosphorylamino-8-oxo-5 -thia-1-azabicyclo [4.2.0]oct-2-ene (E isomer) (5.3 g) is obtained in the form of a yellow crystalline powder (m.p.=193°-194° C.).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH3:5][O:6][C:7]1[CH:28]=[CH:27][C:10]([C:11](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:3][CH2:2][CH2:1][OH:4])=[CH:17][CH:16]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OCCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(OCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
Ethylene glycol (0.92 g, 14.8 mmol) (Wako Pure Chemical Industries, Ltd.), 4,4′-dimethoxytrityl chloride (1.00 g, 2.95 mmol) (Wako Pure Chemical Industries, Ltd.), and triethylamine (0.89 g, 8.81 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in methylene chloride (25 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was stirred at room temperature overnight. Water (50 mL) was added to reaction solution, and mixture was extracted with methylene chloride (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.51 g, 47% yield).
Reaction SMILES: O[C:2]1([C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9].[Br:21]Br.[C:23]([O:26]C(=O)C)(=O)[CH3:24]>C(O)(=O)C>[C:23]([O:20][C:11]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:2]2([Br:21])[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7]2)[C:8](=[O:10])[O:9]1)(=[O:26])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)C2(O)CCCCC2C(=O)O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(C2(OC(C)=O)OC(=O)C3CCCCC32Br)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
40 g (0.153 mol) of 2-hydroxy-2-(4-methoxy-benzoyl)-cyclohexanecarboxylic acid (=compound of example 6) are dissolved in 125 ml of acetic anhydride. 24.37 g (0.153 mol) of bromine in 24 ml of acetic acid are added slowly to this solution over 1 hour 40 minutes while keeping the temperature at 20° C. After addition of ⅓-½ equivalent of the bromine solution, a yellowish suspension is formed. The reaction mixture is stirred for 30 minutes at 20° C., followed by 1 hour at 0° C. in order to achieve complete precipitation of the product. The yellowish solid is filtered and washed with acetic acid anhydride to give 51 g (88%) 7a-bromo-1-(4-methoxy-phenyl)-3-oxo-octahydro-isobenzo-furan-1-yl acetate as a yellowish-white solid that is dried in vacuum at 40° C. and used for the next step without further purification.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:16]([Br:17])=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:21])[N:12]3[C:18](=[O:20])[CH3:19])=[C:4]([F:24])[CH:3]=1.C(O)(=O)C.N([O-])=O.[Na+].S(=O)(O)[O-].[Na+]>C(O)C>[Br:17][C:16]1[C:7]([O:6][C:5]2[CH:22]=[CH:23][CH:2]=[CH:3][C:4]=2[F:24])=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:18](=[O:20])[CH3:19])[C@@H:11]([CH3:21])[CH2:10][CH2:9]2
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ccc(N)cc3F)c2CC[C@@H]1C
Agent: O=N[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)N1c2ccc(Br)c(Oc3ccccc3F)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A 100-mL round-bottom flask was charged with 1-[(2S)-5-(4-amino-2-fluorophenoxy)-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (370 mg, 0.92 mmol) and acetic acid (5 mL). Sodium nitrite (1.3 g, 18.8 mmol) was added in portions, and the mixture stirred at room temperature for 30 minutes. Sodium bisulfite (2.0 g, 18.8 mmol) and ethanol (5 mL) were added, and the resulting mixture stirred for 12 h at room temperature. The reaction mixture was concentrated under vacuum, diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (eluting with 5:1, ethyl acetate/petroleum ether) to afford 1-[(2S)-6-bromo-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (300 mg, 86%) of as yellow oil. MS (ESI, pos. ion) m/z 378, 380 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][NH:20][NH2:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[NH2:10][C:6]1[NH:21][N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C=C(N)OCC
Product: Nc1cc(=O)n(Cc2ccc([N+](=O)[O-])cc2)[nH]1

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 16.7 g of 4-nitrobenzylhydrazine, analogously to the procedure described in Example 1 yield 17.3 g of the compound identified above as yellowish crystals of melting point 182°, corresponding to 74% of theory.