Azzindani/Open_Reaction_Data huggingface dataset:
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](O)=[O:49])[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(CC)C(C)C)(C)C.[Cl:60][C:61]1[CH:66]=[CH:65][C:64]([CH:67]([NH2:73])[CH2:68][CH2:69][N:70]([CH3:72])[CH3:71])=[CH:63][CH:62]=1>CN1C(=O)CCC1.CO>[Cl:60][C:61]1[CH:62]=[CH:63][C:64]([CH:67]([NH:73][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:49])[CH2:68][CH2:69][N:70]([CH3:72])[CH3:71])=[CH:65][CH:66]=1
Reactant: CN(C)CCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.044 g, 0.12 mmol) was added to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.040 g, 0.11 mmol) and N,N-diisopropylethylamine (0.023 mL, 0.13 mmol) in NMP (5 mL) at 22° C. The resulting suspension was stirred at 50° C. for 10 minutes. The mixture was cooled to ambient temperature and 1-(4-chlorophenyl)-N3,N3-dimethylpropane-1,3-diamine (Intermediate 33) (0.023 g, 0.11 mmol) was added as a solution in NMP (2 mL). The mixture was stirred at 22° C. for 3 days. The mixture was diluted with methanol and purified by ion exchange chromatography using an SCX column; the desired product was eluted from the column using 30% (2M NH3 in MeOH) in DCM and product-containing fractions were evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% (10:1 MeOH/conc. NH3 (aq)) in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-(1-(4-chlorophenyl)-3-(dimethylamino)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (0.047 g, 76%) as a white solid.
Reaction SMILES: O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].CCOCC.[Br:19][CH2:20][CH:21]([OH:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CC(C)=O.O.S(=O)(=O)(O)O>[Br:19][CH2:20][C:21](=[O:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCC(O)CBr
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCC(=O)CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
In a 1000 ml eggplant-shaped flask, 14 g of 1-bromo-2-dodecanol was dissolved in 110 ml of acetone. A solution obtained in advance by dissolving 35 g of sodium dichromate dihydrate in 150 ml of distilled water and 25 ml of sulfuric acid was dropped thereto. These substances were stirred at room temperature for 1.5 hours, and then 250 ml of ether was added thereto. The resultant substance was dehydrated, and the solvent was removed. As a result, a white solid was obtained. The yield was 80%.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([O:36]CC3C=CC([N+]([O-])=O)=CC=3)=[O:35])[CH2:25][N:24]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:22])[CH2:3]1.[ClH:67]>O1CCCC1.O>[ClH:67].[CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:3]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)[C@@H](C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CCN1

Procedure:
170 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3S)-3-methyl-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 3.5 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.19 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2.5 hours in the presence of 170 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 8(b), to give 25.0 mg of the title compound as a powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[OH:12].S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl-].[Na+]>O.CO>[NH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[OH:12]
Reactant: COc1cccc([N+](=O)[O-])c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(N)c1O
Temperature: 60 °C
Yield: 94 %

Procedure:
To a suspension of 4.72 g of 2-methoxy 6-nitrophenol in a mixture of 100 ml of water and 30 ml of methanol was added 29.3 g of sodium dithionite. The mixture was stirred at 60° C. until it became a uniform and colorless solution. To the reaction mixture was added a saturated aqueous solution of sodium chloride. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to give 3.65 g of crude 2-amino-6-methoxyphenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]([CH3:18])([CH3:17])[CH2:11]/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:41][N:42]([CH2:59][CH2:60][C:61]1[S:62][CH:63]=[CH:64][CH:65]=1)[C:43](=[O:58])[C@H:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C:10]([CH3:18])([CH3:17])[CH2:11]/[CH:12]=[CH:13]/[C:14](=[O:16])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[CH2:59][CH2:60][C:61]1[S:62][CH:63]=[CH:64][CH:65]=1)[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1cccs1
