Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[CH2:3][OH:4].FC(F)(F)C(O[CH2:16][N:17]([N+:19]([O-:21])=[O:20])[CH3:18])=O.[Cl-].[Na+]>C(#N)C>[F:1][C:2]([N+:8]([O-:10])=[O:9])([N+:5]([O-:7])=[O:6])[CH2:3][O:4][CH2:16][N:17]([N+:19]([O-:21])=[O:20])[CH3:18]
Reactant: CN(COC(=O)C(F)(F)F)[N+](=O)[O-]
Reactant: O=[N+]([O-])C(F)(CO)[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CN(COCC(F)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Reaction time: 3 h

Procedure:
2-Fluoro-2,2-dinitroethanol (7.62 g, 49.5 mmol) was stirred with acetonitrile (2.5 ml) under nitrogen as 2-nitro-2-azapropyl trifluoroacetate (10.0 g, 49.5 mmol) in acetonitrile (3.5 ml) was added in one portion. The reaction flask was immediately connected to a vacuum pump and brought to 1-2 mm during several minutes. After stirring 22/3 hours, the solution was stirred 1/3 hour at ambient pressure before pouring onto a saturated sodium chloride solution (50 ml), which was extracted with dichloromethane (3×25 ml). The organic portion was washed with a 1:1 mixture of saturated sodium chloride solution: 0.04 N sodium hydroxide solution (10×150 ml), dried with magnesium sulfate, and concentrated to crude 1-fluoro-1,1,5-trinitro-3-oxa-5-azahexane; yield: 8.67 g (72%). Recrystallization from ether/hexane at -78° C. gave 1-fluoro-1,1,5-trinitro-3-oxa-5-azahexane; yield: 7.5 g (63%).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]([CH:17](N(C)C)[CH3:18])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl[C:29]1[N:37]=[CH:36][N:35]=[C:34]2[C:30]=1[N:31]([CH3:39])[C:32](=[O:38])[NH:33]2.C[CH2:41][N:42](C(C)C)[CH:43](C)C>CN1C(=O)CCC1>[F:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:23][CH2:24][N:25]([C:29]4[N:37]=[CH:36][N:35]=[C:34]5[C:30]=4[N:31]([CH3:39])[C:32](=[O:38])[NH:33]5)[CH2:26][CH2:27]3)[N:15]([CH2:17][CH2:18][N:42]([CH3:43])[CH3:41])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CC(N(C)C)n1cc(-c2ccc(F)c(F)c2)nc1C1CCNCC1
Reactant: Cn1c(=O)[nH]c2ncnc(Cl)c21
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CN1CCCC1=O
Product: CN(C)CCn1cc(-c2ccc(F)c(F)c2)nc1C1CCN(c2ncnc3[nH]c(=O)n(C)c23)CC1
Yield: 9.8 %

Procedure:
Combine 2-(4-(3,4-difluorophenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl-N,N-dimethyl ethanamine 3HCl (0.3 g; 0.00068 mol), 6-chloro-7-methyl-7,9-dihydro-purin-8-one (0.15 g; 0.00081 mol), DIPEA (1.07 mL; 0.0062 mol) in NMP (9 mL) and stir at 150° C. in microwave for 45 min. Cool, and quench the reaction with saturated sodium bicarbonate solution and extract with EA. Evaporate the EA layer and purify on silica gel using DCM and methanol as eluent to give the title compound (0.032 g; 9.3%). MS (ES+): m/z=484 (M+1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]2[CH2:13]4)[CH2:17]3)=[O:9])[CH2:4]1.Cl[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23]>>[CH2:25]([O:24][C:22]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:12]3[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]2[CH2:19]4)[CH2:20]3)=[O:9])[CH2:4]1)=[O:23])[CH:26]([CH3:28])[CH3:27]
Reactant: N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Product: CC(C)COC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1

