Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([C:9]([O:11]CC)=[O:10])[CH2:3][C@@H:2]1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].C(O)C.Cl>O>[C@@H:1]1([C:9]([OH:11])=[O:10])[CH2:3][C@@H:2]1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)[C@H]1C[C@H]1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A stirred mixture of diethyl cis-1,2-cyclopropanedicarboxylate (53.0 g, 284.6 mmol) and sodium hydroxide (32.4 g, 809.1 mmol) in water (200 mL) was heated at reflux for 5 h. The mixture was then allowed to stir at room temperature overnight. The ethanol formed was evaporated under reduced pressure and the remaining aqueous solution was acidified with a slight excess of concentrated aqueous HCl (74.8 mL, 92.8 mmol). The mixture was evaporated to dryness under reduced pressure, and the residue was washed with hot ethyl acetate (3 times with 200 mL). The ethyl acetate layer was separated, dried (MgSO4) and evaporated to dryness under reduced pressure to give 35.5 g of the title compound of Step B as a white solid (96% yield); m.p. 122°-124° C. IR (mineral oil, cm-1), 1691.0 (C=O); 2600-3100, broad (OH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:20][CH2:21][C:22]([O:24]C)=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COC(=O)COC1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C1(OCC(=O)O)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 13 h
Yield: 95.1 %

Procedure:
To a suspension of 8.00 g of the compound obtained in Step 53-1 in MeOH (400 ml) was added an aqueous solution of 1.3 mol/L NaOH, and the reaction mixture was stirred at room temperature for 13 hours. The reaction solution was concentrated, under ice cooling, 3 mol/L hydrochloric acid was added until it became acidic. The obtained suspension was ultrasonicated for one hour, then, the insoluble matter was collected by filtration to obtain 7.31 g of the title compound (pale yellow solid).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[C:12]([OH:17])(=O)[C:13]([CH3:15])=[CH2:14]>>[CH3:14][CH:13]([CH2:15][NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)[C:12]([NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)=[O:17]
Reactant: C=C(C)C(=O)O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Product: CC(CNC1CC(C)(C)NC(C)(C)C1)C(=O)NC1CC(C)(C)NC(C)(C)C1
Temperature: 145 °C
Yield: 55.4 %

Procedure:
Into a 3 liter flask, 1560 g of 4-amino-2,2,6,6-tetramethylpiperidine was placed. After the temperature was raised to 145° C., 430 g of methacrylic acid was added dropwise thereto. The inner temperature rose gradually and then the reaction mixture was kept at 170°±5° C., while collecting water distilled off, until the water collected had amounted to 90 g. Then the reaction mixture was cooled down to 50° C., and 500 g of acetone was added to the mixture to obtain a light yellowish slurry. The slurry thus obtained was cooled down to 20° C. and filtered. The filter cake was washed with acetone and dried to obtain 1053 g of pure white 2-methyl-3-(2,2,6,6-tetramethyl-4-piperidylamino)-N-(2,2,6,6-tetramethyl-4-piperidyl)propionamide (hereinafter referred to as Compound 1). M.p.: 115.5°-116.5° C. Mass spectrometry (FD-MS): m/z 380 (M+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:42]=[CH:43][N:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-butylimidazol-2-yl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (108 mg) in dichloromethane (10 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-butylimidazol-2-yl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (140 mg) (Compound 346) as yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH2:16]([S:13]([NH:12][C:3]1[C:2]([NH:1][C:24]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:25])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)(=[O:15])=[O:14])[CH3:17]
Reactant: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1N
Reactant: O=C(Cl)C1CCCCC1
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1NC(=O)C1CCCCC1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
2.36 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was dissolved in 24 ml of dry tetrahydrofuran, and 1.54 g of cyclohexanecarbonyl chloride was dropwise added thereto under cooing with ice. After the dropwise addition, the mixture was stirred for one hour and further reacted at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, the obtained crystals were washed with ethyl ether to obtain 2.94 g of the desired product having a melting point of from 153° to 155° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:23][CH2:22]2)=[CH:17][C:16]=1[F:24])=[O:4].[OH-].[Na+].Cl>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:6]3[C:7]4[N:8]([CH:11]=[N:12][CH:13]=4)[CH:9]=[CH:10][C:5]=3[C:3]([OH:4])=[O:2])=[C:16]([F:24])[CH:17]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Temperature: 65 °C
Yield: 82.2 %