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)C/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCc1cccs1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
(2E)-5-(N-(tert-Butoxycarbonyl)-N-methylamino)-5-methylhex-2-enoic acid (146 mg, 0.57 mmol) was dissolved in dichloromethane (2 ml) and N,N-dimethylformamide (2 ml). 1-Hydroxy-7-azabenzotriazole (72 mg, 0.57 mmol) was added as a solid. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (109 mg, 0.57 mmol) was added. The solution was stirred for 15 min at 0° C. A solution of (2R)-N-Methyl-2-(methylamino)-3-(2-naphthyl)-N-(2-(2-thienyl)ethyl)propionamide (200 mg, 0.57 mmol) in dichloromethane (2 ml) was added. Ethyldiisopropylamine (0.1 ml, 0.57 mmol) was added. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (50 ml) and washed with 1 N hydrochoric acid. The aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (40 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using ethyl acetate/heptane as eluent, to give 270 mg of N-methyl-N-((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:10][C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:10][C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:17][C:26](=[O:27])[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=1
Reactant: CN(Cc1ccc(Cl)s1)c1ccc(N)c(Cl)c1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(Cc1ccc(Cl)s1)c1ccc(NC(=O)Cc2ccc(Cl)cc2)c(Cl)c1
Temperature: 150 °C
Yield: 16.5 %

Procedure:
2-Chloro-N(4)-(5-chloro-thiophen-2-ylmethyl)-N(4)-methyl-benzene-1,4-diamine (100 mg) was added to a solution of 4-chlorophenylacetyl chloride (69 mg) in dry acetonitrile (2 mL) in a rubber-capped glass vial. The reaction mixture was heated in a microwave device to 150° C. for 15 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with water (5 mL) and brine (5 mL), dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (heptane/ethyl acetate, gradient) to furnish 25.2 mg title compound. Yield: 16%.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:12]=1[NH:13][C:14](=[O:23])[C:15](=[O:22])[NH:16]2)C)C1C=CC=CC=1>CN(C=O)C.[Pd]>[CH3:21][C:20]1[C:11]([CH2:10][NH:8][CH3:1])=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:22])[C:14](=[O:23])[NH:13]2
Reactant: Cc1ccc2[nH]c(=O)c(=O)[nH]c2c1CN(C)Cc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CNCc1c(C)ccc2[nH]c(=O)c(=O)[nH]c12

Procedure:
A solution of 5-[(benzyl-methyl-amino)-methyl]-6-methyl-1,4-dihydro-quinoxaline-2,3-dione (3.23 g, 10.45 mmol) in DMF (100 mL) was hydrogenated (Pd/C, 20%, 0.5 g) in DMF (100 mL). The suspension was filtered, and the filtrate was evaporated to give a solid, which was crystallized from methanol.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@:3]1([CH3:26])[C:9]1[CH:10]=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[C:21][Si](C)(C)C)[CH:15]=2)[CH:13]=1.C[O-].[Na+].C(=O)=O>CO.O.ClCCl>[C:20]([C:16]1[CH:15]=[C:14]([N:12]2[CH:13]=[C:9]([C@:3]3([CH3:26])[C:2]([F:1])([F:27])[CH2:7][O:6][C:5]([NH2:8])=[N:4]3)[CH:10]=[N:11]2)[CH:19]=[CH:18][CH:17]=1)#[CH:21]
Reactant: C[C@]1(c2cnn(-c3cccc(C#C[Si](C)(C)C)c3)c2)N=C(N)OCC1(F)F
Agent: C[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: C#Cc1cccc(-n2cc([C@@]3(C)N=C(N)OCC3(F)F)cn2)c1
Yield: 51.8 %

Procedure:
A solution of (R)-5,5-difluoro-4-methyl-4-(1-(3-((trimethylsilyl)ethynyl)phenyl)-1H-pyrazol-4-yl)-5,6-dihydro-4H-1,3-oxazin-2-amine (68.6 mg, 177 μmol) in methanol (2 ml) was treated at room temperature with sodium methoxide (5.4M in methanol; 1 μl, 5.4 μmol). After 90 minutes a small quantity of dry ice was added to neutralize the reaction mixture. After evaporation at reduced pressure the residue thus obtained was dissolved in a mixture of water and dichloromethane. The aqueous layer was extracted with dichloromethane, thereafter, the combined organic layers were washed with water, dried over sodium sulphate, and evaporated. The residue was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (R)-4-[1-(3-ethynyl-phenyl)-1H-pyrazol-4-yl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (29 mg, 52% yield) was obtained as a light yellow solid. MS (ISP): m/z=317.1 [M+H]+.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH:10]([Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C>C(OCC)C>[ClH:1].[CH3:20][Si:18]([CH3:19])([CH3:21])[CH:10]([NH2:9])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)[Si](C)(C)C
