Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][S:24][C:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:22]3)[C:4]=2[CH:3]=1.[CH3:31][C:32]([CH3:36])([CH3:35])[C:33]#[CH:34].C(NC(C)C)(C)C>[Cu]I.CN(C=O)C>[C:27]([NH:26][C:23]1[S:24][CH2:25][C:5]2([N:22]=1)[C:4]1[CH:3]=[C:2]([C:34]#[C:33][C:32]([CH3:36])([CH3:35])[CH3:31])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:16]2[CH:21]=[N:20][CH:19]=[N:18][CH:17]=2)=[CH:9][CH:10]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)NC1=NC2(CS1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Reactant: C#CC(C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)C#Cc1ccc2c(c1)C1(CSC(NC(C)(C)C)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A resealable tube was charged with (t-4)-tetrakis(triphenylphosphine)palladium (27.1 mg, 0.023 mmol), copper(i) iodide (8.94 mg, 0.047 mmol),2′-bromo-N-tert-butyl-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (113 mg, 0.235 mmol), 3,3-dimethylbut-1-yne (144 μL, 1.174 mmol), diisopropylamine (669 μL, 4.69 mmol) and DMF (1.9 mL). The mixture was heated at 80° C. After 18 hrs, the mixture was cooled to RT, filtered through celite with EtOAc, and concentrated in vacuo. The residue was adsorbed onto silica gel and purified by silica gel chromatography using 30-75% Hexanes:EtOAc to afford N-tert-butyl-2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine as an off-white foam. MH+=483.2.
Reaction SMILES: [CH:1]([N:3]([CH:7]1[C:16]2[C:11](=[C:12]([CH2:17][OH:18])[CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][CH3:20])[CH2:9][CH2:8]1)[CH:4]1[CH2:6][CH2:5]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C(OCC)C>O1CCCC1>[CH3:1][N:3]([CH:7]1[C:16]2[C:11](=[C:12]([CH2:17][OH:18])[CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][CH3:20])[CH2:9][CH2:8]1)[CH:4]1[CH2:6][CH2:5]1
Reactant: CCN1CCC(N(C=O)C2CC2)c2cccc(CO)c21
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN1CCC(N(C)C2CC2)c2cccc(CO)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 4-(N-formyl-N-cyclopropylamino)-8-hydroxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (0.34 g) in tetrahydrofuran (10 ml), lithium aluminum hydride (0.10 g) was added under ice-cooling and the mixture was refluxed gently for 1.5 hours. A saturated aqueous solution of Rochelle salt was added to the reaction mixture under ice-cooling, followed by addition of diethyl ether, the mixture was stirred for 1 hour at room temperature. After filtering off the precipitates, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 4-(N-methyl-N-cyclopropylamino)-8-hydroxymethyl-1-ethyl-1,2,3,4-tetrahydroquinoline (0.30 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([F:57])=[C:10]([CH:16]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([NH2:56])=[N:47]C(=O)C3C=CC=CC=3)=[CH:42][CH:41]=2)[C:17]2[N:18]=[C:19]([O:28][CH2:29][O:30][C:31](=[O:38])[C:32]([CH3:37])([CH3:36])[CH2:33][O:34][CH3:35])[N:20]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:21]=2)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)(=[O:3])[CH3:2].CO>C(O)(=O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([F:57])=[C:10]([CH:16]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([C:46](=[NH:47])[NH2:56])=[CH:42][CH:41]=2)[C:17]2[N:18]=[C:19]([O:28][CH2:29][O:30][C:31](=[O:38])[C:32]([CH3:37])([CH3:36])[CH2:33][O:34][CH3:35])[N:20]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:21]=2)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Solvent: CO
Solvent: CC(=O)O
Product: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Temperature: 40 °C
Reaction time: 15 h
Yield: 168.1 %