Procedure:
The title compound was prepared from (R)-2-adamantyl 3-aminopyrrolidine-1-carboxylate HCl salt and isobutyl chloroformate following a procedure analogous to that described in Example 3 Step 2. LC-MS Method 1 tR=2.1 min, m/z=365; 1H NMR (CDCl3) 0.97 (d, 6H), 1.58 (d, 2H), 1.70-2.05 (14H), 2.18 (m, 1H), 2.80 (1H), 3.29 (dd, 1H), 3.53 (m, 2H), 3.70 (m, 1H), 3.84 (m, 1H), 4.28 (1H), 4.80 (1H), 4.83 (s, 1H)
Reaction SMILES: [CH2:1]1[C@H:3]2[CH:4]([OH:28])[CH2:5][C@H:6]3[C@:19]([CH3:20])([C@@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:28][CH:4]1[C@@H:3]2[CH2:1][C@@H:2]2[C@@:19]2([CH3:20])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:5]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Solvent: c1ccncc1
Product: CC(=O)OC1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](OC5CCCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2C[C@@H]12
Temperature: 0 °C

Procedure:
9.0 g of 1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstan-3-ol is allowed to stand in 20 ml of pyridine and 10 ml of acetic anhydride for 20 hours at room temperature. The solution is stirred into ice water, the resultant precipitate is filtered off, taken up in diethyl ether, washed with water, and dried. After evaporation, 11 g of 3-acetoxy-1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstane is obtained.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][C:12]([OH:17])([CH3:16])[CH2:13][CH2:14]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[C:1]([O:9][CH2:10][CH2:11][C:12]([OH:17])([CH3:16])[CH2:13][CH2:14][Br:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(CCO)CCOC(=O)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(CCBr)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.5 %

Procedure:
To a solution of 3,5-dihydroxy-3-methylpentyl benzoate (1.0 g) and carbon tetrabromide (2.78 g) in tetrahydrofuran (30 mL) was added dropwise a solution of triphenylphosphine (2.20 g) in tetrahydrofuran (10 mL) under ice-cooling. After stirring at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=9:1→6:4) to give the title compound (979 mg) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14]([S:15][CH3:16])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:17]=1.[Se](=O)=[O:19]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:19])[C:10]3=[N:12][N:13]=[C:14]([S:15][CH3:16])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: O=[Se]=O
Reactant: CSc1nnc2n1C=Cc1cc(C)ccc1C2
Product: CSc1nnc2c(=O)c3ccc(C)cc3ccn12

Procedure:
By a procedure similar to that described in Examples 13, the reaction of 8-methyl-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine with selenium dioxide gave 8-methyl-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepin-11-one as crystals. Recrystallization from methanol yielded colorless platelets melting at 178°-179° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9].C(N(CC)CC)C.ClC[O:20][CH2:21][CH3:22]>C1COCC1>[CH:1]12[CH2:7][CH:4]([CH:3]=[CH:2]1)[CH2:5][CH2:6]2.[CH3:22][CH2:21][O:20][CH2:2][C:8]([O-:10])=[O:9]
Reactant: O=C(O)C1CC2C=CC1C2
Reactant: CCOCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C1=CC2CCC1C2
Product: CCOCC(=O)[O-]
Reaction time: 6 h
Yield: 89 %

Procedure:
1 mol of 5-norbornene-2-carboxylic acid was dissolved in 1.5 l of THF, and 1.1 mol of triethylamine and 1.1 mol of chloromethylethylether were added thereto. The reaction was carried out at room temperature for 6 hours. After completion of the reaction, the resultant mixture was distilled under reduced pressure to provide 5-norbornene-2-ethoxymethylcarboxylate (ANCA) in 89% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][NH:10][C:11]#[N:12].[C:13]1(N)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>C(O)(C(F)(F)F)C(F)(F)F>[ClH:1].[NH:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:19]=[C:11]1[NH:10][CH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: N#CNCc1c(Cl)cccc1Cl
Reactant: Nc1ccccc1N
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: Cl
Product: Clc1cccc(Cl)c1CNc1nc2ccccc2[nH]1
Temperature: 100 °C
Yield: 4.1 %

