Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:10])([F:11])[CH2:3][CH2:4][C:5]([CH2:13][CH2:12][C:14](=[O:15])[CH3:16])([C:8]#[N:9])[C:6]#[N:7]
Reactant: C=CC(C)=O
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CCC(C#N)(C#N)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.3 %

Procedure:
3.2 g of 2-(3,3,3-trifluoropropyl)malononitrile and 2.1 g of methyl vinyl ketone were dissolved in 30 ml of acetone, 3.3 g of potassium carbonate was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.7 g of 2-(3,3,3-trifluoropropyl)-2-(3-oxobutyl)malononitrile.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]2=[N:7][CH:8]=1.[CH:25]12[CH2:31][CH2:30][CH:29]1[CH2:28][N:27]([C:32]1[N:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[CH2:26]2>>[CH:29]12[CH2:30][CH2:31][CH:25]1[CH2:26][N:27]([C:32]1[N:37]=[CH:36][C:35]([NH:38][C:12]([C:10]3[N:9]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)[C:6]4=[N:7][CH:8]=[C:3]([C:2]([F:23])([F:1])[F:24])[CH:4]=[C:5]4[CH:11]=3)=[O:14])=[CH:34][CH:33]=1)[CH2:28]2
Reactant: Nc1ccc(N2CC3CCC3C2)nc1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Product: O=C(Nc1ccc(N2CC3CCC3C2)nc1)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Yield: 67.3 %

Procedure:
According to a method similar to that described in Stage 12.3, starting from 0.12 g (0.35 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, described in Stage 1.3, and 0.075 g (0.38 mmol) of 6-(3-azabicyclo[3.2.0]hept-3-yl)-3-aminopyridine, prepared in the preceding stage, we obtain 0.12 g of the expected product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1.[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[CH:23]=[CH:22]1>>[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([C:15]2[CH2:14][CH2:13][N:12]([C:9]3[CH2:10][CH2:11][C:6]4[N:7]([C:3]([C:2]([F:20])([F:19])[F:1])=[N:4][N:5]=4)[N:8]=3)[CH2:17][CH:16]=2)=[CH:22]1
Reactant: O=C1CCN(C2=Nn3c(nnc3C(F)(F)F)CC2)CC1
Reactant: c1cnc2[nH]ccc2c1
Product: FC(F)(F)c1nnc2n1N=C(N1CC=C(c3c[nH]c4ncccc34)CC1)CC2
Yield: 27 %

Procedure:
Obtained in 27% yield by an analogous method to Example 2, starting from 1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one and 1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[C:10](O)([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:11][C:10]1([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:2]([CH3:3])([CH3:1])[CH2:12]1
Reactant: C=C(C)c1ccccc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1(C)CC(C)(C)c2ccccc21
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
A mixture of 117.26 g of α-Methylstyrene (Aldrich 99%, 0.98 mol) and 73.0 g of t-Butanol (Aldrich 99%, 0.97 mol) were slowly added (1 hour) to a mixture of 200 g of acetic acid and 200 g of sulfuric acid, previously warmed at 40° C. The suspension so-obtained was stirred 30 min at 40° C. and then the 2 layers were separated. The organic layer was washed with a 0.7 M NaOH acqueous solution (3×50 ml, neutrality) and water (2×50 ml). The opaque yellow solution obtained was then distilled at 26 mbar. At about 100° C. a colourless transparent liquid was distilled off (28.43 g), which was characterized by NMR as pure 1,1,3,3 tetramethylindane (16.6% yield).
Reaction SMILES: [CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][NH:20]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[CH:31]([S:34](Cl)(=[O:36])=[O:35])([CH3:33])[CH3:32].C1CCN2C(=NCCC2)CC1>>[CH3:10][CH:8]([S:5]([NH:4][CH2:3][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][NH:20][S:34]([CH:31]([CH3:33])[CH3:32])(=[O:36])=[O:35])=[CH:15][CH:16]=1)[CH3:1])(=[O:6])=[O:7])[CH3:9]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCNC(=O)OCc2ccccc2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCNS(=O)(=O)C(C)C)cc1
Yield: 42 %