Procedure:
Under nitrogen atmosphere, a mixture of 3-methoxy-2,2-dimethylpropionic acid 5-[[3-(2-acetoxyethoxy)-2-fluoro-5-methoxyphenyl]-(4-{amino[benzoylimino]methyl}phenylamino)methyl]-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester (184 mg), methanol (10 mL), and acetic acid (1 mL) was stirred at 40° C. for 15 hours. Under reduced pressure, the solvent in the mixture was distilled off. The residue obtained was purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water, containing 0.1% of acetic acid) to obtain the captioned compound (146 mg).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH:11]=[CH:10]1)(C(C)(C)C)(C)C.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl>[OH:28][CH:11]1[CH:10]2[CH:9]([O:8]2)[CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)N1CC=CC(O[Si](C)(C)C(C)(C)C)C1
Solvent: ClCCl
Product: CCOC(=O)N1CC(O)C2OC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a solution of Compound 239D (25.2 g, 88.3 mmol) in 250 mL of CH2Cl2 at 0° C. was added solid m-CPBA (39.6 g, 176.6 mmol, 77% max) in small portions while the internal temperature was kept below 0° C. during the addition. The mixture was stirred at 0° C. for 30 min and then room temperature for 4.0 hrs. More solid m-CPBA (39.6 g, 176.6 mmol, 77% max) was added in small portions and the mixture was stirred at room temperature for three days. The precipitate was removed by filtration and the filtrate was washed with 20% Na2S2O3 (500 mL×3), sat'd NaHCO3 (500 mL×3) and brine (250 mL), dried over anhydrous Na2SO4. Purification by flash chromatography (hexane-EtOAc: 9.5:0.5 to 9:1) on silica gel afforded 4.33 g of 239E (lower Rf) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:11][CH:12]=[C:13]([CH:19]=1)[C:14]([O:16]CC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].CCOC(C)=O>CCO.O>[CH2:1]([O:8][C:9]1[C:10]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:11][CH:12]=[C:13]([CH:19]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)c(OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)cc1OCc1ccccc1
Temperature: 0 °C

Procedure:
To a cooled (0° C.) stirred mixture of ethyl 5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)nicotinate (1.2 g, 0.0032 mol) in EtOH:water (1:1, 12 mL), was added LiOH (154 mg, 0.0064 mol, Aldrich). The reaction mixture was stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 100% EtOAc), the reaction mixture was quenched with 1N HCl at 0° C. temperature and extracted with EtOAc (2 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 13.24 (s, 1H), 9.18 (s, 1H), 8.45 (d, J=1.2 Hz, 1H), 7.80 (d, J=1.5, Hz, 1H), 7.53 (d, J=5.4 Hz, 2H), 7.41-7.34 (m, 2H), 5.24 (s, 2H), 1.38 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1)(=[O:24])=[O:23]
Reactant: Nc1nc(-c2ccc(Cl)s2)cs1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2ccc(Cl)s2)cs1