Procedure:
A suspension of 8-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (0.28 g, 0.86 mmol) and 1M NaOH (1.03 mL, 1.03 mmol) in IMS (5 mL) was heated to 65° C. for 5 hours. The reaction mixture was then cooled to room temperature and 1M HCl was added to adjust pH to 2. The precipitate formed was filtered off and dried in a drying pistol at 40° C. for 18 hours to afford the title compound as a cream solid (0.22 g, 81%). LCMS (method B): RT=2.84 min, [M+H]+=312.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1(=[O:13])[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1>N1C=CC=CC=1>[CH3:4][CH:3]1[CH:2]=[CH:1][C:7]2[C:6](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]=2[O:12]1
Reactant: O=C1CCCC(=O)C1
Reactant: C/C=C/C=O
Solvent: c1ccncc1
Product: CC1C=CC2=C(CCCC2=O)O1
Temperature: 25 °C
Yield: 33 %

Procedure:
A solution of crotonaldehyde (72.74 g, 1.04 mol) in 500 mL of pyridine was added to 1,3-cyclohexanedione (100 g, 0.892 mol) in 500 mL of pyridine and the mixture was heated to reflux under a nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature and then filtered through magnesium sulfate (328 g). The filtrate was concentrated to dryness and the residue was partitioned between water and diethyl ether. The aqueous phase was extracted with diethyl ether and the combined diethyl ether layers were washed with 10% hydrochloric acid (3×150 mL). The diethyl ether layer was then washed with water to neutrality, dried (MgSO4), filtered and the filtrate concentrated to dryness. The residue was purified by Kugelrohr distillation (bp 109°-112° C. (1 to 2 mm)) to give 2-methyl-5,6,7,8-tetrahydro-2H-1-benzopyran-5-one (48.2 g, 0.294 mol) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][C:17]([CH3:18])([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:25])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CC(C)(C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CC(C)(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1,3-dimethyl-3-phenyl-butyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:12]2(=[O:28])[CH2:17][CH2:16][C:15](C(OCC)=O)([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[OH-].[Li+].O.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:12]2(=[O:28])[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)C1(C(=O)OCC)CCP(=O)(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(P2(=O)CCC(C(=O)O)CC2)ccc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 4 h
Yield: 11.7 %

Procedure:
Diethyl 1-(3-methoxy-4-nitrophenyl)phosphinane-4,4-dicarboxylate 1-oxide (INTERMEDIATE 59) (4.5 g, 10.89 mmol) and lithium hydroxide (1.043 g, 43.55 mmol) were added to a 200-mL round bottomed flask. Water (30 mL) and THF (30 mL) were added to give a brown suspension. The mixture was heated to 75° C. and stirred at that temperature for 4 h. The reaction mixture was concentrated to give a solid residue. To the mixture was added HCl (aq., 4 N, 60 mL) to give a suspension and further diluted with THF (30.0 mL). The mixture was microwaved at 110° C. for 2 h. After cooling to RT, water (60 mL) was added to the reaction solution. The solution was extracted with 30% iPrOH in chloroform (5×40 mL), and the combined organic layers were concentrated to give the title compound (0.4 g, 12% yield). m/z 314.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[CH3:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][C:27]([CH3:28])=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(C)c(C)c4)CC3)nn2C(C)(C)C)cc1

Procedure:
89 mg (84%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(3,4-dimethylphenyl)piperazine (42 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]2)[CH:2]=1.[F:13][C:14]([F:22])([F:21])[CH2:15][CH:16]([CH3:20])[C:17](O)=[O:18].Cl.CN(C)CCCN=C=NCC>ClC(Cl)C>[F:13][C:14]([F:22])([F:21])[CH2:15][CH:16]([CH3:20])[C:17]([NH:12][C:10]1[CH:9]=[N:8][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)=[O:18]
Reactant: CC(CC(F)(F)F)C(=O)O
Reactant: Nc1cnn(-c2cccnc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: CC(CC(F)(F)F)C(=O)Nc1cnn(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.150 g, 0.93 mmol) in dichloroethane (1.8 ml) was added 4,4,4-trifluoro-2-methylbutanoic acid (0.14 g, 0.93 mmol) and 4-N,N-dimethylaminopyridine (0.23 g, 1.87 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.36 g, 1.87 mmol). The reaction stirred at room temperature overnight. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography eluting with 0-5% MeOH/dichloromethane to give a white solid (0.15 g, 55%); mp 140-145° C.; 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J=2.4 Hz, 1H), 8.62-8.47 (m, 2H), 8.01 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.68 (s, 1H), 7.53 (bs, 1H), 7.40 (ddd, J=8.3, 4.8, 0.6 Hz, 1H), 2.92-2.61 (m, 2H), 2.32-2.05 (m, 1H), 1.38 (d, J=6.6 Hz, 3H); ESIMS m/z 300 ([M+2]).
Reaction SMILES: [N:1]1[N:2]2[CH:10]=[CH:9][CH:8]=[C:3]2[C:4]([NH2:7])=[N:5][CH:6]=1.[Br:11]N1C(C)(C)C(=O)N(Br)C1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:11][C:8]1[CH:9]=[CH:10][N:2]2[C:3]=1[C:4]([NH2:7])=[N:5][CH:6]=[N:1]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2cccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ncnn2ccc(Br)c12
Reaction time: 4 h

