Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([CH:38]=[CH:39][CH:40]=2)[C:28]([O:30]CC2C=CC=CC=2)=[O:29])O1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[C:10]([O:9][C:8]([NH:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([C:25]2[CH:40]=[CH:39][CH:38]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=2)=[CH:3][CH:4]=1)=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC1(C)OB(c2cccc(C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(C(=O)O)c2)cc1
Temperature: 80 °C
Reaction time: 1.17 h
Yield: 79.8 %

Procedure:
To a mixture of tert-butyl N-(4-bromobenzyl)carbamate (0.425 g), benzyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolane-2-yl)benzoate (0.553 g), sodium carbonate (0.315 g), water (1.3 mL) and N,N-dimethylformamide (6.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.086 g), and the resulting mixture was stirred at 80° C. for 70 minutes. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (35 mL) and water (15 mL). The organic layer was washed successively with water/brine (2/1, 15 mL×2) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the residue (1.0 g) in ethanol (7.4 mL) was added 1 mol/L aqueous sodium hydroxide (2.23 mL), and the resulting mixture was stirred at 80° C. for 80 minutes. One mol/L aqueous sodium hydroxide (2.23 mL) was added and stirring was continued for additional 2 hours. The reaction mixture was cooled to room temperature. One mol/L hydrochloric acid (4.46 mL) was added and then the whole was partitioned between ethyl acetate (35 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2-1/2) to give 4′-(tert-butoxycarbonylaminomethyl)biphenyl-3-carboxylic acid (0.388 g). To a solution of the carboxylic acid (0.330 g) in N,N-dimethylformamide (5.0 mL) were added successively dimethylamine hydrochloride (0.123 g), diphenylphosphoryl azide (0.435 mL) and triethylamine (0.422 mL), and the resulting mixture was stirred at room temperature for 67.5 hours. One mol/L hydrochloric acid (10 mL) was added and the whole was extracted with ethyl acetate (30 mL). The organic layer was washed successively with water (10 mL), saturated aqueous sodium hydrogen carbonate (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/ethyl acetate=8/1) to give the title compound (0.246 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:4]([NH:6][CH3:7])=[S:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[CH2:20]=O>CO>[CH3:1][O:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([CH2:20][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]([NH:6][CH3:7])=[S:5]
Reactant: C=O
Reactant: C1COCCN1
Reactant: CNC(=S)C(OC)c1ccccn1
Solvent: CO
Product: CNC(=S)C(CN1CCOCC1)(OC)c1ccccn1

Procedure:
A solution of 1.96 g. (0.01 mole) of 2-methoxy-N-methyl-2-(2-pyridyl)thioacetamide in 20 ml. of methanol is treated with 1.3 g. (0.015 mole) of morpholine and 0.45 g. (0.015 mole) of formaldehyde. The mixture is refluxed for 48 hours. The solvents are removed in vacuo. The residue is recrystallized twice from 2-propanol to give 2-methoxy-N-methyl-3-morpholino-2-(2-pyridyl)thiopropanamide, m.p. 128°-132°C.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:12]2[O:13][C:14]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:15]=3[S:16](=[O:19])(=[O:18])[CH2:17][C:11]=2[CH:10]=[C:9]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:8]=1.Cl.[CH:35](O)([CH3:37])[CH3:36]>>[ClH:6].[CH:35]([O:26][C:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:14]2[O:13][C:12]3[C:7]([Cl:6])=[CH:8][C:9]([N:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[CH:10][C:11]=3[CH2:17][S:16](=[O:18])(=[O:19])[C:15]=2[CH:20]=1)=[O:27])([CH3:37])[CH3:36]
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Reactant: CC(C)O
Agent: Cl
Agent: O=S(=O)(O)O
