Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:21]=[CH:22][C:23]=2[S:24](O)(=[O:26])=[O:25])[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[CH3:20])=[O:5])[CH3:2].[CH2:28]([NH2:30])[CH3:29]>>[CH2:28]([NH:30][S:24]([C:23]1[CH:22]=[N:21][N:10]2[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH3:20])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8][C:9]=12)(=[O:26])=[O:25])[CH3:29]
Reactant: CCN
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccc(F)cc1C
Product: CCNS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)OCC)cnc12
Yield: 33.3 %

Procedure:
Using 6-ethoxycarbonyl-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.500 g, 1.268 mmol) obtained in Example 1 step 2 and ethylamine (2.0 mol/L THF solution; 2.5 mL, 5.071 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.178 g, 33%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)/[CH:10]=[CH:11]/[C@H:12]2[O:17][C:16](=[O:18])[CH2:15][C@H:14]([OH:19])[CH2:13]2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35](=[O:42])[C@H:36]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH2:37]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[CH:10]=[CH:11][C@@H:12]([OH:17])[CH2:13][C@@H:14]([OH:19])[CH2:15][C:16]([NH:37][C@H:36]([C:35]([O:34][CH3:33])=[O:42])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:18])=[CH:4][CH:3]=1
Reactant: Cn1nnnc1C(/C=C/[C@@H]1C[C@@H](O)CC(=O)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)C[C@H](O)C[C@H](O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C

Procedure:
When a solution of trans-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one in tetrahydrofuran is treated with at least one equivalent of L-leucine methyl ester (prepared in situ from the hydrochloride salt) and heated to reflux temperature, the title compound is thereby produced.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:38])[C:5]2[CH:14]=[C:15]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
134 mg of 3,4-dihydro-2,2-dimethyl-6-(4-nitrobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 15 ml of dichloromethane and 72 mg of m-chloroperbenzoic acid were added. The mixture was stirred at room temperature overnight. After washing in succession with sodium bisulphite solution and sodium bicarbonate solution the organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/methanol (4:1) for the elution. The residue was recrystallized from isopropanol to give 50 mg of 2-[3,4-dihydro-2,2-dimethyl-6-(4-nitrobenzoyl)-2H-1-benzopyran-4-yl]pyridine N-oxide of melting point 209°-211° C.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:14]=1>CN(C=O)C>[Br:8][C:9]1[C:10]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:11][CH:12]=[C:13]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:14]=1
Reactant: CS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc(OCC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A solution of cyclopropylmethanol (146 uL, 1.8 mmol) stirred in DMF (3 mL) at 0° C. was treated with NaH (75 mg, 1.9 mmol, 60% in mineral oil). After stirring at 0° C. for 30 min, the reaction mixture was treated with a solution of 3-bromo-2-chloro-5-methylsulfonylpyridine (400 mg, 1.5 mmol) in DMF (3 mL) by dropwise addition. After the ice bath was removed, the mixture was stirred at rt for 14 h. The reaction mixture was treated with water and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (5 to 85%) in hexanes to give the title compound (298 mg, 65%). LCMS (M+H)+=307.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][CH:29]([F:31])[F:30])[CH2:10]1)(C(C)(C)C)(C)C.Cl>CO>[F:31][CH:29]([F:30])[S:28][CH2:27][C@@H:11]1[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSC(F)F)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1CSC(F)F
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.36 g) in methanol (30 ml) was added conc. hydrochloric acid (0.47 ml) at ambient temperature and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (50 ml). The solution was washed in turn with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (2S,4R)-2-(difluoromethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.03 g).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1C1=CCN(C)CC1
Reaction time: 3 h
Yield: 72.7 %