Procedure:
A suspension of pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.5 g, 0.004 mol) in dichloromethane (100 mL) was stirred and cooled between −10° C. and −14° C. under nitrogen atmosphere. A solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (544 mg, 0.002 mol) in dichloromethane (100 mL) added dropwise over a 1 h. After 4 h, 100 mL of 10% aqueous sodium thiosulfate solution was added, and the mixture was stirred vigorously for a few minutes. The phases were separated, the dichloromethane phase washed with water, then brine, dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The residue was purified by MPLC (dichloromethane/ethyl acetate gradient). Purified material was triturated with dichloromethane, filtered, washed and dried under vacuum to afford 289 mg (36%) of colorless, fluffy solid. 1H-NMR (DMSO-d6): δ 8.01 (br s, 1 H), 7.82 (s, 1 H), 7.70 (d, 1 H), 6.78 (d, br s, 2 H). MS: LC/MS (+esi), m/z=212.5, 213.1 [M+H]. RT=1.34 min. Calc. for C6H5BrN4: C, 33.83; H, 2.37; Br, 37.50; N, 26.3. Found: C, 33.85; H, 2.24; Br, 38.24; N, 26.21.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18]N(C(OC)=O)C[CH2:15]3)[CH2:7]1)(=[O:3])[CH3:2].[CH3:26][O:27]C1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>>[CH2:15]1[C:14]2[CH:13]=[C:12]([N:8]3[CH2:7][C@H:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]3=[O:11])[CH:21]=[CH:20][C:19]=2[CH2:18][CH2:26][O:27]1
Reactant: COC(=O)N1CCc2cc(N3C[C@H](CNC(C)=O)OC3=O)ccc2C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)COCC3)C(=O)O1

Procedure:
Following the general procedure of Example 5, and making non-critical variations but substituting (−)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzopyran-7-yl)-2-oxo-5-oxazolidinyl]methyl]acetamide (Step 4) for methyl 6-[(5S)-5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate, using 0.7 mol-equivalents of Lawesson's reagent and repurifying the product by trituration with MeOH/Et2O or recrystallization from EtOAc/hexane, the title compound is obtained (84%) as a white solid, mp 165° C. (decomp.). MS (ESI+) for C15H18N2O3S m/z 307 (M+H)+; [α]25D=6° (c 0.96, DMSO).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:4]=[C:5]([C:14]([N:16]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][N:25]([C:34]([C:36]3[CH:41]=[C:40]([CH3:42])[C:39]([O:43]C(=O)C)=[C:38]([CH3:47])[CH:37]=3)=[O:35])[CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([CH3:13])[C:8]=1[O:9]C(=O)C.C[O-].[Na+]>CO>[CH3:13][C:7]1[CH:6]=[C:5]([C:14]([N:16]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][N:25]([C:34]([C:36]3[CH:41]=[C:40]([CH3:42])[C:39]([OH:43])=[C:38]([CH3:47])[CH:37]=3)=[O:35])[CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH:4]=[C:3]([CH3:2])[C:8]=1[OH:9]
Reactant: CC(=O)Oc1c(C)cc(C(=O)N2CCOCCOCCN(C(=O)c3cc(C)c(OC(C)=O)c(C)c3)CCOCCOCC2)cc1C
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)N2CCOCCOCCN(C(=O)c3cc(C)c(O)c(C)c3)CCOCCOCC2)cc(C)c1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To 40 ml of mixed solvent of anhydrous methanolmethylene chloride was dissolved 0.5 g/0.8 mmol of 1,10-bis(3',5'-dimethyl-4'-acetoxyphenylcarbonyl)-1,10-diaza-4,7,13,16-tetraoxacyclooctadecane, and the solution was cooled to 0° C. To this solution was added 2.6 ml of freshly prepared 1M methanol solution of sodium methoxide, and the mixture was stirred at 0° C. for 2 hours. After adding Amberlite 15 until the reaction solution became neutral, the resin was separated by filtration and the filtrate was concentrated under reduced pressure to obtain 0.4 g of 1,10-bis(3',5'-dimethyl-4'-hydroxyphenylcarbonyl)-1,10-diaza-4,7,13,16-tetraoxacyclooctadecane. 1H-NMR (CDCl3): δ2.15 (12H, s), 3.6 (16H, br), 3.8 (8H, br), 5.89 (2H, s), 6.90 (4H, s).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19](=[O:40])[CH2:20][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]([C:30]([O:32]CC5C=CC=CC=5)=[O:31])=[CH:22]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19](=[O:40])[CH2:20][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]([C:30]([OH:32])=[O:31])=[CH:22]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C(=O)Cn4cc(C(=O)OCc5ccccc5)c5ccccc54)ccc3o2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(C(=O)Cn4cc(C(=O)O)c5ccccc54)ccc3o2)n1
Yield: 76.9 %