Product: Cc1cc(C(=O)OC(C)C)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Concentrated sulphuric acid (1 mL) was added dropwise to a stirred solution of compound of Example 18 (0.5 g, 1.18 mmol) in dry isopropanol (50 mL) at 90° C. The reaction mixture was stirred at 90° C. for 2 h. Solvent was removed and the residue was taken in chloroform (100 mL) and this was neutralized using sodium carbonate solution (10%). Chloroform layer was washed with water, brine and dried over sodium sulphate. Solvent was removed and the product obtained was converted to hydrochloride salt by using isopropanol/ethereal-HCl to obtain the title compound. Yield: 0.4 g (67.79%); mp: 262-64° C.; 1H NMR (DMSO-d6, 300 MHz): δ 1.29 (d, 6H, 2CH3), 2.63 (s, 3H, CH3), 3.18 (bs, 4H, 2CH2), 3.44 (bs, 4H, 2CH2), 5.11 (s, 1H, CH), 5.17 (s, 2H, CH2), 7.19 (s, 2H, Ar), 8.07 (s, 1H, Ar), 8.11 (s, 1H, Ar), 9.45 (bs, 2H, NH, HCl); MS: m/e (ES+) 465 (M+1, free base).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:12]2[CH2:17][C:16]([CH3:18])=[CH:15][CH2:14][NH:13]2)([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH2:19](I)[CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:19]([N:13]1[CH2:14][CH:15]=[C:16]([CH3:18])[CH2:17][CH:12]1[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([CH3:11])[CH3:10])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCI
Reactant: COc1ccc(C(C)(C)C2CC(C)=CCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCN1CC=C(C)CC1C(C)(C)c1ccc(OC)cc1
Yield: 75.1 %

Procedure:
A mixture of 1,2,3,6-tetrahydro-2-[1-(4-methoxyphenyl)-1-methylethyl]-4-methylpyridine (2.9 g), pentyl iodide (2.34 g), potassium carbonate (3 g) and dimethylformamide (20 ml) was heated to reflux for 4 hours while stirring. After cooling and adding water, the reaction product was extracted with benzene. The extract was washed twice with water, dried over potassium carbonate and distilled to remove benzene to obtain 2.8 g of 1,2,3,6-tetrahydro-1-pentyl-2-[1-(4-methoxyphenyl)-1-methylethyl]-4-methylpyridine as a viscous mass. To the mass was added 20 ml of 47% hydrobromic acid and the mixture was heated to reflux for 10 hours while stirring, after cooling, made alkaline with a concentrated ammonia water under cooling and extracted with chloroform. The extract was dried over sodium sulfate and distilled to remove chloroform. The residue was fed to a column chromatograph on silica gel and eluted with chloroform. Chloroform was distilled off from the eluate to obtain 2.2 g of 1,2,3,4,5,6-hexahydro-8-hydroxy-3-pentyl- 2,6-methano-1,1,6-trimethyl-3-benzazocine as a viscous mass. The product was treated as in Example 1-(5) to obtain the corresponding hydrochloride as colorless fine needles having a melting point above 230° C. (sublimable) after the recrystallization from methanol-ethyl ether.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[C:6]=2[CH3:17])[CH3:2].[Cl:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[N:24]([CH3:39])[C:25]([C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]3)=[N:26][N:27]=1>>[ClH:18].[CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH2:21][S:22][C:23]3[N:24]([CH3:39])[C:25]([C:28]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:29]=4[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]5)=[N:26][N:27]=3)[CH2:12][CH2:13][C:7]=1[C:6]=2[CH3:17])[CH3:2]
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Reactant: CCc1nc2cc3c(c(C)c2o1)CCNCC3
Product: CCc1nc2cc3c(c(C)c2o1)CCN(CCCSc1nnc(-c2cccc4nc(C)ccc24)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-ethyl-10-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (85 mg) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (147 mg) and was obtained as a colourless slightly hygroscopic solid (150 mg).