Procedure:
(2,6-Dichlorophenyl)methylcyanamide (150 mg) and phenylenediamine (81 mg) were dissolved in hexafluoro-2-propanol (1 ml) and heated at 100° C. in a closed vessel for 2 days. After a further day at 60° C. in an open vessel, the solvent was removed and the residue was purified by preparative HPLC. The product-containing fractions were combined, the acetonitrile was stripped off in a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with ethyl acetate. Drying over magnesium sulfate and purification with carbon were followed by evaporation to dryness. The residue was taken up in aqueous hydrochloric acid and freeze dried. 5 mg of the desired compound were obtained.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].N1C=CC=CC=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl>[S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)([O:21][CH2:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4])(=[O:36])=[O:35]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Yield: 138.7 %

Procedure:
Under a nitrogen atmosphere, 29.16 g (97.67 mmol) of phytanol and 9.27 g (117.2 mmol) of pyridine were dissolved in 220 ml of dry methylene chloride, and 20.48 g (107.4 mmol) of p-toluenesulfonyl chloride was added little by little under ice cooling, in order to prevent the liquid temperature from exceeding 10° C. After the completion of addition, agitation was continued for 12 hours until phytanol disappeared, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 61.31 g of phytanyl tosylate.
Reaction SMILES: C([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25]([OH:27])=O)=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:40][C:41]1[S:42][CH:43]=[CH:44][N:45]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[S:42]1[CH:43]=[CH:44][N:45]=[C:41]1[NH:40][C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([OH:14])=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][C:17]=12)=[O:27]
Reactant: Nc1nccs1
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.6 %

Procedure:
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added 2-aminothiazole (0.0077 mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Purified by reverse phase HPLC (0.1% TFA, H2O/ACN) to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid thiazol-2-ylamide 319 (0.01 g, 0.023 mmol, 60%.) 1H NMR (CDCl3) δ 9.02 (dd, 1H), 8.61 (d, 1H), 7.65 (dd, 1H), 7.55 (d, 1H), 7.38 (dd, 2H), 7.21 (d, 1H), 7.07 (dd, 2H), 4.78 (s, 2H), 4.67 (s, 2H.) MS: 435 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]=[N+:12]=[N-:13])[CH:5]=1.[C:15]([O:19][Si](C)(C)C)(=[O:18])[C:16]#[CH:17].CO>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:17]=[C:16]([C:15]([OH:19])=[O:18])[N:13]=[N:12]2)[CH:5]=1)=[O:14]
Reactant: COC(=O)c1ccc(C)c(N=[N+]=[N-])c1
Reactant: C#CC(=O)O[Si](C)(C)C
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2cc(C(=O)O)nn2)c1
Reaction time: 2 h
Yield: 68.5 %

Procedure:
3-Azido-4-methyl-benzoic acid methyl ester (878 mg, 4.60 mmol) and trimethylsilyl propiolate (777 mg, 5.05 mmol) were heated to 80° C. in a sealed tube overnight. The tube was cooled and the contents were mixed with 20 mL of MeOH. After 2 h, the mixture was poured into rapidly stirring cold water, and the resulting precipitate was filtered and dried under air to provide 823 mg of 1-(5-methoxycarbonyl-2-methyl-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH3:3].I[CH2:26][CH2:27][CH3:28]>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]2[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:14]=3[NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:26][CH2:27][CH3:28]
Reactant: CCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3
Reactant: CCCI
Product: CCCCCCOc1ccccc1-c1cccc2[nH]c3c(c12)CCNCC3

Procedure:
Following the procedure for the preparation of 10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole and substituting 1-iodohexane for 1-iodopropane while making non-critical variations the title compound was obtained as 360 mg (66%) of a yellow foam: 1H NMR (400 MHz, CDCl3) δ 7.83 (br s, 1H), 7.36-7.27 (m, 3H), 7.17-7.13 (m, 1H), 7.05-7.01 (m, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 3.95-3.85 (m, 2H), 3.06-3.01 (m, 1H), 2.98-2.93 (m, 2H), 2.90-2.85 (m, 1H), 2.82-2.79 (m, 1H), 2.42-2.37 (m, 2H), 1.57-1.51 (m, 2H), 1.22-1.16 (m, 6H), 0.83 (t, J=6.9 Hz, 3H); HRMS (FAB) calcd for C24H30N2O+H1: 363.2436 found 363.2444.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.Cl>ClCCCl.CCCCO>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:2]2[S:3][C:4]3[CH:10]=[C:9]([CH:11]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:28][CH:27]=1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCCCO
Solvent: ClCCCl
Product: CCC(C(c1ccc2nc(Nc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C

