Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[C:14](=[O:29])[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([CH3:27])[C:17]=1[CH3:28])CCCCCCCCCCC.[CH3:30][NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>>[CH3:30][N:31]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:14](=[O:29])[CH2:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:19]([OH:26])=[C:18]([CH3:27])[C:17]=1[CH3:28]
Reactant: CCCCCCCCCCCCNC(=O)Cc1cc(C(C)(C)C)c(O)c(C)c1C
Reactant: CCCCCCCCCCCCCCCCCCNC
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)Cc1cc(C(C)(C)C)c(O)c(C)c1C

Procedure:
N-n-dodecyl-(5-tert.-butyl-2,3-dimethyl-4-hydroxyphenyl)acetamide is made by an analogous procedure by substituting n-dodecylamine for N-methyl-N-n-octadecylamine.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:1][C@@H:3]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][NH:4]2)[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Product: CN1CCN(C[C@@H]2Cc3ccccc3CN2)CC1

Procedure:
Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (57 mg, 0.22 mmol) and 1-methylpiperazine (26 mg, 0.26 mmol) provided a crude oil which was used without purification in the preparation of Example 112. MS(ESI+) m/z 246.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([N:13]2[CH2:18][CH2:17][C:16]([CH2:25][C:26]3([CH3:29])[CH2:28][O:27]3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.O>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([N:13]2[CH2:18][CH2:17][C:16]([CH2:25][C:26]([OH:27])([CH3:29])[CH3:28])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:15][C:14]2=[O:30])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(CC2(c3ccccc3)CCN(C(C)(C)C#Cc3ccc(F)cc3)C(=O)O2)CO1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)C#Cc2ccc(F)cc2)C(=O)O1
Temperature: 0 °C