Procedure:
A solution of acryloyl chloride (0.026 mL, 0.32 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine (Intermediate 55, 150 mg, 0.32 mmol) and DIPEA (0.062 mL, 0.36 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (120 mg, 72%) as a yellow foam; 1H NMR: 2.28 (3H, s), 2.38 (2H, s), 2.54 (2H, t), 2.98 (2H, d), 3.81 (3H, s), 5.62-5.73 (2H, m), 6.14 (1H, dd), 6.43 (1H, dd), 6.88 (1H, s), 7.12 (1H, dt), 7.39-7.47 (1H, m), 7.83 (1H, s), 8.41-8.50 (2H, m), 8.63 (1H, s), 8.85 (1H, d), 8.95 (1H, s), 9.36 (1H, s); m/z: ES+ MH+ 516.25.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:19]=[C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[CH:17]=[CH:16][C:13]=1[C:14]#N.C[OH:26].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:11][C:12]1[CH:19]=[C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)[CH:17]=[CH:16][C:13]=1[CH:14]=[O:26]
Reactant: CO
Reactant: N#Cc1ccc(-n2cccn2)cc1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-n2cccn2)cc1F
Reaction time: 1 h
Yield: 65 %

Procedure:
Diisobutylaluminum hydride (1.0 M in toluene, 11.00 mL, 11.00 mol) was added dropwise over 10 min to a vigorously stirred suspension of the compound from step A (1.88 g, 10.04 mmol) in toluene (100 mL) at −78° C. After 1 h at −78° C., methanol (1 mL) was added, the mixture was stirred for 5 min, and then poured into a stirred, cold (0° C.) mixture of 1.2 N HCl (100 mL) and ethyl acetate (100 mL). After stirring for 30 min at RT, the layers were separated and the aqueous layer was extracted with additional ethyl acetate (100 mL). The combined organic layers were washed with sat. aq. NaHCO3 (100 mL) and brine (100 mL), dried (MgSO4), and concentrated. Recrystallization from IPA followed by chromatography (SiO2, dichloromethane) provided 1.25 g (65%) of the title compound as a colorless solid. MS 191 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]2[N:12]=[CH:13][CH:14]=[C:4]2[N:3]=1.C(N(CC)CC)C.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C(Cl)Cl>[Si:26]([O:10][CH2:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]2[N:5]([N:12]=[CH:13][CH:14]=2)[C:6]=1[Cl:11])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: OCCc1c(Cl)nc2ccnn2c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1c(Cl)nc2ccnn2c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.4 %

Procedure:
To a methylene chloride (50 mL) solution containing 2-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)ethanol (640 mg, 2.77 mmol), triethylamine (3.86 mL, 27.7 mmol) and tert-butylchlorodimethylsilane (1.25 g, 8.31 mmol) were added, and this mixture was stirred at room temperature for 16 hr. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (15% ethyl acetate-hexane) to obtain the title compound (1.04 g).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:35][CH2:34][CH2:33][CH2:32][N:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCCCN1CCOCC1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCCCN3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 3-morpholinopropan-1-amine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH3:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH2:32]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][CH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[CH2:32]1
Reactant: CC1CNc2ccccc21
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CN(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)c2ccccc21

Procedure:
0.15 g (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 61 mg (0.37 mmol) 3-methyl-2,3-di-hydro-1H-indole, 150 μL (0.87 mmol) DIPEA and 0.13 g (0.41 mmol) TBTU in 1.8 mL DMF were stirred for 1 h at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[N+:20]([C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][CH2:29][C:30]2=O)=[CH:25][CH:24]=1)([O-:22])=[O:21].O>C1COCC1>[N+:20]([C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][CH2:29]/[C:30]/2=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: COC(=O)C[Si](C)(C)C
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C1\CCCc2ccc([N+](=O)[O-])cc21
Temperature: -78 °C
Yield: 83 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide, (1.0 M in hexanes) (5 mL, 28 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (4 g, 28 mmol) in THF (30 mL). The reaction was maintained at −78° C. for 16 minutes and then 7-nitro-1-tetralone 6.1 (available from Astratech) (3 g, 16 mmol) was added in one portion, and the resulting mixture was stirred at −78° C. and allowed to warm to room temperature for 20 hours. The resulting mixture was poured into water (30 mL) and then extracted with EtOAc (300 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:4 EtOAc/hexane) to give 6.2 in 83% yield.
Reaction SMILES: [C:1]([O:10]C)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].CO>O>[C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)CCCCC(=O)[O-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCC(=O)O
Yield: 98.4 %

Procedure:
16 g of a strongly acidic ion exchanger (cross-linked polystyrene containing sulfo groups) were suspended in a solution of 160 g of monomethyl adipate prepared according to (c), in 270 g of water. The reaction mixture was heated in a 1 l three-necked flask with an attached spinning band column until no further methanol passed over. The ion exchanger was filtered off; 144.5 g (99% yield) of adipic acid of melting point 153° C. were obtained from the filtrate after crystallization and partial evaporation of the mother liquor.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=O.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: O=C(c1cnccc1Cl)N1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: Clc1ccncc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
Dissolve (4-chloro-pyridin-3-yl)-morpholin-4-yl-methanone (1.17 g, 5.17 mmol) in dry THF (10 mL). Add a solution of 2 M BH3—Me2S/THF (15 mL, 31.0 mmol) dropwise at room temperature under nitrogen. Stir at room temperature for 15 hours under nitrogen. Add methanol (11.0 mL) very slowly dropwise. Heat at 60° C. for 3 hours, and cool to room temperature in vacuo to afford the title compound (1.1 g, 100%). MS (ES) m/z 213 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:30]I.O>CN(C)P(N(C)C)(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:5]([O:7][CH3:30])=[O:6]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Reaction time: 1 h

Procedure:
A solution of 7.20 g of 3-fluoro-4-(hexadecylamino)benzoic acid in 25 ml of hexamethylphosphoramide is added to a stirred mixture of 0.800 g of sodium hydride (57% in mineral oil) and 25 ml of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g of methyl iodide and is then stirred at 25° C. for 18 hours Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 3-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]12[CH2:13][C:10]([C:14]3[NH:22][C:21]4[C:20](=[O:23])[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH2:29][CH3:30])[C:16]=4[N:15]=3)([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2.[OH-].[Na+]>C1COCC1>[O:27]=[C:18]1[N:17]([CH2:28][CH2:29][CH3:30])[C:16]2[N:15]=[C:14]([C:10]34[CH2:13][C:6]([CH2:5][CH2:4][C:3]([OH:31])=[O:2])([CH2:12][CH2:11]3)[CH2:7][CH2:8][CH2:9]4)[NH:22][C:21]=2[C:20](=[O:23])[N:19]1[CH2:24][CH2:25][CH3:26]
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(CCC(=O)OC)(CC3)C4)nc2n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CCC(=O)O)(CC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
A solution of 3-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[3.2.1]oct-1-yl]-propionic acid methyl ester (0.456 mmol, 0.196 g) in THF (10 ml) was treated with 20% NaOH (2 ml) and stirred overnight at RT. The reaction was concentrated to remove the THF. The aqueous residue was acidified (pH 2-3) with conc. HCl and iPrOH was added to homogeneity. The solution was concentrated on the rotovap until solids just began to separate. After chilling in ice 1 h, the precipitated solids were collected by vacuum filtration, rinsed with a little H2O and chased with Et2O. The solids were dried on the filter to provide the desired product (0.061 g, 32%). 13C NMR (100 MHz, CDCl3): 11.11 (q), 11.26 (q), 20.04 (t), 21.25 (t), 21.31 (t), 29.51 (s), 33.97 (t), 35.15 (s), 36.16 (t), 36.39 (t), 43.32 (t), 43.41 (t), 45.38 (t), 49.18 (t), 106.01 (s), 149.40 (s), 150.90 (s), 156.30 (s), 161.56 (s), 178.54 (s).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]([CH3:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.[CH3:14][N:15]=[C:16]=[O:17]>C(OCC)(=O)C>[CH3:13][C:8]1([CH3:12])[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:16]([NH:15][CH3:14])=[O:17])[S:3][C:4]=2[CH:10]([CH3:11])[CH2:9]1
Reactant: CN=C=O
Reactant: CC1CC(C)(C)Cc2nc(N)sc21
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1nc2c(s1)C(C)CC(C)(C)C2
Reaction time: 2 h

Procedure:
2-Amino-5,5,7-trimethyl-4,5,6,7-tetrahydrobenzothiazole (0.1 mole) is dissolved in ethyl acetate (100 ml) and the solution is charged into a glass reaction vessel fitted with a stirrer and thermometer. Methyl isocyanate (0.11 mole) is added dropwise to this solution over a period of about 30 minutes. The temperature of the reactant is held at about 20° C. to 30° C. during the addition. At the end of the addition, stirring is continued at room temperature for a period of about 2 hours. The reaction mixture is then filtered and the filtered-off solids are air dried to yield the desired product N-(5,5,7-trimethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl)-N'-methylurea.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:31](=[O:32])[C:11]3=[CH:12][NH:13][C:14]4[CH2:15][CH2:16][CH:17]([O:20]C(OCC5C=CC=CC=5)=O)[CH2:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[H][H]>CN(C=O)C.CCO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:31](=[O:32])[C:11]3=[CH:12][NH:13][C:14]4[CH2:15][CH2:16][CH:17]([OH:20])[CH2:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)OC1CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=c1c2c[nH]c3c(c-2nn1-c1ccc(Cl)cc1)CC(O)CC3

Procedure:
2-p-chlorophenyl-8-benzyloxycarbonyloxy-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one (1.60 g) is dissolved in 100 mL of 1:1 mixture of DMF and EtOH and subjected to catalytic hydrogenation with 10% palladium on carbon (0.4 g) for 24 hours under one atmosphere pressure of hydrogen. After the reaction is complete the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is triturated with EtOH to obtain 2-p-chlorophenyl-8-hydroxy-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:16][C:17](=[O:31])[CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:27]([SH:30])=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][O:25]2>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:30][C:27]3[CH:28]=[CH:29][C:20]([O:19][CH2:18][C:17]([OH:31])=[O:16])=[C:21]4[C:26]=3[O:25][CH2:24][CH2:23][CH2:22]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Reactant: COC(=O)COc1ccc(S)c2c1CCCO2
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(Cl)cc3)on2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole and (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester. mp 131-133° C.; MS m/z 446 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[C:5](=O)[NH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].P(Cl)(Cl)([Cl:26])=O>>[Br:1][C:2]1[C:3]2[S:11][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][C:4]=2[C:5]([Cl:26])=[N:6][CH:7]=1
Reactant: O=c1[nH]cc(Br)c2sc(-c3ccccc3)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Clc1ncc(Br)c2sc(-c3ccccc3)cc12

Procedure:
A mixture of 7-bromo-2-phenyl-5H-thieno[3,2-c]pyridin-4-one 3 (2.28 g, 7.5 mmol) in phosphorus oxychloride (27 mL) was heated at reflux for 21 h. The reaction mixture was basified to pH 5-6 by the addition of saturated aqueous sodium carbonate and extracted with dichloromethane (1×). The organic layer was dried over Na2SO4, filtered, and the filtrate was purified by silica gel column chromatography (eluent: hexane:EtOAc, 97:3) to give 95.
Reaction SMILES: C([O:4][C:5]([C@@H:7]1[CH2:22][C@@:15]2([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:23])[CH:13]=2)[O:8]1)=O)CC.O.[NH2:25][NH2:26]>C(O)C>[F:23][C:12]1[CH:13]=[C:14]2[C@:15]3([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]3)[CH2:22][C@@H:7]([C:5]([NH:25][NH2:26])=[O:4])[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: CCCOC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Yield: 46.7 %

Procedure:
To a solution of (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic acid n-propyl ester (30.0 g, 93.1 mmol) in 600 ml of ethanol was added hydrazine hydrate (46.6 g, 0.931 mol). After refluxing the mixture under an argon atmosphere for 2 hours, the reaction mixture was evaporated in vacuo to dryness. To the residue was added 100 ml of saturated aqueous sodium chloride and the aqueous layer was extracted with ethyl acetate (300 ml×5). The combined ethyl acetate layers were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 17.3 g (Yield: 63.1%) of crude crystals. The crystals were recrystallized from ethanol to give colorless needles of the desired compound (12.8 g, 46.7%).