Procedure:
A solution of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethyl-butan-2-amine (30 mg, 0.079 mmol), methyl-4-aminobenzoate (24 mg, 0.16 mmol) in 300 μL DCE and 300 μL n-BuOH was treated with 4N HCl (40 μL, 0.16 mmol) and refluxed overnight. The mixture was then partitioned between DCM and saturated NaHCO3 and the aqueous phase was extracted with DCM. The combined organic extracts were dried over Na2SO4, decanted and concentrated in vacuo. The residue was purified by PTLC using two 1 mm silica plates eluting with 5% MeOH (2N NH3)/DCM to provide methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoate. MS (ESI+) m/z 450.19 [M+H]
Reaction SMILES: [CH2:1]=O.[N:3]1([C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:19]1([CH:27]=[CH:26][CH:25]=[C:23]([OH:24])[C:21]=1[OH:22])[OH:20]>C(O)C>[OH:20][C:19]1[C:21]([OH:22])=[C:23]([OH:24])[CH:25]=[CH:26][C:27]=1[CH2:1][N:6]1[CH2:7][CH2:8][N:3]([C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:10])[CH2:4][CH2:5]1
Reactant: Oc1cccc(O)c1O
Reactant: S=C(SCc1ccccc1)N1CCNCC1
Reactant: C=O
Solvent: CCO
Product: Oc1ccc(CN2CCN(C(=S)SCc3ccccc3)CC2)c(O)c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
To a solution of 0.51 g of 35% formalin in 7.7 ml of ethanol was added under chilling with ice a solution of 1.5 g of benzyl 1-piperazinecarbodithioate in 7.5 ml of ethanol. The mixture was stirred at room temperature for 10 min. To the mixture was further added under chilling with ice a solution of 3.7 g of pyrogallol in 15.3 ml of ethanol at once. The mixture was then stirred for 2.5 hours at room temperature. Ethanol was evaporated under reduced pressure, and the residue was extracted with dichloromethane. The dichloromethane solution was washed with water and an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent to give 2.17 g of the desired compound as a pale red powder, m.p. 125°-126° C. (decomp.), yield 92.9%.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=S)[CH2:18][C:19](=O)[CH3:20])=[O:4].[CH2:23]([NH:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:30]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:31]=[C:19]([CH3:20])[CH:18]=1)=[O:4]
Reactant: NNCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with benzylhydrazine (CAS Reg. No. 555-96-4) to give the title compound as brown solid. MS (ESI): m/z=418.2 [M+H]+.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1)[CH2:3][CH2:2]2.[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([Cl:24])=[O:23])([O-:19])=[O:18]>C1COCC1>[ClH:24].[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH:16][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1cnc(N2CCN3CCC2CC3)nc1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cl
Product: O=C(Nc1cnc(N2CCN3CCC2CC3)nc1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-ylamine free base and THF (275 ml) was added to another mixture of 2-nitrobenzoylchloride (10 g, 53.9 mmol) during 45 minutes. The mixture was stirred at room temperature for 15 h. The crystals were filtered and washed with THF. The crystals where boiled in ethanol (100 ml, 96%) and the mixture was stored in the refrigerator for 3 hours. The crystals were filtered and washed with ethanol followed by diethylether. Yield 6.47 g (33%). LC-ESI-HRMS of [M+H]+ shows 369.169 Da. Calc. 369.167514 Da, dev. 4 ppm.
Reaction SMILES: Cl[P:2]1[O:8][C:7]2[C:9]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:12][C:6]=2[C:5]2[CH:21]=[C:22]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[C:24]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=2[O:3]1.[OH2:33].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:33]=[PH:2]1[O:8][C:7]2[C:9]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:12][C:6]=2[C:5]2[CH:21]=[C:22]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[C:24]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:4]=2[O:3]1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2op(Cl)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Reactant: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[PH](=O)Oc1c-2cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6.32 g (13 mmol) of the compound of Example 1 in 150 mL of toluene at ambient temperature is added dropwise a solution of 0.24 mL (13 mmol) of distilled water in 3.0 mL (22 mmol) of triethylamine. After the addition is complete, the reaction mixture is stirred at ambient temperature for 15 minutes. The reaction solvent is removed in vacue and the reaction mass is then recrystallized twice with 50 mL of acetonitrile. The recrystallization solvent is removed under vacuum and the residue is dried under vacuum to afford the title compound in a yield of 5.2 g (86.3%) as an off-white solid melting at 218° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH2:11]([O:13]/[N:14]=[C:15](/[C:44]1[N:48]=[C:47]([NH2:49])[S:46][N:45]=1)\[C:16]([NH:18][C@@H:19]1[C:26](=[O:27])[N:25]2[C@@H:20]1[S:21][CH2:22][C:23]([S:31][C:32]1[S:33][CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][N+:40]([CH3:43])=[CH:39][CH:38]=3)[N:36]=1)=[C:24]2[C:28]([O-:30])=[O:29])=[O:17])[CH3:12].CC(C)=O>CC(N(C)C)=O>[CH2:11]([O:13]/[N:14]=[C:15](/[C:44]1[N:48]=[C:47]([NH:49][C:1](=[O:3])[CH3:2])[S:46][N:45]=1)\[C:16]([NH:18][C@@H:19]1[C:26](=[O:27])[N:25]2[C@@H:20]1[S:21][CH2:22][C:23]([S:31][C:32]1[S:33][CH:34]=[C:35]([C:37]3[CH:38]=[CH:39][N+:40]([CH3:43])=[CH:41][CH:42]=3)[N:36]=1)=[C:24]2[C:28]([O-:30])=[O:29])=[O:17])[CH3:12]
Reactant: CC(=O)Cl
Reactant: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3nc(-c4cc[n+](C)cc4)cs3)CS[C@H]12)c1nsc(N)n1
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3nc(-c4cc[n+](C)cc4)cs3)CS[C@H]12)c1nsc(NC(C)=O)n1
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 91 %