Procedure:
Scheme Vc, step C: {2-[4-(3-Aminopropyl)phenyl]propyl}[(methylethyl)sulfonylamine (0.3 g, 1 mmol, prepared in example 10), isopropylsulfonyl chloride (0.12 mL, 1.06 mmol), and DBU (0.2 mL, 1.17 mmol) were combined and sulfonylation was carried out in a manner analogous to the procedure described in example 2 to provide the title compound, [(methylethyl)sulfonyl]{2-[4-(3-{[(methylethyl)sulfonyl]amino}propyl)phenyl]propyl}amine, (0.17 g, 42%) as a white crystalline solid. Electron spray M.S. 405 (M*+H). Analysis for C18H32N2O4S2:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=NN(C)[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][C:18]1C=C(B2OC(C)(C)C(C)(C)O2)C=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:15]=[CH:20][N:19]=[C:18]([CH3:17])[CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccnc(C)c2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. ESI-MS (m/z): 228 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:60])([F:59])[C:10]1[CH:11]=[C:12]([CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1)[CH2:13][N:14]([C:46]1[N:47]=[N:48][N:49]([CH3:51])[N:50]=1)[C@H:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[C:17]2[C:36]([CH3:45])=[C:37]([C:41]([F:44])([F:43])[F:42])[C:38]([CH3:40])=[CH:39][C:16]1=2.C(=O)(O)[O-].[Na+]>ClCCl>[F:58][C:55]([F:56])([F:57])[C:53]1[CH:52]=[C:12]([CH:11]=[C:10]([C:9]([F:8])([F:59])[F:60])[CH:54]=1)[CH2:13][N:14]([C@H:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[C:17]2[C:36]([CH3:45])=[C:37]([C:41]([F:42])([F:43])[F:44])[C:38]([CH3:40])=[CH:39][C:16]1=2)[C:46]1[N:47]=[N:48][N:49]([CH3:51])[N:50]=1
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCN(C(=O)OC(C)(C)C)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 4.5 h
Yield: 46.3 %

Procedure:
Add trifluoroacetic acid (1.7 mL) slowly to a solution of (S)-tert-butyl 4-{5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepin-1-ylmethyl}-piperidine-1-carboxylate (Example 159) (0.251 g, 0.329 mmol) in dichloromethane (4 mL) at 0° C. under an atmosphere of nitrogen and stir for 4.5 h. Pour the reaction into saturated sodium bicarbonate (25 mL) and dilute with dichloromethane (15 mL). Separate the layers and extract the aqueous layer with dichloromethane (10 mL). Combine the organic layers, wash with saturated sodium bicarbonate (25 mL), dry over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with dichloromethane/methanol/concentrated ammonium hydroxide (90:10:1), to provide the title compound as a white solid (0.101 g, 46%): 1H NMR (CDCl3, 500 MHz) δ 1.01-1.11 (m, 2H), 1.47-1.66 (m, 3H), 1.73-1.95 (m, 5H), 2.34 (s, 6H), 2.55-2.60 (m, 2H), 2.84-2.87 (m, 2H), 2.98-3.09 (m, 3H), 3.25 (br s, 1H), 4.13 (m, 3H), 4.73-4.96 (m, 1H), 5.12 (br s, 1H), 5.56 (br s, 1H), 6.58 (s, 1H), 7.77 (s, 3H); ESI MS m/z 664 [C30H34F9N7+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2-c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Yield: 94.9 %