Procedure:
The title compound was prepared from 4-(5-chloro-2-thienyl)-1,3-thiazol-2-amine (METHOD H) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (19.5 mg) with purity >90%. MS (pos) m/z 439.0, 441.0.
Reaction SMILES: C1(=O)OCC=C1.[P:7]([CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]=[CH:16]1)([OH:10])([OH:9])=[O:8].P([O:29][CH2:30][C@H:31]1[O:35][C@@H:34]([N:36]2[C:45]3[N:44]=[CH:43][N:42]=[C:40]([NH2:41])[C:39]=3[N:38]=[CH:37]2)[C@H:33]([OH:46])[C@@H:32]1[OH:47])(O)(O)=O>>[C@@H:34]1([N:36]2[C:45]3[N:44]=[CH:43][N:42]=[C:40]([NH2:41])[C:39]=3[N:38]=[CH:37]2)[O:35][C@H:31]([CH2:30][OH:29])[C@@H:32]([OH:47])[C@H:33]1[OH:46].[P:7]([CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]=[CH:16]1)([OH:10])([OH:9])=[O:8]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: Nc1ncnc2ncn(CCOCP(=O)(O)O)c12
Agent: O=C1C=CCO1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Dinucleotide 24 afforded phosphonate 20 and adenosine 5′-monophosphate 21 in about 60% yield. 9-(β-D-Furanosyl)adenine-3′-[[1-(adenin-7-yl-ethoxy)methyl]-phosphonate] gave adenosine (40% yield) and 20 (60% yield). Dinucleotide analog 25, having a butenolide ester unit, was found to be stable to the enzyme.Compound 24, possessing both the skeletons of phosphonate 20 and 5′-adenosine monophosphate 21, was dephosphorylated at the 5′-position by snake venom in 80% yield after 8 h. The resultant 9-(b-D-furanosyl)adenine-3′-[[1-(adenin-7-yl-ethoxy)methyl]phosphonate] was hydrolyzed further in the presence of spleen phosphodiesterase to afford adenosine and phosphonate 20 in about 40-60% yield after 8 h. See, Hakimelahi et al. (1995) J. Med. Chem. 38: 4648-4659 and references cited therein. Spleen phosphodiesterase also degraded compound 24 to give 5′-adenosine monophosphate 21 and phosphonate 20 in an overall yield of 60% after 8 h. These results indicate that the phosphodiesterases recognized dinucleotide analog 24 as a normal substrate. In addition, it was found that nucleotide-containing butenolide 25 was completely resistant to snake venom and spleen enzymes.
Reaction SMILES: [OH-].[Na+].C([NH:6][C:7]1[C:12]([NH:13][C:14](=O)[CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=1[OH:17])(=O)C.Cl>>[OH:17][C:8]1[C:7]2[NH:6][C:14]([CH3:15])=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)Nc1cccc(O)c1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cccc(O)c2[nH]1

Procedure:
To a solution of 6.8M NaOH 15.8 g (0.076 mol) of 2,3-diacetamidophenol was added and the mixture was heated under reflux for 2 h. Upon cooling the pH of the solution was adjusted to 8.5 with 2M HCl. The solid was filtered off, washed with water and dried to give 7.6 g of the title compound.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([O:20][CH3:21])=[O:19])[CH2:10]1)=O)(C)(C)C.[ClH:22].O1CCOCC1>C(O)(=O)C>[ClH:22].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([O:20][CH3:21])=[O:19])[CH2:10]1
Reactant: COC(=O)c1cccc2c1CC(NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1CC(N)C2