Procedure:
A stirred solution of crude 3-(4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one (18 mg, ≦0.038 mmol) in dry THF (2 mL) was cooled in an ice bath and 1 M LiEt3BH in THF (0.2 mL, 0.2 mmol) was added. The mixture was stirred in the ice bath for 3 h and 30% H2O (1 mL) and water (5 mL) were added. The mixture was diluted with EtOAc (90 mL), washed with brine (10 mL), 30% aq Na2S2O3 (10 mL) and brine (10 mL), and dried over Na2SO4. Removal of the solvent left an oil (17 mg) which was purified by prep HPLC to afford 3-(4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (6.9 mg) as an oil. LC-MS Method 1 tR=1.90 min, m/z=; 1H NMR (CDCl3) δ 1.06 (s, 3H), 1.19 (s, 3H), 1.74 (s, 3H), 1.80 (s, 3H), 2.23 (s, 2H), 2.32 (m, 2H), 2.65 (br s, 1H), 2.91 (m, 1H), 3.62 (m, 1H), 6.97 (m, 2H), 7.25-7.45 (7H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[Sn](CCCC)(CCCC)CCCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cn1cccc1-c1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1-(3-bromophenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide (85 mg, 0.209 mmol), Pd(PPh3)2Cl2 (28 mg, 0.040 mmol) and Ag2O (45 mg, 0.196 mmol) was added in one portion to a flask charged with 1-methyl-2-tributylstannanyl-1H-pyrrole (0.391 g, 1.06 mmol). The flask was evacuated and backfilled with N2 (2×) then charged with anhydrous DMF (3.0 mL). After stirring at rt for 5 min the reaction mixture was heated to 90° C. under N2 for 2 d. Later, the reaction was cooled to rt and treated with 1 M aq KF (3 mL) and stirred overnight at rt. Then filtered through Celite (using MeOH to rinse the Celite) and purified by MDPS to provide the product as a white solid. MS (ES+): m/z 408.46 (100) [MH+].
Reaction SMILES: C(O)C.C(OC(=O)[NH:10][CH2:11][CH2:12][S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32]C3CCCCO3)=[CH:28][CH:27]=2)[CH:25]=1)(=[O:15])=[O:14])(C)(C)C.[ClH:40]>O>[ClH:40].[ClH:40].[NH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][N:20]=[CH:21]2)(=[O:14])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCS(=O)(=O)c1cc(-c2ccc(OC3CCCCO3)cc2)cc2cnccc12
Agent: Cl
Solvent: O
Solvent: CCO
Product: NCCS(=O)(=O)c1cc(-c2ccc(O)cc2)cc2cnccc12
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
The 60 L reactor is charged with ethanol (24 L) and (2-{7-[4-(Tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester (2.652 kg; 5.173 moles). The (2-{7-[4-(Tetrahydro-pyran-2-yloxy)-phenyl]-isoquinoline-5-sulfonyl}-ethyl)-carbamic acid tert-butyl ester is rinsed in with ethanol (2.6 L). Hydrochloric acid solution (31.9%; 1780 g; 15.6 moles) is diluted with water (1.42 L). This HCl solution is charged to the reactor and rinsed in with water (0.2 L). The reaction is warmed to 70° C. A yellow solution forms around 30° C. and a yellow slurry reforms near 70° C. The reaction is held at 70° C. for ½ hr and then is warmed up to reflux (78° C.). HPLC indicates a complete reaction after 1.5 hrs at reflux. Water (14.5 L) is added to the reaction over 13 minutes. The temperature drops to 69° C. The reaction is heated back to reflux (80° C.) and a solution forms. The reaction is cooled to 68° C. and solid begins forming. The reaction is held at 68° C. for ½ hr and then cools to 2° C. over 1.5 hrs. The slurry is held at 1-2° C. for 1 hr. The solid is filtered and washed with ethanol (4.6 L). The wet cake weight is 3.236 kg. The solid is dried in vacuo at 50° C. to give 2.106 kg (101.4% of theory) 4-[5-(2-amino-ethanesulfonyl)-isoquinolin-7-yl]-phenol di-hydrochloride salt. Mass Spectrum (LCMS) m/z=402.31) (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.Cl.[CH3:53][N:54]1[CH2:57][CH:56]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([N:61]3[CH2:62][CH2:63][N:58]([CH:56]4[CH2:55][N:54]([CH3:53])[CH2:57]4)[CH2:59][CH2:60]3)=[O:14])[CH:7]=2)[CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[O:49])[CH2:39][CH2:38]1)=[O:36]
Reactant: CN1CC(N2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)c(F)c4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.2 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) were added 1-(1-methylazetidin-3-yl)piperazine trihydrochloride (79.4 mg), triethylamine (0.125 ml) and water (0.10 ml), followed by stirring at room temperature for 6 hr. To the reaction mixture were added 1-(1-methylazetidin-3-yl)piperazine trihydrochloride (19.9 mg) and triethylamine (0.032 ml), followed by stirring at room temperature for 2 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol=20:1 then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (19.7 mg, 43.4%).
Reaction SMILES: Cl[C:2]1C=[CH:6][C:5]([C:8]2[CH:12]3[CH2:13][N:14]([C:16]4[N:25]=[C:24]5[C:19]([C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]5[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[CH:18][C:17]=4[F:38])[CH2:15][CH:11]3[O:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.FC(F)(F)C(O)=O.[N:53]1C=CC=C(C2[C@@H]3CNC[C@@H]3ON=2)C=1>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:38])=[C:16]([N:14]3[CH2:15][CH:11]4[CH:12]([C:8]([C:5]5[CH:6]=[N:53][CH:2]=[CH:3][CH:4]=5)=[N:9][O:10]4)[CH2:13]3)[N:25]=2)[C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O
Reactant: c1cncc(C2=NO[C@H]3CNC[C@@H]23)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5cccnc5)C4C3)c(F)cc2c1=O

Procedure:
The title compound was prepared in an analogous manner to acid 101, but using a suitably substituted TFA salt 4f. Acid 105 was isolated as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH3:13])[CH:7]=1.[N:15]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[F:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[NH2:15])=[CH:7][C:8]=1[CH3:13]
Reactant: O=N[O-]
Reactant: COC(=O)CNc1ccc(F)c(C)c1
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(N)c1ccc(F)c(C)c1
Reaction time: 1 h
Yield: 17.4 %

