Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(C(=O)N(CCCC)CCCC)=NN(C2C=CC(C(O)=O)=CC=2C(N2CCC3C(=CC=CC=3)C2)=O)C=1C.[CH2:40]([N:44]([CH2:82][C:83]1[CH:88]=[CH:87][C:86]([Cl:89])=[C:85]([Cl:90])[CH:84]=1)[C:45]([C:47]1[C:51]([Cl:52])=[C:50]([CH3:53])[N:49]([C:54]2[CH:69]=[CH:68][C:57]([C:58]([O:60]CC3C=CC=CC=3)=[O:59])=[CH:56][C:55]=2[C:70]([N:72]2[CH2:81][CH2:80][C:79]3[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=3)[CH2:73]2)=[O:71])[N:48]=1)=[O:46])[CH2:41][CH2:42][CH3:43]>>[CH2:40]([N:44]([CH2:82][C:83]1[CH:88]=[CH:87][C:86]([Cl:89])=[C:85]([Cl:90])[CH:84]=1)[C:45]([C:47]1[C:51]([Cl:52])=[C:50]([CH3:53])[N:49]([C:54]2[CH:69]=[CH:68][C:57]([C:58]([OH:60])=[O:59])=[CH:56][C:55]=2[C:70]([N:72]2[CH2:81][CH2:80][C:79]3[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=3)[CH2:73]2)=[O:71])[N:48]=1)=[O:46])[CH2:41][CH2:42][CH3:43]
Reactant: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Agent: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Br
Product: CCCCN(Cc1ccc(Cl)c(Cl)c1)C(=O)c1nn(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Cl
Yield: 98.2 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 164B, benzyl 4-(3-(butyl(3,4-dichlorobenzyl)carbamoyl)-4-chloro-5-methyl-1H-pyrazol-1-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (2.20 g, 2.96 mmol) was converted to the title compound (1.90 g, 98%). 1H NMR (DMSO-d6, mixture of amide rotamers) δ 8.15 (d, J=8.4 Hz, 1H), 8.05 (d, J=2.2 Hz, 0.5H), 8.01-7.96 (m, 0.5H), 7.88-7.69 (m, 1H), 7.60-7.48 (m, 1.5H), 7.46-7.38 (m, 0.5H), 7.35-7.26 (m, 1H), 7.24-6.94 (m, 3H), 6.85 (d, J=7.5 Hz, 0.5H), 6.45-6.31 (m, 0.5H), 5.13 (br s, 0.5H), 4.85-4.15 (m, 4H), 3.74-3.36 (m, 2H), 3.23-2.92 (m, 1.5H), 2.82-2.60 (m, 2H), 2.31-2.11 (m, 3H), 1.45-1.08 (m, 3H), 1.05-0.90 (m, 1H), 0.82 (quin, J=7.2 Hz, 2H), 0.71-0.54 (m, 1H); MS (ESI+) m/z 655.1 (M+H)+.
Reaction SMILES: [C:1]([O:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])(=O)[CH:2]([CH3:4])[CH3:3].[CH:12](=O)[C:13]1[CH:18]=CC=CC=1.[C-:20]#[N:21].[Na+]>O>[C:7]([O:6][CH:1]([C:20]#[N:21])[C:2]1[CH:4]=[CH:18][CH:13]=[CH:12][CH:3]=1)(=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C(=O)OC(=O)C(C)C
Reactant: O=Cc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Product: CC(C)C(=O)OC(C#N)c1ccccc1
Temperature: 25 °C

Procedure:
A 100-ml round-bottomed flask equipped with a magnetic stirrer was charged with isobutyric anhydride (10 mmol), benzaldehyde (10 mmol), a mixture of alkanes (25 ml) having a boiling range of from 62° C. to 82° C., sodium cyanide (12 mmol) and water (3 ml). The mixture formed was stirred at a temperature of 25° C. The table presents the yields of the title ester after the reaction times indicated (Embodiment IV).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][C:16]3=[CH:18][N:19]=[C:20]([CH3:21])[N:15]3[C:14]2=[O:22])[CH2:9][CH2:8]1)=[O:6].C1CCN2C(=NCCC2)CC1.[C:40]1([N:46]=[C:47]=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[CH3:21][C:20]1[N:15]2[C:14](=[O:22])[N:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:5](=[O:6])[CH:4]([NH:3][C:47]([NH:46][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:48])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:8][CH2:9]3)[CH2:17][C:16]2=[CH:18][N:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(N)c3ccccc3)CC1)C2
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)Nc3ccccc3)c3ccccc3)CC1)C2
