Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.O[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][N:26]3[CH:33]=2)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]2[N:26]([CH:33]=[C:23]([C:20]3[CH:19]=[CH:18][C:17]([O:14][CH2:13][CH2:12][CH2:11][O:10][S:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=4)(=[O:8])=[O:9])=[CH:22][CH:21]=3)[N:24]=2)[CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCO)cc1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)cn2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(OCCCOS(=O)(=O)c4ccc(C)cc4)cc3)cn2c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 45.1 %

Procedure:
To a solution of 554 mg (corresponding to 2.40 mmol) of 1,3-propanediol mono-p-toluenesulfonate in 10 mL of tetrahydrofuran, 260 mg (corresponding to 1.08 mmol) of 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine and 636 mg (corresponding to 2.42 mmol) of triphenylphosphine were added. Further, 5 mL of N,N-dimethylformamide was added thereto to completely dissolve the contents. To the reaction mixture, 0.48 mL (corresponding to 2.42 mmol) of diisopropylazodicarboxylate was added. After the resulting mixture was stirred at room temperature for 23 hours, the reaction solution was concentrated. The resulting crude product was purified by flash silica gel column chromatography (elution solvent: chloroform/ethyl acetate=19/1), further purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name: manufactured by Japan Analytical Industry Co., Ltd.); column: two of JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), and further purified again by flash silica gel column chromatography (elution solvent: hexane/ethyl acetate=35/65) to obtain 220 mg (corresponding to 0.487 mmol) of 6-methoxy-2-[4′-(3″-p-toluenesulfonyloxypropoxy)phenyl]imidazo[1,2-a]pyridine (FIG. 1, Step 7).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:12].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22].Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([NH:12][C:21]([O:23][CH3:24])=[O:22])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)Cl
Reactant: Nc1c(C(=O)O)ccc(Cl)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Nc1c(C(=O)O)ccc(Cl)c1Cl
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
3,4-Dichloroanthranilic acid (61.8 g) was stirred in THF at -15° C., and triethylamine was added. Methyl chloroformate (36.9 g) was then added at -15° C. and the mixture stirred for 45 minutes. Water was then added, followed by concentrated hydrochloric acid solution until pH 1 was achieved, and the solution was stirred overnight. Excess water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (anhydrous magnesium sulphate) and the solvent evaporated. The resulting solid was recrystallized from a solution of toluene and cyclohexane to give 3,4-dichloro-2-(methoxycarbonylamino)benzoic acid (65.1 g) as a fawn solid, m.p. 155-156° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14]C(C)(C)C)=O)[CH2:4]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>CO>[CH2:19]([NH:23][C:12](=[O:14])[CH2:11][C@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:8][C:7]([CH3:9])([CH3:10])[O:6]1)[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reactant: CCCCN
Solvent: CO
Product: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 65 °C

Procedure:
Mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (50 grams), methanol (300 ml) and n-butyl amine (200 ml) was heated to 60-70° C. under nitrogen pressure and stirred. After the completion of the reaction, distilled off the reaction mixture completely followed by co-distillation with methylene chloride at below 55° C. Methylene chloride (500 ml) was added to the obtained residue at 25-30° C. and stirred for 15 minutes. The unwanted solid was filtered off and the filtrate was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[CH:28][CH:27]=1)[C:20](=O)[CH:21]([CH3:23])[CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)=[CH:28][CH:27]=1)=[C:20]([CH:21]([CH3:23])[CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)C(C)C
Reactant: COC(=O)COc1ccc(F)c(N)c1
Product: COC(=O)COc1ccc(F)c2[nH]c(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(=O)c12

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-fluorophenoxy)acetic acid methyl ester and 4-methyl-3-oxo-2-(4-pyrazol-1-ylbenzyl)pentanoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[C@@H:19]([CH3:21])[NH2:20])=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:21][C@H:19]1[NH:20][C:31](=[O:33])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:12][CH:13]=2)[C:18]1=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(C)c(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C)c(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-(4-{[2-methyl-5-(methyloxy)phenyl]oxy}phenyl)-D-alaninamide (Intermediate 16, 118 mg) was dissolved in dry dichloromethane (18 mL). The reaction mixture was cooled down in an ice bath. Triethylamine 0.327 mL, 2.350 mmol) was added. Then a solution of triphosgene in dry dichloromethane (46.5 mg, 0.157 mmol) dissolved in 7 mL of dichloromethane was added. The reaction was stirred at 0° C. for 10 min under argon. A saturated aqueous solution of NaHCO3 was added (18 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×15 mL). After drying over sodium sulphate, the solvents were removed under vacuum. The residue was purified by silica gel chromatography (Companion system, 12 g cartridge) eluting with a gradient cHex/EOAc from to 100/0 to 60/40 during 20 min and 60/40 during 30 min. This afforded the title compound (91 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Br)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:13]1[C:25]2[NH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1.C1O[CH2:42][CH2:41]OCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1Cl>[CH:22]1[C:23]2[N:24]([C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([N:24]4[C:42]5[CH:41]=[CH:14][CH:15]=[CH:16][C:17]=5[C:18]5[C:23]4=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:11]=3)[C:5]([O:7][CH3:8])=[O:6])[C:25]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(Br)nc(Br)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc(-n2c3ccccc3c3ccccc32)nc(-n2c3ccccc3c3ccccc32)c1
Reaction time: 9 h