Procedure:
N-(4-Fluoro-3-methylphenyl)glycine methyl ester (Intermediate 63, 7.5 g, 0.038 mol) was dissolved in a mixture of glacial acetic acid (60 ml) and water (8 ml) and the solution was cooled to ~5° C. To this was added a solution of sodium nitrite (4.3 g, 0.063 mol) in water (15 ml) at the same low temperature over 20 minutes. Stirring was continued for 1 hour and the temperature was then lowered to between -10° and 0° C. Zinc dust (15.3 g, 0.234 mol) was added at the maintained low temperature and the resulting suspension was stirred at ~0° C. for 4 hours. It was then poured into water (250 ml) and extracted with ethyl acetate (2×200 ml). The extract was washed with 8% sodium bicarbonate solution until all effervescence had ceased. It was then dried (MgSO4) and evaporated to give a brown semi-solid. This was triturated with ether/hexane (1:2, ~15 ml) to give a white solid which was filtered and washed with ice-cold ether. The liquors were evaporated to give a brown oil and this was purified by flash column chromatography on silica (Merck 9385; 225 g) eluting with ether/hexane (1:1) to give the title compound (Intermediate 64) as an orange oil (1.4 g, 17%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:23][C:24]([N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C@H:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].[CH:36](=[O:39])[CH2:37][CH3:38].[Cl-].[NH4+]>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[C:30](=[O:31])[CH:29]([CH:36]([OH:39])[CH2:37][CH3:38])[CH2:28][C@H:27]1[C:32]([O:34][CH3:35])=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: CCC=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCC(O)C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To 40 ml of tetrahydrofuran were added 1.5 ml of diisopropylamine and 6.9 ml of 1.6M butyllithium-hexane solution at -78° C. in a stream of nitrogen, followed by stirring for 10 minutes. A solution of 2.43 g of methyl (S)-N-tert-butoxycarbonylpyroglutamate in 15 ml of tetrahydrofuran was added to the reaction mixture and the resulting mixture was stirred for 10 minutes at -78° C. and then for 20 minutes at -40° C. To the reaction mixture which was again cooled to -78° C. and then was added dropwise a solution of 0.8 ml of propionaldehyde in 4 ml of tetrahydrofuran. After stirring for 10 minutes, the reaction mixture was added with a saturated ammonium chloride aqueous solution and stirred until the temperature of the mixture reached room temperature. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with water and a saturated saline solution, dried over sodium sulfate and distilled to remove the solvent. The residue was subjected to a column (2.5×40 cm) chromatography (developed by ethyl acetate-hexane×1:3→1:2→1:1) to obtain 1.2 g (40%) of methyl (S)-N-tert-butoxycarbonyl-4-(1-hydroxy-1-propyl)pyroglutamate as colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([OH:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+:25].[K+]>CC(C)=O.O>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O-:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4].[K+:25]
Reactant: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)[O-]
Temperature: 25 °C
Yield: 163.7 %

Procedure:
The (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylic acid (4.83 g) prepared in Example 6 or 7 was dissolved in acetone (23 mL), and potassium carbonate (1.11 g) dissolved in water (4.5 mL) was slowly added. The solution was stirred at room temperature until the deposited inorganic salt was dissolved. While the solution was heated at 50° C. in a bath, acetone (100 mL) was dropped and a seed crystal was placed in the solution, and then the solution was stirred for 30 minutes. Acetone (94 mL) was again dropped, and the solution was stirred for 1 hour while the temperature was kept. While gradually cooled to room temperature, the solution was stirred overnight. The precipitated crystalline product was collected by filtration, washed with a mixture of 2% water-acetone (20 mL), dried in air to obtain white solid potassium (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (4.28 g, 81.7%). The NMR data of the solid product were the same as those in Example 11.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[OH-:23].[K+].O>C(O)(C)(C)C>[C:1]([C:3]1[C:8]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:23])[NH2:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C#N
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of (R)-tert-butyl 2-((2-cyanopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate (3.62 g, 11.9 mmol, EXAMPLE 1 Step 1) in tert-butanol (110 mL) was added potassium hydroxide pellet (10.0 g, 179 mmol) at room temperature. The resulting mixture was stirred at 80° C. for 0.5 h. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (dichloromethane to methanol/dichloromethane 1:15) to give 3.43 g (90%) of the title compound as a white amorphous powder.
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]2=[N:3][C:2]=1[CH:10]=O.[CH:12]1([C:17]2([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([CH2:33][CH3:34])[C:30]([OH:35])=[C:29]([CH2:36][CH3:37])[CH:28]=3)[O:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:17]2([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([CH2:33][CH3:34])[C:30]([OH:35])=[C:29]([CH2:36][CH3:37])[CH:28]=3)[O:22][C:21](=[O:23])[C:20]([CH2:10][C:2]3[N:3]=[C:4]4[N:9]=[CH:8][CH:7]=[CH:6][N:5]4[N:1]=3)=[C:19]([OH:24])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(CC)c1O
Reactant: O=Cc1nc2ncccn2n1
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncccn4n3)C(=O)O2)cc(CC)c1O