Yield: 60.1 %

Procedure:
2-(1-(2-Amino-2-phenylacetyl)-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.21 g) obtained in Example 115a) and DBU (0.15 g) were dissolved in acetonitrile (10 ml). Phenyl isocyanate (66 mg) was added thereto, and mixed at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate to ethyl acetate/methanol=5/1) and solidified with ethyl acetate and diethyl ether to obtain the title compound (0.14 g, 59%) as colorless powder.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8].[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:41])[C:20]2[CH:25]=[N:24][C:23](S(C)(=O)=O)=[N:22][C:21]=2[N:30]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[CH:31]=1)=[O:17])[CH3:14].C(N(CC)CC)C>>[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:41])[C:20]2[CH:25]=[N:24][C:23]([NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[C:5]([N:4]([CH3:12])[CH3:3])[CH:6]=3)=[N:22][C:21]=2[N:30]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[CH:31]=1)=[O:17])[CH3:14]
Reactant: CN(C)c1cccc(N)c1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(N(C)C)c3)ncc2c1=O
Yield: 39 %

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 3-dimethylaminoaniline dihydrochloride (7.6 mg, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 15 mg, 0.036 mmol) at the presence of triethylamine (11 μL, 0.072 mmol). 6.6 mg of 2-(3-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.41 (br, 1H), 8.53 (s, 1H), 7.47 (br, 1H), 7.40 (d, 1H), 7.29 (s, 1H), 7.18 (d, 1H), 6.90 (m, 2H), 6.50 (m, 2H), 4.39 (q, 2H), 3.00 (m, 4H), 2.80 (s, 6H), 2.21 (m, 2H), 1.37 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H27N5O3: 470.21 (M+H), Found: 470.4.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:16][OH:17])/[CH:4]=[CH:5]/[P:6](=[O:15])([O:11][CH:12]([CH3:14])[CH3:13])[O:7][CH:8]([CH3:10])[CH3:9].[C:18](OC)(OC)([O:20]C)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1.C(N(CC)CC)C>[C:18]([O:17][CH2:16][CH:3]([CH2:2][OH:1])/[CH:4]=[CH:5]/[P:6](=[O:15])([O:7][CH:8]([CH3:10])[CH3:9])[O:11][CH:12]([CH3:13])[CH3:14])(=[O:20])[CH3:19]
Reactant: CC(C)OP(=O)(/C=C/C(CO)CO)OC(C)C
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(/C=C/P(=O)(OC(C)C)OC(C)C)CO
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A solution of diisopropyl (E)-4-hydroxy-3-hydroxymethylbut-1-enylphosphonate (5 g, 19 mmol), trimethyl orthoacetate (7 ml, 56 mmol) and p-toluenesulphonic acid (0.36 g, 1.9 mmol) in anhydrous THF (50 ml) was stirred at room temperature for 1.5 h. The solution was treated with water (5 ml), stirred for a further 30 min, then treated with triethylamine (0.1 ml). The solvent was removed in vacuo and the residue chromatographed on silica, eluting with chloroform-methanol (30:1) to give diisopropyl (E)-3-acetoxymethyl-4-hydroxybut-1-enylphosphonate as an oil (4.94 g, 85%);υmax (film) 3382, 2980, 2934, 2877, 2361, 2333, 1741, 1631, 1468,and 1455 cm-1 ; δH (CDCl3) 1.30 (6H, d, J 6.3 Hz, 2×CH3CH), 1.34 (6H, d, J 6 Hz, 2×CH3CH) 2.06 (3H, s, CH3CO), 2.40 (1H, br.s, D2O exchangeable OH), 3.68 (2H, m, CH2OH), 424 (2H, m, CH2), 4.64 [2H, m, 2×CH(CH3)2 ], 5.83 (1H, ddd, J 1, 17 and 19 Hz, PCH=CH), 6.67 (1H, ddd, J 8, 17 and 22 Hz, PCH=CH) (Found: C, 50.15; H, 8.46%; MH+ 309.1466. C13H17O6P.0.25 H2O requires: C, 49.95; H, 8.22%; MH+ 309.1467).