Procedure:
Using 2-(tert-butoxycarbonylamino)-4-methoxycarbonylindan (45 mg, 0.15 mmol) synthesized in the above Reference Production Example 7, 4N hydrochloric acid-dioxane (0.7 ml) and acetic acid (2.1 ml), a similar procedure to Production Example 213 was carried out to obtain 2-amino-4-methoxycarbonylindan hydrochloride. Then, using the 2-amino-4-methoxycarbonylindan hydrochloride, 4-chloro-5-methylthieno[2,3-d]pyrimidine (28 mg, 0.15 mmol), triethylamine (63 μl, 0.45 mmol), and ethanol (1 ml), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (15 mg, 0.044 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:26][C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)[CH2:39][C:35]2[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=2)=[CH:20][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)CCN(CCCCN1CCCCC1)Cc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCN(CCCCN1CCCCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
The compound (403 mg) obtained in Example 62-2 was dissolved in anhydrous methanol (16 ml) and added with 1-methyl-2-imidazole carboxaldehyde (151 mg) and sodium cyanoborohydride (172 mg). After the solution was adjusted to pH 5 with acetic acid, the whole was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off. The resultant was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (333 mg) as a colorless oily substance.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C@H:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][C:20](O)=[O:21])=[O:16])[CH:12]=[CH:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:5][C:4]=1[O:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39].[CH3:41][S:42]([NH2:45])(=[O:44])=[O:43].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C@@H:18]([CH2:19][C:20]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])=[O:21])[C:23]([CH3:25])([CH3:24])[CH3:26])=[O:16])[CH:12]=[CH:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[CH:5][C:4]=1[O:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CC(=O)O)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N[C@@H](CC(=O)NS(C)(=O)=O)C(C)(C)C)nc1-c1ccc(Cl)c(OCCCN(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 250 mg (0.42 mmol) of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]-carbonyl}amino)-4,4-dimethylpentanoic acid hydrochloride and 49 mg (0.51 mmol) of methanesulfonamide in 2 mL of DCM are successively added 52 mg (0.42 mmol) of DMAP and 89 mg (0.47 mmol) of EDC.HCl. The reaction medium is stirred for 16 hours at room temperature. A further 0.42 mmol of EDC.HCl and 0.42 mmol of methanesulfonamide are added and the reaction mixture is stirred for a further 3 days and then concentrated under reduced pressure. The residue is taken up in 100 mL of EtOAc and the organic phase is washed with 30 mL of water and then with 30 mL of aqueous 4M NaHCO3 solution. After drying over Na2SO4 and concentrating under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a DCM/methanol gradient of from 0 to 10% methanol. After concentrating under reduced pressure, the residue is taken up in 2 mL of methanol and 0.5 mL of aqueous 1N HCl solution and then purified by reverse-phase HPLC (RP18), eluting with a 10−2N HCl/acetonitrile gradient of from 5% to 100% acetonitrile over 90 minutes. After concentrating under reduced pressure and freeze-drying, 130 mg of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-N-[(1S)-2,2-dimethyl-1-{2[(methylsulfonyl)amino]-2-oxoethyl}propyl]-5-(2-methylphenyl)pyridine-2-carboxamide hydrochloride are obtained in the form of a white powder.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([N:30]=[C:31]=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:33]1([NH2:36])[CH2:35][CH2:34]1>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([NH:30][C:31]([NH:36][CH:33]4[CH2:35][CH2:34]4)=[O:32])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC1CC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(NC(=O)NC4CC4)C3)ccc2n1CC1CCC(F)(F)CC1
Yield: 44.2 %

Procedure:
Following the same procedure in Example 105, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(3-isocyanatoazetidin-1-yl)sulfonyl]-1H-benzimidazole (0.095 mmol) and cyclopropylamine (13 uL, 11 mg, 0.19 mmol) in THF (6.0 mL). The crude product was purified by MPLC using EtOAc/MeOH (20:1) on silica gel to give 22 mg (44%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.29-0.40 (m, 2 H), 0.57-0.66 (m, 2 H), 1.49-1.64 (m, 2 H), 1.67 (s, 9 H), 1.70-1.86 (m, 4 H), 1.99-2.15 (m, 2 H), 2.20-2.31 (m, 1 H), 2.31-2.41 (m, 1 H), 3.65-3.78 (m, 2 H), 3.94-4.06 (m, 2 H), 4.15-4.30 (m, 1 H), 4.55 (d, J=7.42 Hz, 2 H), 7.92 (dd, J=8.69, 1.66 Hz, 1 H), 8.05 (d, J=8.79 Hz, 1 H), 8.18 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=524.3; Anal. Calcd for C25H35F2N5O3S+1.20 TFA+0.60H2O+0.40 EtOAc (711.33): C, 49.64; H, 5.75; N, 9.85. Found: C, 49.62; H, 5.71; N, 9.83.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH2:20]([C:22]1[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[C:24]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:26][CH:27]=1)[CH3:21]
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: CCc1cccc(N)c1
Product: CCc1cccc(Nc2nc(Nc3cc[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-ethyl-phenylamine give N1-(3-ethyl-phenyl)-6-methoxy-N3-(1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 360(MH+).
Reaction SMILES: [Na].Br[C:3]1[N:10]=[C:9]([NH2:11])[CH:8]=[C:7]([NH2:12])[C:4]=1[C:5]#[N:6].[CH3:13][OH:14]>>[NH2:12][C:7]1[C:4]([C:5]#[N:6])=[C:3]([O:14][CH3:13])[N:10]=[C:9]([NH2:11])[CH:8]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: CO
Agent: [Na]
Product: COc1nc(N)cc(N)c1C#N
Temperature: 150 °C
Yield: 70 %