Procedure:
The title compound was prepared analogously to Example A(224) where [1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3,5-diethyl-4hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione (Example A(235)) was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.20 (t, J=2.56 Hz, 6H), 1.30-1.80 (brm, 6H), 2.00-2.18 (brm, 5H), 2.40 (q, J=20.06 Hz 4H), 2.80 (m, 4H), 3.45 (m, 3H), 6.70 (s, 2H), 7.17 (d, J=2.54 Hz, 1H), 8.80 (m, 2H), 9.29 (s, 1H). Anal. Calcd. For C28H34O4N4, C, 68.55; H, 6.99; N, 11.42. Found: C, 68.80; H, 7.31; N, 11.45.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]([CH3:20])([CH3:19])[CH2:9][C:10]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:11](=O)[CH3:12])[CH:7]=1.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]2.[Na+].[Cl-].C(OCC)(=O)C>O1CCCC1.[Ti]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]([CH3:20])([CH3:19])[CH2:9][C:10]([C:14]([F:16])([F:17])[F:15])([OH:18])[C:11](=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]3)[CH3:12])[CH:7]=1
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)=O)C(F)(F)F
Agent: [Ti]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C(C)=Nc1cccc2nc(C)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
645 mg (2 mmol) of 5-(5-fluoro-2-methoxyphenyl)-3-hydroxy-5-methyl-3-(trifluoromethyl) hexan-2-one is refluxed in 4 ml of tetrahydrofuran under nitrogen with 0.84 ml (4 mmol) of titanium tetraethylate and 348 mg (2.2 mmol) of 5-amino-2-methylquinoline for 24 hours. After cooling to room temperature, the reaction mixture is stirred into 20 ml of saturated NaCl solution, 50 ml of ethyl acetate is added, and it is stirred for 30 minutes, suctioned off on Celite, and rewashed with ethyl acetate and with tetrahydrofuran. The organic phase is separated, dried (sodium sulfate) and concentrated by evaporation. Chromatography on silica gel with hexane-ethyl acetate yields 578 mg of the product.
Reaction SMILES: [C:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1C(O)=O)(=O)[CH2:2][CH3:3].[C:17]([C:23]([O:25][CH3:26])=[O:24])#[C:18][C:19]([O:21][CH3:22])=[O:20].C(=O)=O>C(OC(=O)C)(=O)C>[CH3:22][O:21][C:19]([C:18]1[C:17]([C:23]([O:25][CH3:26])=[O:24])=[C:1]([CH2:2][CH3:3])[N:5]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7][C:6]=12)=[O:20]
Reactant: CCC(=O)N1c2ccccc2CC1C(=O)O
Reactant: COC(=O)C#CC(=O)OC
Agent: O=C=O
Solvent: CC(=O)OC(C)=O
Product: CCc1c(C(=O)OC)c(C(=O)OC)c2n1-c1ccccc1C2
Temperature: 120 °C