Procedure:
Acetyl chloride (129.90 g, 1654.77 mmol) and pyridine (23.47 g, 296.67 mmol) were added to a solution of (6R,7R)-7-[[(2Z)-2-(ethoxyimino)-2-[5-(amino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[[4-(1-methylpyridinium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicylo[4.2.0]oct-2-ene-2-carboxylate (100 g, 164.82 mmol) in dimethylacetamide (1300 ml) and the resulting mixture was stirred at 0-5° C. for 4 to 6 hours. The reaction mixture was then poured into excess acetone to form a slurry which was filtered and dried at room temperature overnight in vacuo to afford 97 g of crude (6R,7R)-7-[[(2Z)-2-(ethoxyimino)-2-[5-(acetamido)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[[4-(1-methylpyridinium-4-yl)-1,3-thiazol-2-yl]sulfanyl]-8-oxo-5-thia-1-azabicylo[4.2.0]oct-2-ene-2-carboxylate. 63% purity by HPLC area % assay (Luna 3 micron C18, 3.0 mm×50 mm; NH4OAc/CH3CN; 1.0 ml/min flow rate)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][CH:4]=1.[Br-:14].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>ClCCl.CO>[Br:14][C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[C:7]([NH:9][CH3:10])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: CNc1nc(OC)ccc1[N+](=O)[O-]
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CNc1nc(OC)c(Br)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
6-Methoxy-N-methyl-3-nitropyridin-2-amine (7 g, 38 mmol) in 150 mL dichloromethane and 50 mL methanol were combined with tetrabutylammonium-tri-bromide (20.3 g, 42.0 mmol). The mixture was stirred at ambient temperator for 2 h. The mixture was poured into water, filtered and washed with water and ethanol and reacted without further purification.