Procedure:
A solution of benzyl 1-{2-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-2-oxoethyl}indole-3-carboxylate (140 mg) in tetrahydrofuran (4 ml) was hydrogenated over 10% Pd(OH)2 (22 mg) at room temperature under atmospheric pressure. After removal of the catalyst by filtration the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of dichloromethane and methanol. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 1-{2-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-2-oxoethyl}indole-3-carboxylic acid (90 mg).
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([O:7]CC)=O)(=O)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:28]1([CH3:43])[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[C:36]1[C:37]([CH3:42])=[N:38][NH:39][C:40]=1[NH2:41]>C1(C)C(C)=CC=CC=1>[C:28]1([CH3:43])[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[C:36]1[C:37]([CH3:42])=[N:38][N:39]2[C:5](=[O:7])[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:1]([CH3:2])[NH:41][C:40]=12
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Reaction time: 3 h

Procedure:
Diethyl acetylsuccinate (0.3 mL) and a catalytic amount of 4-toluenesulfonic acid monohydrate were added to a solution of 4-mesityl-3-methyl-1H-5-pyrazoleamine (100 mg) of Reference Example 1 in xylene (5 mL). Under heating under reflux, the mixture was stirred for three hours while distilling water off with Dean-Stark. The reaction solution was cooled, water was added thereto. the mixture was extracted twice with ethyl acetate, and washed twice with an aqeous saturated solution of sodium bicarbonate. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography, to give the title compound (200 mg) as a yellow amorphous material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[C:7]1[S:11][C:10](/[CH:12]=[CH:22]/[CH:23]=[O:24])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2ncccn2)s1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2ncccn2)s1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 5-(2-pyrimidinyl)-2-thiophenecarboxaldehyde (prepared as described in Reference Example 86) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:19].[K+].[K+].OO>CS(C)=O.C(Cl)Cl>[CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:15])=[O:19])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1cnc(Oc2ccc(C=O)cc2)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)c1cnc(Oc2ccc(C=O)cc2)cn1
Temperature: 25 °C
Reaction time: 22 h
Yield: 47.4 %

Procedure:
Dissolve 5-(4-formylphenoxy)pyrazine-2-carbonitrile (1.87 g, 8.30 mmol) and K2CO3 (0.573 g, 4.15 mmol) in DMSO (21 mL). Add 30% H2O2 (2.4 mL, 20.8 mmol) and stir at room temperature for 22 hours. Add additional K2CO3 (0.573 g, 4.15 mmol) and heat at 55° C for about 2.5 hours. Cool the reaction mixture and dilute with CH2Cl2, (200 mL). Wash with water (1×100 (mL) and saturated aqueous NaHCO3 (1×100 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 0-50% ethyl acetate in dichloromethane to give the title compound (0.478 g, 23.7%): TOF MS ES+ 244.1 (M+H)+, HRMS calcd for C12H10N33 244.0722 (M+H)+, found 244.0709, time 0.38 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.2 min, 100% purity.
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)#[CH:7].[C:14](=[O:16])=[O:15]>C1COCC1>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]#[C:7][C:14]([OH:16])=[O:15]
Reactant: O=C=O
Reactant: C#Cc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C#Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.3 mL of n-butyllithium solution (1.6M in hexane) is added dropwise at −10° C. to a solution of 1 g (9.7 mmol) of 2-ethynylpyridine in 30 mL of absolute THF and stirred for 30 minutes. At −78° C., dry ice is added batchwise and the reaction mixture is allowed to heat up to ambient temperature. After about 1 hour, the reaction mixture is evaporated down and the residue is taken up in 10 mL of 1N hydrochloric acid while cooling with ice. The precipitate is filtered off, rinsed with isopropanol and diethyl ether, and dried in the vacuum drying chamber at 70° C. Yield: 0.6 g (42% of theory); melting point: 130° C.; C8H5NO2 (M=147.13); calc.: molecular ion peak (M+H)+: 148; found: molecular ion peak (M+H)+: 148.