Agent: Cl
Solvent: CCOCC
Product: C[Si](C)(C)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 3N solution of HCl in diethyl ether (3 ml) was added at room temperature to a mixture of N-tertbutoxycarbonyl-α-(trimethylsilyl)benzeneethanamine (0.150 g, 0.51 mmol) in diethyl ether (3 ml). The mixture was stirred at room temperature for 48 hours. The resulting solid was filtered off and dried, in vacuo, to yield 0.106 g of the expected α-(trimethylsilyl)-benzeneethanamine hydrochloride, m.p. 193° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:13]1[C:22]([OH:23])=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5](=[O:12])[N:6]2[CH3:11].F[C:25]1C=C(O)C(C2C3C(=CC=CC=3)N(CC3C=CC(OC)=CC=3)C2=O)=CC=1C#N>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:13]3[C:22](=[CH:21][C:16]4[O:17][CH2:18][CH2:19][O:20][C:15]=4[CH:14]=3)[O:23][CH2:25]1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Reactant: CN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c(Br)cccc21
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.40 and making non-critical variations using 4-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one to replace 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile, 4′-bromo-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one was obtained (95%): 1H NMR (300 MHz, CDCl3) δ 7.23-7.14 (m, 2H), 6.87-6.79 (m, 1H), 6.43 (s, 1H), 6.16 (s, 1H), 4.93 (ABq, 2H), 4.22-4.07 (m, 4H), 3.24 (s, 3H); MS (ES+) m/z 387.9 (M+1), 389.9 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N:64]1[N:65]=[N:66][N:67]2[C:72]=1[CH:71]=[CH:70][C:69]([SH:73])=[N:68]2>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:34][C:18]([C@@H:15]1[C:14](=[O:35])[N:13]2[C@@H:16]1[CH2:17][C:11]([S:73][C:69]1[CH:70]=[CH:71][C:72]3[N:67]([N:66]=[N:65][N:64]=3)[N:68]=1)=[C:12]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=1)=[O:22])[CH3:19]
Reactant: Sc1ccc2nnnn2n1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccc4nnnn4n3)C[C@H]12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.231 ml) in dichloromethane (2.08 ml) was added to a solution of 4-nitrobenzyl (2R, 5R, 6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]1-azabicyclo[3.2.0]heptane-2-carboxylate (600 mg) and 4-(N,N-dimethylamino)pyridine (13.5 mg) in dichloromethane (30.0 ml) at -30° C. To this mixture was added a solution of trifluoromethanesulfonic anhydride (0.196 ml) in dichloromethane (3.72 ml) and stirring was continued at -30° C. for 20 minutes. N,N-Diisopropyl-N-ethylamine (0.680 ml) and a solution of tetrazolo[1,5-b]pyridazine-6-thiol (0.256 g) in N,N-dimethylformamide (2.30 ml) were added to the mixture at -30° C. The resultant mixture was allowed to warm to 20° C. over a period of 2 hours, and then evaporated in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed in turn with cold water (x3) and an aqueaus sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on deactivated silica gel with 15% water (7.5 g), eluting with a mixture of benzene and acetone (20:1 to 6:1). The fractions containing the desired compound were collected and diluted with benzene to result in precipitation of crystals, which, after cooling in a refrigerator, were collected by filtration to give 4-nitrobenzyl (5R, 6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-3-(tetrazolo[1,5-b]pyridazin-6-ylthio)-1azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.533 g). Crystallization of the mother liquor from ethyl acetate and n-hexane gave the same product (0.0663 g) as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7](N)[CH:8]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:31].[K+].[I-].N>O.C(O)(=O)C>[I:31][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[CH2:11]1
Reactant: [I-]
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C2CCc3cc(OC)ccc3C2)c(I)c1
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