Procedure:
A mixture of 1-propionyl-2,3-dihydro-1H-indole-2-carboxylic acid (4.49 g, 20.5 mmol) and dimethyl acetylenedicarboxylate (5.68 g, 40 mmol) in acetic anhydride (40 mL) was stirred in a flask equipped with a reflux condenser and a gas bubbler to monitor carbon dioxide evolution during the reaction. The mixture was heated to 120° C. for 4 hours until no gas was eliminated. The dark solution was concentrated in vacuo to dryness and the solid residue was recrystallized from methanol to yield 3-ethyl-8H-3a-aza-cyclopenta[a]indene-1,2-dicarboxylic acid dimethyl ester, 4.61 g (75%): mp 86-88° C.; 1H NMR (DMSO-d6) δ 1.22 (3H, t, J=7.4 Hz, Me), 3.08 (2H, q, J=7.4 Hz, CH2), 3.75 and 3.76 (each 3H, s, 2×OMe), 4.07 (2H, s, CH2), 7.27-7.31 (1H, m, ArH), 7.43-7.47 (1H, m, ArH), 7.59-7.64 (2H, m, ArH). Anal. Calcd. for C17H17NO4: C, 68.21; H, 5.72; N, 4.68. Found: C, 68.22; H, 5.74; N, 4.65.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1>CO>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([CH3:9])[O:3]1
Reactant: Cc1cc(=O)cc(C)o1
Solvent: CO
Product: CC1CC(=O)CC(C)O1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
The 2,6-dimethyl 4-pyrone (2.0 g, 16.1 mmol) was dissolved in methanol (20 mL), degassed with nitrogen, 10% Pd on carbon was added, the reaction was charged to 50 psi hydrogen and shaken for 2 h. The reaction was filtered through Celite® and concentrated to give 2,6-dimethyl tetrahydo-4H-pyran-4-one (2.0 g, 100%) as an oil MS (M+H)+=129.
Reaction SMILES: O[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[S:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)=[O:10].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CC1C=CC(C)=CC=1>N1C=CC=CC=1>[N+:16]([C:13]1[S:12][C:11]([C:9]2[O:10][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[N:8]=2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: O=C(Nc1ccncc1O)c1ccc([N+](=O)[O-])s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccc(C)cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2nc3ccncc3o2)s1
Temperature: 160 °C
Yield: 17.2 %

Procedure:
To a stirred solution of N-(3-hydroxypyridin-4-yl)-5-nitrothiophene-2-carboxamide (1.1 g, 4.1 mmol) in pyridine (5 mL) was added P2O5 (1.2 g, 8.3 mmol) and p-xylene (21 mL). After refluxing at 160° C. overnight, the reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel eluted with 5% of ethyl acetate in CH2Cl2 to give 2-(5-nitrothiophen-2-yl)oxazolo[5,4-c]pyridine as brown solid (174 mg, yield 17%). 1H NMR (400 MHz, CDCl3) δ: 8.97 (1H, s); 8.59 (1H, d, J=5.6); 7.94 (1H, d, J=4.4); 7.86 (1H, d, J=4.4), 7.69 (1H, d, J=5.6,0.8).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)(=[O:32])=[O:31])=[CH:26][C:25]=1[S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)(=[O:44])=[O:43].Cl.[N:55]1([CH2:61][CH2:62][CH2:63][S:64]C(=N)N)[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1.[OH-].[Na+]>O>[N:55]1([CH2:61][CH2:62][CH2:63][S:64][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)(=[O:32])=[O:31])=[CH:26][C:25]=2[S:42]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)(=[O:44])=[O:43])[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1
Reactant: O=S(=O)(CCCN1CCOCC1)c1ccc(Cl)c(S(=O)(=O)CCCN2CCOCC2)c1
Reactant: N=C(N)SCCCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=S(=O)(CCCN1CCOCC1)c1ccc(SCCCN2CCOCC2)c(S(=O)(=O)CCCN2CCOCC2)c1
Reaction time: 3.5 h

Procedure:
A solution of 5.0 g (0.0060 mole) of 4,4'-((4-chloro-1,3-phenylene)bis(sulfonyl-3,1-propanediyl))bismorpholine bis(4-methylbenzenesulfonate), 1.4 g (0.0060 mole) of S-(3-(4-morpholinyl)propyl)isothiourea hydrochloride and 0.8 g (0.02 mole) of sodium hydroxide in 80 ml of water was heated under reflux with stirring for 3.5 hours, cooled and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation, leaving the product as 4,4'-((4-((3-(4-morpholinyl)propyl)thio)-1,3-phenylene)bis(sulfonyl-3,1-propanediyl))bismorpholine a yellow, viscous oil.