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]([Si](C)(C)C)[Si](C)(C)C)=[CH:9][CH:8]=1.[C:22]1(=[O:32])[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[C:24](=[O:31])[O:23]1.S(=O)(=O)(O)O>O1CCCC1>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]([C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=2[C:22]([OH:32])=[O:23])=[O:31])=[CH:8][CH:9]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: C[Si](C)(C)N(c1ccc(Br)cc1)[Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Nc1ccc(C(=O)C2=C(C(=O)O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.2 g magnesium turnings (83.5 mmol) in 15 ml tetrahydrofuran were added 0.1 mL 1,2-dibromethane to start the Grignard reaction followed by slow addition of 13.0 g 2-(4-bromphenyl)-1,1,1,3,3,3-hexamethyldisilazane (41 mmol) in 70 mL tetrahydrofuran over a period of 20 minutes at room temperature with subsequent stirring for further 30 minutes. The resulting mixture was added dropwise at −78° C. to a solution of 4,5,6,7-tetrahydro-isobenzofuran-1,3-dione (5.6 g) in 70 mL tetrahydrofuran. The reaction mixture was slowly warmed to room temperature. Sulfuric acid (2 mL, 1 M) was added and the solvent was removed under reduced pressure. The residue was added carefully to 20 mL of 0.5 M sulfuric acid solution and the desired product started to precipitate and was extracted with ethyl acetate. Acidification of the water phase and extraction with ethyl acetate was continued until pH˜4-5 (at least three times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and the solvent was subsequently evaporated under reduced pressure. Purification of the raw material by column chromatography with ethyl acetate/hexane 1:1 and subsequently 100% ethyl acetate resulted in the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[CH:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1ccc(Cl)cc1)C1CCOCC1
Product: O=C(NCC(c1ccc(Cl)cc1)C1CCOCC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=378.1, tR (minutes, Method G)=2.34
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:42]([N:45]([CH:48]([CH3:50])C)[CH2:46]C)([CH3:44])C.FC(F)(F)S(O)(=O)=O.FC(F)(F)S(O)(=O)=O.[SH:67][C@@H:68]1[CH2:72][N:71]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][C:80]([N+:83]([O-:85])=[O:84])=[CH:79][CH:78]=2)=[O:74])[C@H:70]([C:86](=[O:96])[NH:87]C(C)CN2CCCC2)[CH2:69]1>C(#N)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[CH:8][C@@:9]([CH3:10])([S:67][C@@H:68]3[CH2:72][N:71]([C:73]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][C:80]([N+:83]([O-:85])=[O:84])=[CH:81][CH:82]=4)=[O:74])[C@H:70]([C:86](=[O:96])[NH:87][CH:42]4[CH2:44][CH2:50][CH2:48][N:45]4[CH3:46])[CH2:69]3)[C@H:5]12)[CH3:3]
Reactant: CC(CN1CCCC1)NC(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCN(C(C)C)C(C)C
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C[C@@](C)(S[C@H]3C[C@@H](C(=O)NC4CCCN4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H]12
Temperature: 0 °C
Reaction time: 48 h

Procedure:
180 mg of 4-nitrobenzyl (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate were dissolved in 2.3 ml of anhydrous acetonitrile, and the solution was placed on an ice bath. Maintaining the solution on the ice bath, 109 μl of diphenylphosphoryl chloride and 92 μl of diisopropylethylamine were added dropwise to the solution. The resulting mixture was then stirred for 1 hour at this ice-cooled temperature, after which, whilst still maintaining the reaction mixture on the ice bath, 313 μof diisopropylethylamine and 1.9 ml of an anhydrous acetonitrile solution containing 440 mg of (2S, 4S)-4-mercapto-2-(1-methyl-2-pyrrolidinylethylcarbamoyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine bis(trifluoromethanesulfonate) [prepared as described in step (1) above] were added dropwise to the mixture. The mixture was then stirred at this ice-cooled temperature for 5 hours and allowed to stand for 2 days in a refrigerator. At the end of this time, the solvent was removed by distillation under reduced pressure. An aqueous solution of sodium hydrogencarbonate was added to the residue, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was subjected to Lobar column chromatography (Merck, LiChroprep Si60). From fractions eluted with a 1:2 by volume mixture of acetonitrile and methanol were obtained 65 mg of the title compound.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCCCCCCO
Reactant: CC(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)C(C)O
Yield: 35.7 %

Procedure:
A 2 liter one neck round bottom flask equipped with a Dean Stark trap, condenser and nitrogen, inlet outlet was charged with 150.0 g (1.66 moles) lactic acid, 293.0 g (2.25 moles) octyl alcohol, 6 ml sulfuric acid and 500 ml toluene. Mixture was heated to 130° for 2.5 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. Approximately 50 ml ether was needed to break the emulsion. The organic layer was collected and dried over magnesium sulfate. Octyl lactate was distilled under high vacuum to yield 119.85 g (35.6% yield) of clear colorless liquid. According to GC the product is 96.2% pure.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:14]1([CH:20]([O:27][C:28]([C:30]2[N:31]3[CH:34]([CH2:35][CH2:36][C:37]=2Cl)[C@@H:33]([NH:39][C:40](=[O:70])/[C:41](/[C:63]2[N:64]=[C:65]([NH2:69])[S:66][C:67]=2[Cl:68])=[N:42]\[O:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:32]3=[O:71])=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([CH:20]([O:27][C:28]([C:30]2[N:31]3[CH:34]([CH2:35][CH2:36][C:37]=2[S:7][C:5]2[S:6][C:2]([NH2:1])=[N:3][N:4]=2)[C@@H:33]([NH:39][C:40](=[O:70])/[C:41](/[C:63]2[N:64]=[C:65]([NH2:69])[S:66][C:67]=2[Cl:68])=[N:42]\[O:43][C:44]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:32]3=[O:71])=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Cl)CCC23)c(Cl)s1
Reactant: Nc1nnc(S)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nnc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4nc(N)sc4Cl)C3CC2)s1
Reaction time: 18 h
Yield: 72 %

Procedure:
To a solution of 5-amino-1,3,4-thiadiazole-2-thiol (0.6 g., 0.0045 mol) in dimethylformamide (25 mL) was added potassium carbonate (1.0 g, 0.0076 mol). The mixture was stirred for 1 hour at room temperature after which (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]acetamido]-3-chloro-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (3.2 g., 0.0039 mol) was added. Stirring was continued for 18 hours. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, washed with water (30 mL), dried over anhydrous MgSO4 and the solvent was removed with a rotary evaporator. The resultant thick oil was treated with diethyl ether (50 mL) and the solid which formed was filtered and dried to give 2.6 g of crude product.
Reaction SMILES: C[CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)=[O:19])=[CH:12][C:11]=12.[N+](C1C=CC([C:36](O)=[O:37])=CC=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:5][CH2:4][C@@H:3]4[CH2:2][CH2:6][O:37][CH2:36]4)=[O:26])=[CH:22][CH:21]=3)=[O:19])=[CH:12][C:11]=12
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccn3ccnc3c2)cc1
Reactant: CC(C)CCN
Product: O=C(NCc1ccn2ccnc2c1)c1ccc(C(=O)NC[C@@H]2CCOC2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting (S)-(tetrahydrofuran-3-yl)methanamine for 3-methylbutan-1-amine and 4-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)benzoic acid for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.21 (t, J=5.9 Hz, 1H), 8.69 (t, J=5.7 Hz, 1H), 8.49 (dd, J=6.9, 0.9 Hz, 1H), 8.07-7.71 (m, 5H), 7.52 (d, J=1.2 Hz, 1H), 7.41 (s, 1H), 6.87 (dd, J=7.0, 1.7 Hz, 1H), 4.52 (d, J=5.9 Hz, 2H), 3.80-3.56 (m, 4H), 3.48 (dd, J=8.5, 5.2 Hz, 1H), 2.02-1.87 (m, 1H), 1.68-1.53 (m, 1H), 1.32-1.00 (m, 2H); MS (ESI(+)) m/e 379 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]([CH3:34])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>>[CH3:34][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:32][CH:33]=1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CN(C)CCCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(3-dimethylaminopropoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-dimethyl-3-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenoxy]propan-1-amine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[CH2:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: c1ccc2c(c1)CCN2