The title compound was synthesized by referring to J. Org. Chem., 1984, 49, 296. To 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (5.0 g) was added dropwise acetic acid (50 ml) and concentrated sulfuric acid (2 ml) over 30 minutes on an ice bath, a solution of sodium nitrite (1.3 g) in water (20 ml) was then added thereto followed by stirring for 30 minutes. A solution of potassium iodide (3.5 g) and iodide (2.7 g) in water (30 ml) was added dropwise thereto over 30 minuntes followed by stirring for 3 hours at room temperature. The reaction solution was neutralized with ammonia solution and a saturated aqueous solution of sodium carbonate on an ice bath, extracted with ethyl acetate, then sequentially washed with an aqueous solution of sodium thiosulfate, water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (3.1 g).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CO.CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH2:12][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[CH3:18]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CSc1nc2ccccc2[nH]1
Yield: 92.7 %

Procedure:
A solution of 2-mercaptobenzimidazole (200 mg, 1.33 mmol) and ethyl 3-bromopyruvate (0.20 mL, 1.43 mmol) in methanol (2.5 mL) and acetone (2 mL) was shaken at 20° C. for 4 hours. The solvents were removed under the reduced pressure on a rotary evaporator. The residue was triturated with ethyl acetate. Solvent was decanted and the residue was dissolved in methylene chloride. The solution was washed with diluted aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. Removal of the solvent gave the expected product, 3-(1H-Benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (326 mg, 93%). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.31 (br. s, 1H), 7.24 (br s, 1H), 7.15-7.05 (m, 2H), 4.32 (q, J=7.1 Hz, 2H), 4.29 (br. s, 1H), 3.90 (br. s, 1H), 1.24 (t, J=7.1 Hz, 3H). MS (ESI): m/z 265 (M+1, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([OH:17])(=O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([Cl:20])(=[O:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCS(=O)(=O)O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of taurine (12.5 g, 100 mmol), benzyl chloroformate (15.1 mL, 105 mmol) and sodium carbonate (10.6 g, 100 mmol) in water (250 mL) was stirred at room temperature for overnight. The product mixture was extracted with diethyl ether. The organic extract was concentrated under vacuum to provide 2-{[(benzyloxy)carbonyl]-amino}ethanesulfonic acid. Without further purification, the sulfonic acid was treated with thionyl chloride (15 mL, 206 mmol) with external ice-water bath cooling. The resultant mixture was stirred at room temperature for 1 hour, and poured into ice water. The mixture was extracted with diethyl ether. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound as white solid.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][N:17](C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[C@H:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].O.C(=O)([O-])[O-].[K+].[K+]>CO>[F:39][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C@H:10]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:9]2)=[O:7])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(C(=O)C(F)(F)F)CC2)[C@H](c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
Rac-cis-1-{4-[1-(3,5-Bis-trifluoromethyl-benzoyl)-3-phenyl-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone (4.15 g, 7.14 mmol) was dissolved in methanol (25 mL). Water (1 mL) and potassium carbonate (2.96 g, 21.4 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. Water (100 mL) was added and the mixture was extracted twice with 200 mL methylene chloride. Organic phases were pooled and dried with magnesium sulfate. Evaporation of the solvent gave the title compound (3.4 g, 98%) as a white foam which was used without any further purification, MS: m/e=486.3 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:25]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 110 °C
Yield: 84.9 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.6769 g, 2.004 mmol), (S)-3-amino-1-Boc-piperidine (0.4269 g, 2.132 mmol), and diisopropylethylamine (0.45 mL, 2.6 mmol) in propan-2-ol (12 ml) was heated in a microwave reactor at 110° C. for 20 minutes. The solvent was evaporated in vacuo and then purified by column chromatography on silica gel (gradient: 0 to 30% ethyl acetate in heptanes) affording 853.7 mg (85%) of (S)-3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. LCMS (Method F, ESI): RT=1.19 min, m+H=502.3.