Reaction SMILES: [C:1]1([C@@H:7]([C@H:9]([C:11](N)=[O:12])[OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:15].[O-]S([O-])(=O)=O.[Ba+2]>O>[C:1]1([C@@H:7]([C@H:9]([C:11]([OH:12])=[O:15])[OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: NC(=O)[C@H](O)[C@@H](N)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O
Product: N[C@@H](c1ccccc1)[C@@H](O)C(=O)O
Temperature: 80 °C
Yield: 73.6 %

Procedure:
(2R,3S)-3-phenyl-isoserinamide (200 mg, 1.11 mmol), as prepared in Example 32, was combined with 354 mg (1.12 mmol) of Ba(OH)2 ·8H2O and water (2 ml). The resulting suspension was heated to reflux for nine hours. After the reaction mixture was cooled to 80° C., 15 ml of water was added to the solution. The temperature of the solution was maintained at 80° C. for 20 minutes before a solution of 110 mg, 1.11 mmol of concentrated sulfuric acid in 1 ml of water was added. A white precipitate appeared in the solution which was determined to have a pH of between 5 and 7. Heating at 80° C. was maintained for another 20 minutes, and the mixture was then cooled to room temperature. The resulting precipitate (BaSO4) was centrifuged to the bottom of the container, the supernatant was separated, and solvent was removed under vacuum. The resulting white solid was extracted with acetone and collected by filtration to provide 148 mg of the title compound, for a yield of 74%. The material melted with decomposition at 238° C. The 1H NMR (D2O/NaOD) data were as follows: δ 3.94 (d, J=3.9 Hz, 1H), 4.01 (d, J=3.9 Hz, 1H), 7.0-7.5 (aromatic, 5H). Analytical for C9H11NO3 : Calculated: C, 59.66; H, 6.07, N, 7.73. Found: C, 59.10; H, 6.11; N, 7.61.
Reaction SMILES: O.CC1(C)CO[C:6]2([CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)OC1.[CH2:16]([NH2:19])[CH2:17][CH3:18].O.[C:21]1(C)[CH:26]=CC(S(O)(=O)=O)=C[CH:22]=1>C1(C)C=CC=CC=1>[CH2:16]([N:19]1[C@H:6]2[C@@H:9]([CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)[CH2:26][CH2:21][CH2:22]1)[CH2:17][CH3:18]
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCN1CCC[C@@H]2CC(=O)CC[C@H]21

Procedure:
A 250 ml single neck round bottom flask fitted with a water separator containing 20 g of 3A sieves (Linde) was charged with 100 ml of toluene, 10.25 g (0.052 mol) of 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-one (Aldrich Chemical Company), 17.97 g (3.04 mmol) of n-propylamine (Baker) and 18 mg (0.09 mmol) of p-toluenesulfonic acid monohydrate (Aldrich). The reaction mixture was refluxed for 24 hours and cooled, and the toluene was evaporated under reduced pressure to produce the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]>CC#N.CCOC(C)=O.O>[C:16]([O:20][C:21](=[O:46])[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([N:32]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=3)[S:33]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)(=[O:34])=[O:35])=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:43][CH2:44][CH3:45])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: ClCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc2cc(N(Cc3cccc(Cl)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Chlorobenzyl chloride (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1NC.[CH2:12]([N:14](CC)CC)C.[C:19]([O:23]C(=O)CC)(=O)[CH2:20][CH3:21]>C1COCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:12][NH:14][C:19](=[O:23])[CH2:20][CH3:21]
Reactant: CCN(CC)CC
Reactant: CCC(=O)OC(=O)CC
Reactant: CNC1Cc2ccccc2C1
Solvent: C1CCOC1
Product: CCC(=O)NCC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.7 %

Procedure:
A solution of indan-2-yl-methylamine (5.55 g, 37.7 mmol) and triethylamine (5.67 g, 56.0 mmol) in 100 mL THF was stirred at 5° C. and propionic anhydride (5.15 g, 39.6 mmol) added dropwise. After the mixture was stirred for 18 h at room temperature, the solvent was removed and ethyl acetate/water were added. The organic layer was washed with water and dried over MgSO4. The filtrate was concentrated to give a brown oil (8.79 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:19]([OH:21])=O)[CH:6]=1)=[O:4].C1(C)C=CC=CC=1.S(Cl)(Cl)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:19]([N:33]=[N+:34]=[N-:35])=[O:21])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)nn1Cc1ccc(OC)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)N=[N+]=[N-])nn1Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
In a round bottom flask, 1-(4-methoxy-benzyl)-1H-pyrazole-3,5-dicarboxylic acid 5-methyl ester (105, 5.48 g, 18.9 mmol) was combined with 20 mL of toluene and thionyl chloride (6 mL, 80 mmol). The reaction was heated at reflux for 40 minutes, then concentrated 2× from toluene and the resulting solid dried under vacuum. This was dissolved in 30.0 mL of acetone and sodium azide (3.8 g, 58 mmol) in 10.0 mL of water was added and stirred for 1 minute. The reaction was poured into 250 mL of ice water and stirred slowly. The resulting precipitate was collected by filtration and dried under vacuum to provide the desired compound.