Procedure:
To a solution of methyl 2,6-dibromo-isonicotinate (5.0 g, 16.95 mmol) (YZ_I-131), carbazole (6.0 g, 35.88 mmol) Cu (15.0 g, 236.04 mmol) and 18-crown-6 (0.1 g, 0.38 mmol) in 1,2-dichlorobenzene (50.0 ml) was added potassium carbonate (20.0 g, 144.71 mmol) under nitrogen and stirring. The reaction was carried out at 180° C. for 9 hours. After cooling, the reaction mixture was filtrated. Then, the solid residues were carefully washed with dichloromethane. Dichloromethane and 1,2-dichlorobenzene were evaporated from the combined filtration solution. After which, methanol (100.0 ml) was added to a dark brown solid. After stirring for 30 minutes, a yellow solid product was collected by filtration. The pure product was obtained in the amount of 6.4 g (81.4%) by recrystallization from acetone/methanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[C:11](=[O:21])[N:12](CC(O)=O)[C:13]([CH3:16])=[CH:14][N:15]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:24]=1[CH2:25]N>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]1[C:11](=[O:21])[N:12]([NH:12][C:11](=[O:21])[CH2:10][CH2:25][C:24]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:23]=2[Cl:22])[C:13]([CH3:16])=[CH:14][N:15]=1
Reactant: Cc1cnc(NCCc2ccccn2)c(=O)n1CC(=O)O
Reactant: NCc1cc(Cl)ccc1Cl
Product: Cc1cnc(NCCc2ccccn2)c(=O)n1NC(=O)CCc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared from 3-[2-(2-pyridyl)ethylamino]-6-methyl-1-carboxymethylpyrazinone and 2,5-dichlorobenzylamine using the procedure of EXAMPLE V, Step F, mp 188°-191° C.: MS (FAB) 446 (M+1)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[NH2:60][CH:61]([C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[CH2:62][S:63]([NH2:66])(=[O:65])=[O:64]>CN1C(=O)CCC1.O>[Cl:73][C:70]1[CH:69]=[CH:68][C:67]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:34][CH2:35][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:37][CH2:38]2)=[O:50])[CH2:62][S:63](=[O:64])(=[O:65])[NH2:66])=[CH:72][CH:71]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(CS(N)(=O)=O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CS(N)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (128 mg, 0.34 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (115 mg, 0.32 mmol) and N-ethyldiisopropylamine (0.066 mL, 0.38 mmol) in NMP (2.5 mL). The mixture was treated with 2-amino-2-(4-chlorophenyl)ethanesulfonamide (Intermediate 80) (75 mg, 0.32 mmol). The solution was stirred for 1 hour at room temperature. The mixture was treated with water (5 mL) and the resulting colourless precipitate was isolated by filtration, washed with water and then acetonitrile to give tert-butyl 4-(1-(4-chlorophenyl)-2-sulfamoylethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (157 mg, 85%) as colourless solid.
Reaction SMILES: [CH:1]([C:4]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][C:6]#[CH:7])=[C:2]=[CH2:3].CC(C)C(BC(C(C)C)C)C.C([N+]([O-])(CC)CC)C.[I:36]I>O1CCCC1.C(COC)OC>[I:36]/[CH:3]=[CH:2]/[CH2:1][C:4]([CH:5]=[C:6]=[CH2:7])([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: II
Reactant: C#CCC(C=C=C)(CCCC)O[Si](C)(C)C
Agent: CC(C)C(C)BC(C)C(C)C
Agent: CC[N+]([O-])(CC)CC
Solvent: C1CCOC1
Solvent: COCCOC
Product: C=C=CC(C/C=C/I)(CCCC)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2.36 g. (10 mmol.) of 4-propadienyl-4-trimethylsilyloxy-1-octyne in 5 ml. of glyme is added to a solution of 11 mmol. of bis-(3-methyl-2-butyl)borane in 15 ml. of glyme at 0° C. The mixture is stirred at 25° C. for 90 minutes, cooled to 0° C., and treated portionwise with 3.0 g. of triethylamine oxide. The stirred mixture is maintained at 25°-30° C. for 45 minutes, diluted with 20 ml. of tetrahydrofuran and poured into 100 ml. of ice-cold 15% sodium hydroxide solution, followed immediately with a solution of 8.0 g. of iodine in 20 ml. of tetrahydrofuran. The mixture is stirred at ambient temperature for 30 minutes and then extracted with ether. The extract is washed successively with water, sodium thiosulfate solution and brine; dried over magnesium sulfate; and filtered. The residue obtained after solvent evaporation is subjected to chromatography on silica gel with heptane solvent to afford the title compound as a liquid.
Reaction SMILES: C1([NH:7][C:8]([NH2:10])=[O:9])C=CC=CC=1.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH2:13].[C:20](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21]>C(#N)C>[CH3:13][C:12]([NH:7][C:8]([NH:10][C:20]([CH3:22])([CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:9])([CH3:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(Cl)c1ccccc1
Reactant: NC(=O)Nc1ccccc1
Reactant: C=C(C)c1ccccc1
Solvent: CC#N
Product: CC(C)(NC(=O)NC(C)(C)c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
102 parts of phenylurea was suspended in 80 parts of acetonitrile, and 25.4 parts of an α-methylstyrene solution containing 30.5% of cumyl chloride was added. With stirring, they were reacted at 40° C. for 5 hours. After allowing the reaction product to stand for 2 days, the precipitated crystals were collected and recrystallized from hydrous alcohol to afford 7.6 parts of N-phenyl-N'-(α,α-dimethylbenzyl) urea (III: R=C6H5). The melting point of the crystals was 193 to 194° C.
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18]([C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:27]([F:30])([F:29])[F:28])=O)(=O)OC.O.[NH2:32][NH2:33]>>[Cl:26][C:24]1[CH:23]=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[C:20]([C:18]2[N:33]=[N:32][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=3[CH:17]=2)[CH:25]=1
Reactant: NN
Reactant: O=C1CCCCCCC1=O
Reactant: COP(=O)(CC(=O)c1cc(Cl)ccc1C(F)(F)F)OC
Solvent: O
Product: FC(F)(F)c1ccc(Cl)cc1-c1cc2c(nn1)CCCCCC2