Procedure:
A solution of 0.15 g of 5-(4-nitrobenzoyl)-6,7-dihydro-5H-dibenz[b,d]azepine in 20 μl of ethanol-ethyl acetate and 10 mg of 10% palladium-on-carbon is hydrogenated under 35 pounds per square inch of hydrogen for 8 hr. The mixture is filtered through diatomaceous earth and the filtrate evaporated to give 0.13 g of product as a light yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.O=P(Cl)(Cl)Cl.[I:11][C:12]1[N:13]=[C:14]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]2)[N:15]2[C:20]=1C(=O)NC=N2>N1C=CC=CC=1>[NH2:1][C:5]1[C:20]2=[C:12]([I:11])[N:13]=[C:14]([C@H:22]3[CH2:23][CH2:24][C@H:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:26][CH2:27]3)[N:15]2[N:2]=[CH:3][N:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]cnn32)CC1
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(N)ncnn32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1H-1,2,4-triazole (0.881 g, 0.0128 mol) in pyridine (3.00 mL) was charged with POCl3 (0.396 mL, 0.00425 mol) and stirred at rt for 15 min. To this mixture was drop wise added methyl trans-4-(5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.570 g, 0.00142 mol) in pyridine (6.00 mL) and stirred at rt for an additional 2.45 h. The reaction was quenched with excess 2 M of NH3 in i-PrOH (40.00 mL) at 0° C. and allowed to stir at rt for an additional 3 h. The reaction was concentrated in vacuo and partitioned between EtOAc and sat. NaHCO3 and, separated. The aqueous was washed with EtOAc (3×) and the combined organic fractions were washed with brine (1×). The aqueous was re-extracted with CHCl3 (3×) and the organic was added to the EtOAc fractions. The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. The crude brown/red solid was purified by chromatography over silica gel [eluting with 5% MeOH in CHCl3] resulting in 438 mg, (76% yield) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.54 (m, 2H), 1.55-1.71 (m, 2H), 1.92-2.07 (m, 4H), 2.35-2.46 (m, 1H), 3.06-3.19 (m, 1H), 3.61 (s, 3H), 6.77 (br. s., 1H) 7.86 (s, 1H) and 8.44 (br. s., 1H); MS (ES+): m/z 401.85 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]2[N:13]=[C:12](C=O)[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH:17]([C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:21]=1[NH2:22])([CH3:19])[CH3:18]>C(O)=O.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]2[NH:13][C:12](=[N:22][C:21]3[C:23]([CH:27]([CH3:28])[CH3:29])=[CH:24][CH:25]=[CH:26][C:20]=3[CH:17]([CH3:19])[CH3:18])[CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: Cc1ccc(O)c(-c2cccc(C=O)n2)c1
Solvent: CO
Solvent: O=CO
Product: Cc1ccc(O)c(-c2cccc(=Nc3c(C(C)C)cccc3C(C)C)[nH]2)c1
Reaction time: 8 h

Procedure:
To a solution of 6-(5′-methyl-2′-hydroxyphenyl)-2-formyl-pyridine (4) (640 mg, 3.00 mmol) in the minimum volume of methanol was added 1.5 equivalents of 2,6-diisopropylaniline (780 mg, 4.50 mmol). After the addition of a few drops of formic acid, the solution was stirred overnight. The cloudy yellow reaction mixture was then filtered through a frit, and the solid washed with methanol (3×5 mL), giving 6-(5′-methyl-2′-hydroxyphenyl)-2-(N-(2,6-diisopropylphenyl) imino)pyridine (5) as a yellow solid. Yield: 1.06 g (95%).
Reaction SMILES: [NH:1]([CH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4]1)[NH2:2].[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>O1CCOCC1>[CH:14](=[N:2][NH:1][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: NNC1NS(=O)(=O)c2ccccc21
Reactant: CC(C)C=O
Solvent: C1COCCO1
Product: CC(C)C=NNC1=NS(=O)(=O)c2ccccc21
Yield: 87.9 %

Procedure:
19.7 g (0.1 mol) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide are dissolved in 200 ml of dioxane at 40°-50° C., and 8 g (0.11 mol) of isobutyraldehyde are added dropwise to the thoroughly stirred mixture. The product is precipitated directly during this procedure. When the addition is complete, the mixture is heated to 80°-90° C. for about 20 minutes and then cooled, and the crystals are filtered off under suction. 22.1 g (88.1% of theory) of 3-isobutylidenehydrazino-1,2-benzisothiazole 1,1-dioxide of melting point 225° C. are obtained in this manner.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:25]1([CH2:31][CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[OH:39][C:38]1[CH:2]=[C:1]([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[O:3][C:35](=[O:36])[C:34]=1[S:33][CH2:32][CH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccncc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccncc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4-acetylpyridine (2.50 g, 20.63 mmol), lithium bis(trimethylsilyl)amide (5.17 g, 30.94 mmol), chlorotrimethylsilane (3.92 mL, 30.94 mmol), THF (200 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. dec. 149-152° C.; 1H NMR (400 MHz, DMSO-d6) δ2.78 (t, 2 H), 3.04 (t, 2 H), 6.98 (s, 1 H), 7.20 (m, 5 H), 7.74 (d, 2 H), 8.74 (d, 2 H).
Reaction SMILES: [S:1]([CH:5]([N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=[O:15])[C:6](Cl)=[O:7])([OH:4])(=[O:3])=[O:2].[C:16]([O:19][CH2:20][C:21]1[CH2:28][S:27][CH:26]2[N:23]([C:24](=[O:30])[CH:25]2[NH2:29])[C:22]=1[C:31]([OH:33])=[O:32])(=[O:18])[CH3:17].C(=O)(O)[O-].[Na+]>CCOCC.O>[C:16]([O:19][CH2:20][C:21]1[CH2:28][S:27][CH:26]2[N:23]([C:24](=[O:30])[CH:25]2[NH:29][C:6](=[O:7])[CH:5]([S:1]([OH:4])(=[O:3])=[O:2])[N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:14]=[O:15])[C:22]=1[C:31]([OH:33])=[O:32])(=[O:18])[CH3:17]
Reactant: O=Cc1cccn1C(C(=O)Cl)S(=O)(=O)O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(n3cccc3C=O)S(=O)(=O)O)C2SC1