Reaction SMILES: S(O)(O)(=O)=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][NH:13][C:14]([NH2:16])=[NH:15].[OH-:17].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+].C(Cl)(Cl)[Cl:27]>C1COCC1.CC#N>[ClH:27].[ClH:27].[CH2:7]([NH:6][C:11]([NH:15][C:14]([NH:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1)=[NH:16])=[O:17])[CH2:8][CH3:9]
Reactant: [OH-]
Reactant: N=C(N)NCc1ccccn1
Reactant: ClC(Cl)Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCNC(=O)NC(=N)NCc1ccccn1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(2-Pyridylmethyl)guanidine sulfate (13.15 g) and 10 ml of CHCl3 are added to a vigorously stirred solution of 50% aqueous NaOH (5.2 g) and THF (15 ml). The mixture is stirred at RT for 2 hours. A 5 gram portion of solid anhydrous Na2SO4 is added and the mixture is stirred at room temperature for an additional hour. 100 ml of CHCl3 and 50 ml of CH3CN are added to the vigorously stirred mixture followed by an additional 5 g portion of Na2SO4. A solution of N-propyl isocyanate (5.11 g) and 75 ml of THF is added dropwise to the mixture and stirred at RT overnight. The solvent is evaporated in vacuo and the dark residue is mixed with 200 ml of CHCl3, 100 ml of saturated aqueous sodium chloride and 50 ml of water. The organic layer is separated and the aqueous layer is washed with an additional 200 ml portion of CHCl3. The organic phases are combined, washed with 70 ml of aqueous sodium chloride containing 5 ml of 50% aqueous NaOH, dried, filtered and concentrated in vacuo. The concentrate is acidified with ethereal HCl and evaporated to dryness under reduced pressure. The residue is taken up in boiling methanol, treated with Darco G-60 and filtered. The filtrate is concentrated to approximately 200 ml on a hotplate and diluted with approximately 200 ml of acetonitrile with continued heating. The hot solution is allowed to cool and the resultant precipitate collected, washed with acetonitrile and absolute ethanol. The solid is suspended in 200 ml of warm absolute ethanol, filtered while hot and dried in vacuo at 55° C. overnight to give 6.90 g of a blue white solid, MP 216°-218° w/dec.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=O)[C:6]=2[N:7]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.CN(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([NH:23][CH:20]3[CH2:22][CH2:21]3)=[O:16])[C:6]=2[N:7]=1
Reactant: O=C(O)c1cccc(-c2csc3cnc(Cl)nc23)c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cccc(-c2csc3cnc(Cl)nc23)c1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
3-(2-Chlorothieno[3,2-d]pyrimidin-7-yl)benzoic acid (600 mg, 2.06 mmol) was dissolved in N,N-dimethylformamide (20 mL) and then cyclopropylamine (234 mg, 4.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (589 mg, 3.09 mmol), hydroxybenzotriazole (417 mg, 3.09 mmol) and trimethylamine (574 mL, 4.12 mmol) were added. The reaction mixture was stirred at room temperature for a day, diluted with ethyl acetate, and washed with ammonium chloride aqueous solution. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. Purification by chromatography (20% ethyl acetate/hexane) yielded the target compound (580 mg, 85% yield).