Procedure:
yellow oil. MS (ESI): 340.1 (MH+). Prepared from cyclooctane-1,2-dione, [2-(5-Chloro-2-trifluoromethyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][CH:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:4]1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][CH:3]1[CH2:7][CH2:6][CH:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:4]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCC(C=O)C4)c3)ncnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCC(CO)C4)c3)ncnc21
Reaction time: 0.17 h

Procedure:
A solution of 3-(3-formylcyclopentyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (50.0 mg, 0.108 mmol) in methanol (280 μL) was cooled to 0° C., then sodium tetrahydroborate (14 mg, 0.37 mmol) was added. The reaction was held at 0° C. for 10 minutes, at which point LCMS and TLC indicated complete reaction. The reaction was quenched by cautious addition of 1N HCl (3 drops) and methanol (1 mL), followed by addition of aqueous NaHCO3 and CHCl3. The phases were separated and the aqueous phase was washed with additional CHCl3. The combined organic phase was washed with sat'd NaCl, dried over MgSO4 and reduced to dryness. The residue was purified by column chromatography to obtain the product as a mixture of diastereomers (37.4 mg, 74%). 1H NMR (400 MHz, CDCl3): δ □8.84 (s, 1H), 8.31 (s, 2H), 7.40 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.29 (m, 1H), 3.53 (m, 1H), 3.53 (t, 2H), 3.14 (m, 1H), 2.95 (m, 1H), 2.68 (m, 1H), 2.2-1.0 (m, 9H), 0.92 (t, 2H), −0.059 (s, 9H). MS (EI) m/z=467.2 (M+H).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:35])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([O-:11])=[O:10]>CN(C)C=O>[N+:9]([C:12]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[CH:24][C:23]=2[Cl:35])=[CH:17][C:13]=1[C:14]([O:16][CH3:3])=[O:15])([O-:11])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
390 mg (2.76 mmol) of methyl iodide and 320 mg (2.3 mmol) of powdered potassium carbonate were added to 940 mg (2.3 mmol) of 2-nitro-5-(2-chloro-4-pentafluoroethylphenoxy)benzoic acid in 30 ml of dimethylforamide (freshly eluted through neutral alumina). After 1 hour, the mixture was poured into 300 ml of water, extracted with ether, the ether layer was washed with saturated sodium chloride solution, then dried and evaporated to 820 mg of light yellow oil (84%) diphenyl ether methyl benzoate having the following elemental analysis, calculated (found): C: 45.14 (47.54); H: 2.13 (2.69); Cl: 8.33 (6.19); F: 22.31 (21.26); N: 3.29 (2.72); O: 18.79.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[CH2:10][C@H:9]2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[C:22]([C:19]1[CH:18]=[C:17]([NH:16][C:13]([C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:15])[O:21][N:20]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)[C@@H]1CC(=O)N1c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(N)on1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CC(=O)N2c2ccc(Cl)cc2)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold slurry of (S)-1-(4-Chloro-phenyl)-4-oxo-azetidine-2-carboxylic acid (0.2 g; 1.037 mmol) and 5-amino-3-tert-butylisoxazole (0.145 g; 1.037 mmol) in pyridine (1.258 mL; 15.555 mmol) is added phosphorous oxychloride (0.116 mL; 1.244 mmol). The mixture is stirred at 0° C. for 30 minutes and then diluted with water and extracted with ethyl acetate several times. The organics are combined and washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC affords title compound, m/z 348 [M+H+]
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH:16]([OH:17])[C:15]3[S:18][CH2:19][CH2:20][S:21][C:14]=3[C:13]1=[O:22])=[N:7]2.[H-].[Na+].Cl[C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27]>CN(C)C=O.CS(O)(=O)=O.C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:12]1[CH:13]([O:22][C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[O:27])[C:14]3[S:21][CH2:20][CH2:19][S:18][C:15]=3[C:16]1=[O:17])=[N:7]2