Reactant: CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCCCCN1CCc2ccccc21
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of indoline (17 parts), 1-bromoheptane (31 parts), potassium carbonate (24 parts) and N,N-dimethylformamide (30 parts) was stirred at 100° C. for 3 days. The cooled mixture was diluted with toluene, washed with water (×4), dried (MgSO4) and evaporated to leave 1-heptyl-2,3-dihydro-1H-indole (30 parts).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH2:9]([Li])[CH2:10][CH2:11]C.[CH2:14]([Si:17](Cl)(C)[CH3:18])C=C>C1COCC1>[CH2:9]([C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[SiH:17]([CH3:18])[CH3:14])[CH:10]=[CH2:11]
Reactant: C=CC[Si](C)(C)Cl
Reactant: Ic1ccc(I)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCc1ccc(I)cc1[SiH](C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
To a solution 1,4-diiodobenzene (16.5 g, 50 mmol) in dried THF (250 mL) at −78° C. was added n-butyllithium (22 mL, 2.5 M solution in hexanes, 55 mmol) over a period of 30 min. After being stirred for 10 min at −78° C., allylchlorodimethylsilane (6.7 g, 50 mmol) in was added dropwise over a period of 20 min, and the reaction mixture was warmed to room temperature. After stirring for 1 h at room temperature the reaction mixture was concentrated, and the residue was extracted with ether and brine. The organic layer was dried (Na2SO4) and distilled (Kugelrohr) under reduced pressure to provide a liquid (11.5 g, 76%); 1H NMR (300 MHz, CDCl3) δ 0.32 (s, 6 H), 1.78 (d, J=7.5 Hz, 2 H), 4.89 (m, 1 H), 4.92 (d, J=4.0 Hz, 1 H), 5.78 (m, 1 H), 7.27 (d, J=7.5 Hz, 2 H), 7.74 (d, J=7.5 Hz, 2 H); 13C NMR (75 MHz, CDCl3) −3.5, 23.8, 114.1, 134.4, 135.6, 137.1, 138.3, 139.6; HRMS calcd for C11H15ISi 301.9987, found 301.9990.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:23])[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:22])[CH:14]=1)C(OCC)=O)C>CO.O>[CH3:22][C:15]1[CH:14]=[C:13]([CH2:7][C:6]([OH:23])=[O:5])[CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Potassium hydroxide (0.168 g) was dissolved in 7 mL of methanol and 1 mL of water, and the 2-(3-methyl-4-nitrophenyl)malonic acid diethyl ester (0.250 g) obtained in Example 1-3a) was dissolved in the solution. The solution was stirred at 100° C. for 2 hours and concentrated. The residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and concentrated to give the title compound (0.143 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([OH:15])[CH2:6][O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH3:2].C(N(CC)CC)C.[CH3:23][S:24]([CH2:27][CH2:28][C:29](Cl)=[O:30])(=[O:26])=[O:25]>ClCCl>[CH2:1]([O:3][CH2:4][CH:5]([OH:15])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:29](=[O:30])[CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CS(=O)(=O)CCC(=O)Cl
Reactant: CCOCC(O)COc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(O)COc1ccc(NC(=O)CCS(C)(=O)=O)cc1
Yield: 94.2 %

Procedure:
A 2.11 g quantity of 4-(3-ethoxy-2-hydroxypropoxy)aniline and 1.53 g of triethylamine were dissolved in 50 ml of dichloromethane. To the solution was added 1.71 g of 3-(methylsulfonyl)propionyl chloride with ice cooling. The same subsequent procedure as in Example 2 was repeated and recrystallization from benzene was performed, giving 3.25 g of N-[4-(3-ethoxy-2-hydroxypropoxy)phenyl]-3-(methylsulfonyl)propionamide in a yield of 94.2 %. M.p. 111° to 112° C.