Reaction SMILES: [OH:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([OH:5])=[O:4].[C:16](Cl)(=O)C>CO>[OH:1][CH:2]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2)[C:3]([O:5][CH3:16])=[O:4]
Reactant: CC(=O)Cl
Reactant: O=C(O)C(O)C12CC3CC(CC(C3)C1)C2
Solvent: CO
Product: COC(=O)C(O)C12CC3CC(CC(C3)C1)C2

Procedure:
As shown in Scheme II, in this method, adamantyl bromide (Formula A) is alkylated via zinc chloride catalysis to produce α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B). α-Hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B) is then esterified using acetyl chloride in methanol to produce α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula C). α-Hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula C) is then converted to α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula D) by Swern oxidation. α-Oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula D) is then hydroxylated to form 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula 1a), which is then hydrolyzed to form 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula 1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:26])[CH:8]=2)=[O:4].[NH2:33][C:34]([CH3:42])([CH3:41])[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:23])[NH:33][C:34]([CH3:42])([CH3:41])[CH2:35][C:36](=[O:37])[N:38]([CH3:40])[CH3:39])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:26])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(Cc2ccc(C(=O)O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: CN(C)C(=O)CC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(Cc2ccc(C(=O)NC(C)(C)CC(=O)N(C)C)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 3-(4-carboxy-benzyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester (75 mg, 0.17 mmol), 3-amino-3,N,N-trimethyl-butyramide (24 mg, 0.17 mmol), BOP (150 mg, 0.34 mmol) and DIPEA (1 mL) in THF (15 mL) was stirred at RT overnight. The reaction mixture was partitioned between water and EtOAc, the organic layer separated, washed with water, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by preparative TLC (EtOAc/hexane, 75:25) to yield 7-chloro-3-[4-(2-dimethylcarbamoyl-1,1-dimethyl-ethylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (71 mg) as a light brown foam. MS=574 [M+H]+; MP=84.1-95.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[C:5]2[CH2:9][CH2:10][N:11]=[C:12]3[C:13]([Cl:18])=[C:14](N)[C:15](=[O:16])[C:3]1=[C:4]23.N([O-])=[O:20].[Na+].Cl>CC(O)=O.O1CCOCC1.O>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[C:5]2[CH2:9][CH2:10][NH:11][C:12]3=[C:13]([Cl:18])[C:14]([C:15](=[O:16])[C:3]1=[C:4]23)=[O:20]
Reactant: O=N[O-]
Reactant: CSc1c2c3c(n1C)C(=O)C(N)=C(Cl)C3=NCC2
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CSc1c2c3c(n1C)C(=O)C(=O)C(Cl)=C3NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
A solution of 20 mg of isobatzelline A in 2 ml of HOAc and 1 ml of dioxane is allowed to react with 20 mg of NaNO2 in 5 ml of H2O at 0° C. for 2 hours. After addition of 3 ml of 1N HCl, the solution was stirred at room temperature overnight, and extracted with 10 ml CHCl3 /MeOH (1:1) twice. The concentrated extract was further fractionated on a Superco LC-NH2 column (50 ml×3 ml) with 1% MeOH/CHCl3, and subsequently purified on a HPLC LiChrosorb-NH2 column (3% MeOH/CHCl3) to give 4 mg of batzelline A.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:19](=O)([OH:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[C:21]([O:20][C:19](=[O:25])[NH:11][CH2:10][CH:9]([S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:12]([O:13][CH3:14])[O:15][CH3:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)O
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(OC)C(CNC(=O)OC(C)(C)C)SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
2-(Benzylthio)-3,3-dimethoxypropan-1-amine (1 g) was dissolved in tetrahydrofuran (7 mL), and 1N aqueous sodium hydroxide solution (10 mL) was added. A solution of t-butyl bicarbonate (993 mg) in tetrahydrofuran (3 mL) was added dropwise to the reaction solution under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over sodium sulfate. The obtained solution was filtrated through basic silica gel, and concentrated to give the title compound (1.39 g, yield 99%) as a pale-yellow oil.