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc2c(Cl)ccnc2n1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3c(Cl)ccnc3n2)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
6-(5-Chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (11.9 g.) is added, at 0° C., to a suspension of sodium hydride (1.2 g.) in anhydrous dimethylformamide (120 cc.). The reaction mixture is stirred for 1 hour at 5° C., and 1-chlorocarbonyl-4-methylpiperazine (16.6 g.) dissolved in anhydrous dimethylformamide (80 cc.) is then added. After stirring for 21/2 hours at 5° C., the crystals which have appeared are filtered off and washed twice with diethyl ether (60 cc.). The product thus isolated is dissolved in an ice-cold 2N aqueous solution of methanesulphonic acid (200 cc.). The aqueous acid solution is washed with diethyl ether (80 cc.), and rendered alkaline by adding an excess of 10N sodium hydroxide solution. The oil which separates out is extracted twice with methylene chloride (total 400 cc.). The organic solution is washed three times with distilled water (total 240 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.2 g.) and evaporated. The crystals obtained (10.1 g.), m.p. 238° C., are dissolved in a boiling mixture of acetonitrile (200 cc.) and methylene chloride (180 cc.). After distilling off the methylene chloride and then cooling the residue for 1 hour at 2° C., the crystals which have appeared are filtered off, washed twice with ice-cold acetonitrile (total 40 cc.) and dried under reduced pressure (20 mm. Hg). 6-(5-Chloro-1,8-naphthyridin-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (8.0 g.), melting at 240° C., is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][OH:27].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:27][CH2:26][CH2:25][O:24][CH3:23])[N:3]=1
Reactant: COCCO
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COCCOc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N

Procedure:
From 2-amino-4-benzo [1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-methoxyethanol and DBU in DME. EI-MS m/e (%): 314 (M+, 54), 256 ([M—MeOCH═CH2]+, 100), 214 (59).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH2:37])=[O:36])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].ON1C(=O)CCC1=O.[CH2:59]([O:66][C:67]([NH:69][C@H:70]([C:83]([OH:85])=O)[CH2:71][CH2:72][CH2:73][CH2:74][NH:75][C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])=[O:68])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CO.[Pd]>[NH:69]([C:67]([O:66][CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:68])[C@H:70]([C:83]([NH:1][C@H:2]([C:15]([NH:17][C@H:18]([C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH2:37])=[O:36])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])=[O:85])[CH2:71][CH2:72][CH2:73][CH2:74][NH:75][C:76]([O:78][C:79]([CH3:80])([CH3:81])[CH3:82])=[O:77]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: O=C1CCC(=O)N1O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 4 °C
Reaction time: 8 h
Yield: 5.7 %

Procedure:
Compound XV (1.06 g, 1.5 mmoles) is hydrogenolyzed over palladium in methanol for 3 hours. After the solvent have been removed by evaporation in vacuo the residue is dissolved in ethyl acetate and chilled in an ice bath. To this is added Nα -benzyloxycarbonyl-Nε -t-butyloxycarbonyl-L-lysine N-hydroxy-succinimide (0.72 g, 1.5 mmoles) and the mixture is stirred at 4° C overnight. The precipitates which has separated are filtered off, washed with ice-cold ethyl acetate and dried in vacuo (1.31 g). An additional quantity of the product is obtained upon concentration of the filtrate (0.08 g). The combined precipitates are dissolved in methanol and most of the solvent is removed by evaporation in vacuo. The resulting sirupy residue is precipitated from ethyl acetate (20 ml)-ether (20 ml); yield 1.35 g (96%).