Procedure:
A solution of 2-sulfo-2-(2-formyl-1-pyrryl)acetyl chloride (0.01 m) in ether is added to 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.01 m) and sodium bicarbonate (0.03 m) in water. After 30 minutes the phases are separated, the pH adjusted to about 6.5 and the aqueous extracted with ethyl acetate. The ethyl acetate is separated from the aqueous phase, dried over magnesium sulfate and flash evaporated to give the title compound.
Reaction SMILES: C(O)(C)C.[OH-].[Na+].[C:7]1([C:13]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH:14]2[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[N:26]1([CH2:32][CH2:33]Cl)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>O>[CH2:29]1[CH2:30][CH2:31][N:26]([CH2:32][CH2:33][O:17][C:16]([CH:14]2[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:15]2)=[O:18])[CH2:27][CH2:28]1
Reactant: O=C(O)C1CC1(c1ccccc1)c1ccccc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(OCCN1CCCCC1)C1CC1(c1ccccc1)c1ccccc1

Procedure:
100 ml. of isopropanol and 0.21 mol of powdered sodium hydroxide are added to a mixture of 0.1 mol of 2,2-diphenyl-cyclopropane-carboxylic acid and 0.11 mol of piperidino-β-chloroethane hydrochloride. The mixture is heated under reflux for 8 hours, 300 ml. of water are added and the mixture extracted with diethyl ether. The ether phase is washed with water, dried over sodium sulphate, and the ether removed in vacuo to yield the base.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([O:11][CH2:12][C:13]#[CH:14])(=[O:10])[CH3:9].[I-].CO>CCN(CC)CC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1](=[O:6])[C:14]#[C:13][CH2:12][O:11][C:8](=[O:10])[CH3:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)OCC#CC(=O)C(C)(C)C