Procedure:
A heavy walled, sealable tube suitable for microwave heating was charged with 3 mL of methanol and 40 mg (1.7 mmol) of sodium. The mixture was stirred until all of the sodium had reacted, then 212 mg (1.00 mmol) of 2-bromo-4,6-diaminonicotinonitrile was added. The tube was sealed, and the mixture was heated with a microwave apparatus at 150° C. for 10 minutes then cooled and concentrated under reduced pressure. The residue was suspended in 10 mL of water, and extracted with ethyl acetate (1×20 mL, then 2×10 mL). The combined ethyl acetate layers were back extracted with brine (1×10 mL), dried over MgSO4, filtered, and concentrated to a solid. This was purified via silica gel chromatography, eluting with 60:40 hexanes:ethyl acetate to provide 114 mg (70%) of a white solid.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:39]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([NH:44][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: NC1CCCC1
Product: O=C(NC1CCCC1)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 70.3 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 42 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([S:7]([CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:8])=[N:5][N:6]=1.[NH2:15][CH:16]1[C:30](=[O:31])[N:18]2[C:19]([C:27]([OH:29])=[O:28])=[C:20]([CH2:23][N:24]=[N+:25]=[N-:26])[CH2:21][S:22][C@H:17]12>>[CH3:1][C:2]1[S:3][C:4]([S:7]([CH:9]([CH3:14])[CH2:10][C:11]([NH:15][CH:16]2[C:30](=[O:31])[N:18]3[C:19]([C:27]([OH:29])=[O:28])=[C:20]([CH2:23][N:24]=[N+:25]=[N-:26])[CH2:21][S:22][C@H:17]23)=[O:13])=[O:8])=[N:5][N:6]=1
Reactant: Cc1nnc(S(=O)C(C)CC(=O)O)s1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: Cc1nnc(S(=O)C(C)CC(=O)NC2C(=O)N3C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]23)s1

Procedure:
468 mg. of 3-(2-methyl-1,3,4-thiadiazol-5-ylsulfinyl)butyric acid and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 163 mg. of 7-[3-(2-methyl-1,3,4-thiadiazol-5-ylsulfinyl)butyramido]-3-azidomethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16]C)[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:18][CH3:19])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:20])[CH:5]=1.ClC1C(Cl)=C(OCC(O)=O)C=C2C=1C1C(CC)(C2)CCC(=O)C=1>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([OH:16])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:18][CH3:19])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:20])[CH:5]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2
Agent: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Product: CCC12CCC(=O)C=C1c1c(cc(O)c(Cl)c1Cl)C2

Procedure:
Carrying out a reaction as described in Example 1, Step C, except that the 5,6-dichloro-9a-ethyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one is replaced by an equimolar quantity of [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid (Example 20, Step D), there is obtained 5,6-dichloro-9a-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][C:4](=O)[C:3]=1[N+]([O-])=O.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=1
Reactant: CC(C)c1cc(N)c([N+](=O)[O-])c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1cc(N)cc(Cl)n1

Procedure:
A mixture of 4-amino-6-isopropyl-3-nitro-1H-pyridin-2-one (555 mg, 2.81 mmol) in POCl3 (10 mL) is stirred at reflux under N2 for 1.5 h. After cooling, the solution is concentrated in vacuo. The reaction flask is then placed in an ice bath, and crushed ice (˜20 g) is added to the residue. The mixture is swirled vigorously for several minutes and then stirred at room temperature for 30 min. The mixture is then extracted with EtOAc. The extract is washed with an additional 20 mL of H2O. The aqueous washes are reextracted once with EtOAc, and the combined extracts are dried over Na2SO4 and concentrated, yielding 2-chloro-6-isopropyl-pyridin-4-ylamine as an orange oil. This material is used without further purification. 1H NMR (DMSO-d6, 300 MHz) δ 7.27 (br s, 2H), 6.65 (s, 1H), 2.77 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm.