Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].[CH3:14][OH:15]>>[CH3:14][O:15][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13]
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Reactant: CO
Product: COc1c(C=O)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method C was followed. 6-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.270 g, 1.33 mmol) and methanol were used to obtain the title compound. The crude product was purified by column chromatography with a mixture of n-hexane:ethyl acetate (4:1) as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>CNC1CCCCC1.C(O)C>[CH:22]1([N:23]([CH3:26])[CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:21][CH2:2][CH2:3][CH2:4]1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CNC1CCCCC1
Solvent: CCO
Product: CN(C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1)C1CCCCC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and N-methylcyclohexylamine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=399.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH3:25])[CH:20]=O.[CH3:26][NH:27][CH3:28]>O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:20]([N:27]([CH3:28])[CH3:26])[C:19]2[CH:22]=[CH:23][C:24]([CH3:25])=[C:17]([CH3:16])[CH:18]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: Cc1ccc(C=O)cc1C
Solvent: O
Product: Cc1ccc(C(c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)N(C)C)cc1C
Temperature: 140 °C
Yield: 59 %

Procedure:
A mixture of 26.82 g (0.13 mol) of 2,4-di-tert-butylphenol, 17.44 g (0.13 mol) of 3,4-di-methylbenzaldehyde and 22.0 g (0.20 mol) of a 40% aqueous solution of dimethylamine is heated in a closed vessel at 140° C. for 10 hours, the internal pressure rising to 4 bar. After cooling to room temperature, the reaction mixture is poured into 100 ml of water and extracted twice using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Crystallisation of the residue from isopropanol yields 28.25 g (59%) of 2,4-di-tert-butyl-6-[dimethylamino-(3,4-dimethyl-phenyl)-methyl]-phenol, m.p. 82-85° C., (compound (201), Table 2). Molecular weight C25H37NO (367.58). Analysis, calculated: C 81.69; H 10.15; N 3.81%. Analysis, found: C 81.78; H 10.05; N 3.80%. 1HNMR (300 MHz, CDCl3, ppm): 1.18 (s, 9H); 1.43 (s, 9H); 221 (s, 6H); 2.24 (s, 6H); 4.27 (s, 1H); 6.74 (d, 1H); 7.11 (m, 4H); 12.43 (s, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]>C(#N)C.C(=O)([O-])O.[Na+]>[NH2:9][C:10]1[C:11]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])=[C:12]([CH:17]=[CH:18][C:19]=1[Cl:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccc(N)c1NCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.4 %

Procedure:
N-Chlorosuccinimide (74.1 g, 555 mmol) was added to a stirred solution of methyl 3-amino-2-[(3-hydroxypropyl)amino]benzoate (81.9 g, 370 mmol) in acetonitrile (1480 mL) at room temperature, and the mixture was stirred at room temperature for 16 hr. Additional N-chlorosuccinimide (9.88 g, 74.0 mmol) was added to the mixture, and the mixture was stirred at room temperature for 90 min. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, concentrated in vacuo, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-45% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a brown oil (15.7 g, 60.8 mmol, 16%).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:31]=1[C:37]1[S:38][CH:39]=[C:40]([C:42](O)=[O:43])[N:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:42]([C:40]3[N:41]=[C:37]([C:31]4[C:30]([F:29])=[CH:35][CH:34]=[CH:33][C:32]=4[F:36])[S:38][CH:39]=3)=[O:43])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1csc(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (7.0 mg, 0.018 mmol), 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (5.2 mg, 0.022 mmol), HATU (17 mg, 0.045 mmol), DMF (0.042 mL) and DIPEA (7.0 mg, 0.054 mmol) were mixed together and the mixture was stirred at room temperature for 1 h. The mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give pure sub-title compound as light yellow powder (3.7 mg, 34%). LCMS calc. for C30H34F2N5O5S (M+H)+: m/z=614.2. Found: 614.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[S:63]1[C:71]2[CH2:70][CH2:69][NH:68][CH2:67][C:66]=2[CH:65]=[CH:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][C:71]3[S:63][CH:64]=[CH:65][C:66]=3[CH2:67]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1cc2c(s1)CCNC2
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCc4sccc4C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:27]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4].B1([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)C2CCCC1CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd].C1COCC1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:27]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4]
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Br)cc3)c(C3CCCCC3)c(=O)n2n1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]c(-c3ccc(Cc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
According to a modification of a literature procedure (Suzuki, A. et al Tetrahedron Lett. 1986, 27, 6369-6372) a mixture of 43 mg (0.1 mmol) of 5-(4-bromo-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester, 7.3 mg (0.01 mmol) of Pd catalyst, 0.4 mL (0.2 mmol) of B-Benzyl-9-BBN 0.5 M solution in THF, and 63 mg (0.3 mmol) of potassium phosphate, was purged with argon, 1 mL of 1,4-dioxane was added, and the resulting mixture was shaken at 80° C. in a sandbath overnight. The reaction mixture was then diluted with dichloromethane, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a residue, which was purified via reverse-phase chromatography (Gilson) to afford desired 5-(4-benzyl-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by LC-MS—calcd for C27H27N3O3 [M++H]+: 442.21, found: 442.2. This material was then converted to 5-(4-benzyl-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (581) via a LiOH saponification (33% yield over 2 steps); LC-MS—calcd for C26H25N3O3 [M++H]+: 428.19, found: 428.2.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[N+:52]([O-:55])([OH:54])=[O:53]>C(Cl)(Cl)Cl.C(#N)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[N+:52]([O-:55])([O-:54])=[O:53]
Reactant: O=[N+]([O-])O
Agent: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])[O-]

Procedure:
The compound is prepared starting from an erythromycin solution (2 g, 2.72 mmoles) dissolved in a mixture of chloroform (30 ml)/acetonitrile (20 ml), by adding a 65% nitric acid solution (0.200 ml) in acetonitrile (5 ml), following then the procedure described in Example 5. Erythromycin nitrate as amorphous solid is obtained. Yield 83%.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([N:18]([CH3:26])[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])C.CC[O-].[Na+].C(O)(=O)C.O>C(O)C>[CH2:24]([O:23][C:21]([CH:20]1[CH2:19][N:18]([CH3:26])[C:7]2[N:8]=[C:9]3[CH:10]=[C:11]([F:17])[C:12]([F:16])=[CH:13][C:14]3=[CH:15][C:6]=2[C:4]1=[O:5])=[O:22])[CH3:25]
Reactant: CCOC(=O)CCN(C)c1nc2cc(F)c(F)cc2cc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1CN(C)c2nc3cc(F)c(F)cc3cc2C1=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A solution of 94 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(b-ethoxycarbonylethyl)amino]quinoline in 300 cm3 of absolute ethanol is added in the course of 80 minutes to a solution of 26.6 g of sodium ethylate brought to reflux in 900 cm3 of absolute ethanol. The suspension obtained, still refluxing, is stirred for a further 15 minutes. 38 cm3 of glacial acetic acid are then introduced in the course of 30 minutes. The reaction mixture is stirred for a further 15 minutes and, with the mixture still refluxing, 500 cm3 of water are then introduced in the course of 45 minutes. The suspension obtained is cooled to approximately 20° C. The precipitate is drained at approximately 20° C. and washed with twice 300 cm3 of water. The wet product is dried under reduced pressure (20 kPa) at approximately 60° C. 71.5 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl- 4-oxo-1,2,3,4-tetrahydro-benzo[b][1,8]naphthyridine are isolated in the form of a yellow solid, melting point 188° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=1[CH:10]=[O:11].Cl[CH2:18][C:19]1[CH2:20][CH2:21][N:22]([CH3:31])[CH2:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:18][C:19]2[CH2:20][CH2:21][N:22]([CH3:31])[CH2:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]=1[CH:10]=[O:11]
Reactant: CN1CCC(CCl)=C(c2ccccc2)C1
Reactant: O=Cc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC(COc2cccc(O)c2C=O)=C(c2ccccc2)C1
Temperature: 50 °C
Yield: 26.6 %

Procedure:
To a suspension of K2CO3 (350 mg, 2.56 mmol) and 2,6-dihydroxybenzaldehyde (180 mg, 1.28 mmol) in DMF (3 ml) was added a solution of 4-(chloromethyl)-1-methyl-5-phenyl-1,2,3,6-tetrahydropyridine (140 mg, 0.64 mmol) in DMF (4 mL), the mixture was heated at 50° C. for 3 h, cooled to room temperature, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO3, brine, dried over Na2SO4, and was concentrated to give crude oil, which was purified by column (Hexane/EtOAc=1:1 followed by DCM/MeOH=90:10) to give 2-hydroxy-6-((1-methyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)benzaldehyde (55 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 11.92 (s, 1H), 10.35 (s, 1H), 7.34 (m, 5H), 7.19 (dd, J=8.4, 8.0 Hz, 1H), 6.46 (d, J=8.4 Hz, 1H), 6.16 (d, J=8.0 Hz, 1H), 4.45 (s, 2H), 3.20 (s, 2H), 2.68 (t, J=5.6 Hz, 2H), 2.47 (m, 2H), 2.42 (s, 3H); MS (ESI) m/z 324.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[S:10](=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]([CH3:39])[CH2:25][CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36](O)=[O:37])[CH3:27]>>[CH3:39][N:24]([CH3:23])[CH2:25][CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([N:13]1[CH2:14][CH:15]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][S:10](=[O:16])[CH:11]2[CH2:12]1)=[O:37])[CH3:27]
Reactant: CC(CN(C)C)Oc1ccccc1CC(=O)O
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Product: CC(CN(C)C)Oc1ccccc1CC(=O)N1CC2C(C1)C(c1ccccc1)(c1ccccc1)CCS2=O
Yield: 9.7 %

Procedure:
By carrying out the procedure according to that described in Example 8 below, using 1.82 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]-pyrrole 1-oxide and 1.39 g of [(3-dimethylamino-2-propoxy)phenyl]acetic acid, 0.3 g of (1RS,4aRS,7aRS)-6-{[(3-dimethylamino-2-propoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide is obtained in the form of white crystals; melting point 150° C.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:9]1[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:11]=[CH:12][C:13]=1[C:14]([O:16]CC)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].CC(C)([O-])C.[Na+].CN(C)C=O.O>C(OCC)(=O)C>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:10]2[C:9]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][NH:1][C:14](=[O:16])[C:13]=3[CH:12]=[CH:11]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(=CN)c1c(C(=O)OCC)ccn1Cc1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c(=O)c2ccn(Cc3ccc(OC)cc3)c12
Reaction time: 0.42 h
Yield: 1711.7 %

Procedure:
A mixture of ethyl 2-{2-amino-1-[(ethyloxy)carbonyl]ethenyl}-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrole-3-carboxylate (0.2 g), sodium tert-butoxide (26 mg) and dimethylformamide (2 ml) was irradiated with microwaves at 160° C. for 8 minutes. The procedure was repeated on a 2 g and 3 g scale, the cooled solutions combined, added slowly to iced water then stirred for 25 minutes. A precipitate formed which was dissolved in ethyl acetate and washed with water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a white solid (3.00 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:37][O:38][CH2:39][CH2:40][OH:41]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:37][O:38][CH2:39][CH2:40][OH:41])=[O:7]
Reactant: NOCCO
Reactant: COCCCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 69 %

Procedure:
The title compound was prepared from reaction of the product of Example 25, Step C, 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]amino]benzoic acid with CDI and 2-(aminooxy)ethanol, by the general procedure of Example 1, Step E, then purified by flash column chromatography on silica gel (50% EtOAc/hexanes) to give 3,4-difluoro-2-[[2-fluoro-4-(3-methoxypropyl)phenyl]-amino]-N-(2-hydroxyethoxy)benzamide as a cream solid (69%); m.p. (Et2O/hexanes) 136–137° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.85 (br s, 1 H), 8.77 (br s, 1 H), 7.43–7.36 (m, 1 H), 7.15–7.00 (m, 2 H), 6.95–6.77 (m, 2 H), 4.71 (br s, 1 H), 3.85 (t, J=4.8, 2 H), 3.56 (t, J=4.8, 2 H), 3.33 (t, J=6.4 Hz, 2 H), 3.23 (s, 3 H), 2.56 (t, J=7.7 Hz, 2 H), 1.80–1.71 (m, 2 H).
Reaction SMILES: N1C=[CH:4][CH:3]=[CH:2]1.[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([CH3:12])[CH:11]=1>>[CH3:12][C:10]1[C:11]2[CH2:4][CH2:3][CH2:2][CH2:6][C:7]=2[NH:8][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: Cc1c[nH]c(C)c1
Product: Cc1c[nH]c2c1CCCC2

Procedure:
Conversion of α-pyrrolecarboxylate esters to α-unsubstituted pyrroles by treatment with phosphoric acid provided a convenient preparation of pyrrole 5b and was extended to 3-n-propyl, 3-n-butyl, and 3-isopropyl derivatives 5d-f of 2,4-dimethylpyrrole 5a. A similar conversion afforded 3-methyl-4,5,6,7-tetrahydroindole 5i from its 2-carboxylate ester derivative 4i. Unsuccessful attempts to extend the method to the preparation of 2,4-dimethyl-3-tert-butylpyrrole 5g led instead to the replacement of both the carboethoxy and tert-butyl groups with hydrogen to give 2,4-dimethylpyrrole 5a. The pyrroles 5g, j, k were obtained from ethyl 3',5'-dimethyl-4-tert-butylpyrrole-2-carboxylate 4g, ethyl 3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrolecarboxylate 4j, and ethyl 3,4-diethyl-5-methylpyrrole-2-carboxylate 4k by saponification with potassium hydroxide followed by decarboxylation of the free acids in ethanolamine at 180° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4]1.[H][H].Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:20][CH2:19]1.Cl>CN(C=O)C>[F:33][C:30]([F:31])([F:32])[C:26]1[CH:25]=[C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][N:3]3[C:11]4[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=4[CH:5]=[CH:4]3)[CH2:23][CH2:22]2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: FC(F)(F)c1cccc(N2CCN(CCCl)CC2)c1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCc2c1ccn2CCN1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Sodium hydride (60% in oil) (85 mg, 2.1 mmol, 1.8 eq.) was added to a 10 ml pear-shaped flask. The solid was rinsed twice with 2 mL hexane to remove oil, then 3 mL anhydrous N,N-dimethylformamide(DMF) was added. 1,5,6,7-Tetrahydroindol-4-one (186.7 mg, 1.38 mmol, 1.159 eq.) was added slowly, with stirring and hydrogen evolved. The walls of the flask were washed with an additional 1 mL of anhydrous DMF. 1-(2-Chloro-ethyl)-4-(3-trifluoromethyl-phenyl)-piperazine (349.00 mg, 1.19 mmol, 1.000 eq) was added as a solution in 2 mL DMF, and the mixture was stirred under nitrogen at 25 C for 8 hours. The resulting mixture was acidified with 1 N HCl to pH 6, and extracted with dichloromethane. The organic layer was washed four times with 25 mL water, dried over sodium sulfate and concentrated in vacuum to an oil which was purified by column chromatography using 5% methanol in dichloromethane as eluant resulting in the title compound as an oil. The oil was dissolved in 5 mL of 50% dichloromethane in hexanes. A solution of 4N HCl in dioxane (200 μL) was added and the mixture stirred for 30 minutes followed by vacuum filtration of the suspension. A white powder of the product HCl salt was recovered.
Reaction SMILES: [CH:1](NC(C)C)(C)C.CCCCCC.C([Li])CCC.[CH3:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[CH:22][CH:21]=1.CI.[Cl-].[NH4+]>C1COCC1>[CH2:19]([C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[CH:22][CH:21]=1)[CH3:1]
Reactant: Cc1ccncc1C#N
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CCc1ccncc1C#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (9.1 ml) in THF (50 ml) was cooled to −30° C. and an n-butyllithium hexane solution (1.61 M, 37 ml) was added. The mixture was stirred for 30 min. After cooling the reaction mixture to −78° C., a solution of 4-methylnicotinonitrile (7.01 g) in THF (50 ml) was added dropwise and the mixture was stirred for 15 min. Methyl iodide (9.1 ml) was added and the mixture was heated to −40° C., and saturated aqueous ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate and the organic layer was dried and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) for purification to give the title compound (6.67 g) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:3]([NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)([CH3:6])[CH2:4][OH:5])#[N:2].F[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C:30]([F:33])([F:32])[F:31])[C:25]#[N:26].[H-].[Na+]>O1CCCC1>[C:1]([C:3]([NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)([CH3:6])[CH2:4][O:5][C:22]1[CH:23]=[C:24]([C:25]#[N:26])[CH:27]=[CH:28][C:29]=1[C:30]([F:31])([F:33])[F:32])#[N:2]
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(C#N)(CO)NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)(COc1cc(C#N)ccc1C(F)(F)F)NC(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
In 5 ml of dried tetrahydrofurane, 651 mg N-[1-cyano-2-hydroxy-1-methylethyl]-4-trifluoromethoxybenzamide and 427 mg 3-fluoro-4-trifluoromethylbenzonitrile are dissolved and 63 mg of sodium hydride are added under stirring at 0°. The reaction mixture is stirred for 20 h at room temperature, then quenched with 5 ml of water and finally diluted with 15 ml of brine. The crude product is extracted with 3×10 ml of ethylacetate, the combined organic phases washed with brine, dried over magnesium sulphate, filtered and evaporated. The residue is purified by flash chromatography to yield the title compound as white crystals of m. p. 75-8°.