Procedure:
Pivaloyl chloride (612 μl), propargyl acetate (644 μl), cupper iodide (12 mg) and bis-(triphenylphosphine) palladium(II)-dichloride (9.1 mg) in NEt3 (10 ml) were stirred at RT for 24 h. MeOH was added and the mixture was evaporated off. The residue was taken up in Et2O and the resulting suspension filtered off. The solution was washed with a 1M HCl solution, water, dried (Na2SO4) and evaporated off. Column chromatography (EA/Hept 1/3) afforded 343 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[CH3:10][N:11]([CH2:54][CH:55]=O)[C:12](=[O:53])[C:13]1[CH:52]=[CH:51][CH:50]=[C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][C:20]=2[C:31]2[CH:36]=[C:35]([C:37](=[O:49])[NH:38][C@@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)[CH:34]=[CH:33][N:32]=2)=[O:17])[CH:14]=1.[BH3-]C#N.[Na+].C(O)(=O)C>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:55][CH2:54][N:11]([CH3:10])[C:12](=[O:53])[C:13]1[CH:52]=[CH:51][CH:50]=[C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][C:20]=2[C:31]2[CH:36]=[C:35]([C:37](=[O:49])[NH:38][C@@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)[CH:34]=[CH:33][N:32]=2)=[O:17])[CH:14]=1
Reactant: COCCNCCOC
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COCCN(CCOC)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This compound was prepared according to the procedure described for the synthesis of Example 187 using bis(2-methoxyethyl)amine in place of L-proline-tert-butyl ester. Into a 25-mL round-bottom flask, was placed a solution of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.16 mmol, 1.00 equiv) in ethanol (1 mL), bis(2-methoxyethyl)amine (25 mg, 0.19 mmol, 1.20 equiv), NaBH3CN (20 mg, 0.32 mmol, 2.00 equiv), acetic acid (1.0 mg, 0.02 mmol, 0.10 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (25% CH3CN up to 38% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 47.9 mg product was obtained. This resulted in 47.9 mg (40%) of (S)—N1-(2-(bis(2-methoxyethyl)amino)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LC-MS (ES, m/z): 747 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.24 (s, 1H), 9.50 (s, 1H), 9.20 (d, J=9 Hz, 1H), 8.89 (d, J=3 Hz, 1H), 8.24-8.32 (m, 2H), 7.99 (d, J=6 Hz, 2H), 7.86 (d, J=6 Hz, 1H), 7.60-7.69 (m, 3H), 7.30 (s, 1H), 7.10-7.24 (m, 4H), 5.25 (t, J=6.9 Hz, 1H), 3.80 (d, J=33 Hz, 5H), 3.63 (s, 6H), 3.33 (s, 12H), 2.97 (s, 4H), 2.74 (s, 2H), 1.96-2.00 (m, 2H), 1.73-1.88 (m, 6H), 1.60 (d, J=6 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[NH:4][CH2:5][CH2:6][CH:7]=[O:8].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([N:4]([CH2:5][CH2:6][CH:7]=[O:8])[C:3]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=1[CH3:1])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(Cl)ccc1NCCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(Cl)ccc1N(CCC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The diethyl acetal of 3-(2-methyl-4-chloroanilino)propionaldehyde (0.2 mole), benzene (150 ml) and sodium carbonate (0.2 mole) dissolved in water (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is cooled in an ice bath and chloroacetyl chloride (0.2 mole) is added dropwise with stirring. After addition is completed stirring is continued and the reaction mixture is allowed to warm up to room temperature. After this time the mixture is filtered and the filtrate washed with dilute aqueous hydrochloric acid. The washed filtrate is dried over anhydrous magnesium sulphate and is stripped of solvent under reduced pressure to yield the desired product the diethyl acetal of 3-[N-(α-chloroacetyl)-2-methyl-4-chloroanilino]propionaldehyde.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].CN1CCOCC1.[CH2:14]([O:21][C:22]([NH:24][CH2:25][CH2:26][NH2:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[C:15]1([CH2:14][O:21][C:22]([NH:24][CH2:25][CH2:26][NH:27][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)C(=O)Cl
Reactant: NCCNC(=O)OCc1ccccc1
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: CN(C)C(=O)NCCNC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 49.6 %

Procedure:
A solution of dimethylcarbamoyl chloride (1.39 g) in diethyl ether (15 ml) was added dropwise to a stirred solution of NMM (1.57 g) and 2-benzyloxycarbonylaminoethylamine (3.02 g) in diethyl ether (110 ml). The mixture was stirred for four hours and allowed to stand for two days. After evaporation of the ether the residual solid was partitioned between 10% aqueous citric acid and ethyl acetate. The ethyl acetate extracts were washed with 10% aqueous citric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, and then dried (Na2SO4) and evaporated to give a solid (1.7 g). A sample crystallised from ethyl acetate/patroleum ether (bp 60°-80°) m.p. 81°-82°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl.[NH2:36][OH:37]>C(O)C>[OH:37][N:36]=[C:1]([NH2:2])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:4]=1
Reactant: NO
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C#N)c1)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Yield: 96 %

Procedure:
(S)-5-(3-Cyanophenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (2.00 g, 5.69 mmol) obtained in Step 1 of Example 71 was suspended in ethanol (30 mL), and the mixture was refluxed for 5 hours after adding diisopropylethylamine (1.90 mL, 10.9 mmol) and hydroxylamine hydrochloride (761 mg, 10.9 mmol). After concentrating the mixture under reduced pressure, water was added to the resulting residue, and the precipitated white solid was filtered off to give (S)—N′-hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (2.10 g, 96%).