Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11]Cl)[C:4]=2[O:3]1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:17][CH:16]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])=[CH:19][CH:20]=3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(CCl)c2O1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Nc1ccc(OCc2cccc3c2OC(C)(C)C3)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
3.0 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranylmethyl chloride and 3.0 g of 1-(4-hydroxyphenyl)-3,3-dimethylurea were dissolved into 20 ml of dried N,N-dimethylformamide, and 2.5 g of anhydrous potassium carbonate was added thereto. After the mixture was stirred at 80° C. for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/1) as a developer to obtain 4.0 g of Compound No. 7 shown in Table 1.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][CH2:26][C:27]([CH2:31][CH3:32])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][CH2:26][C:27]([CH2:31][CH3:32])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1
Reactant: CCC(O)(CC)CCCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)CCCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 79.6 %

Procedure:
Under the same conditions as in Example 9, the crude 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-ethyl-4-hydroxyhexylthio)pregna-5,7,16-triene (71.4 mg) obtained in Example 8, tetrahydrofuran (2 ml) and 1M tetra-n-butyl-ammonium fluoride solution in tetrahydrofuran (2 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichioromethane:ethanol=7:1, developed once) to give the title compound as a colorless oil (45.8 mg, 67%, 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17]C)=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:9]=2)=[C:4]([F:29])[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([OH:17])=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:9]=2)=[C:4]([F:29])[CH:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(Cl)cc1F
Yield: 19 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(4-chloro-2-fluorophenyl)-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.049 g; 0.117 mmol), sodium hydroxide 10N (0.200 mL; 2.00 mmol) in methanol (2 mL) at 60° C. for 18 h. Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane, followed by a purification by preparative HPLC (HPLC method 1) furnished 0.009 g (19%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]C)=O.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:16][C:4](=[O:6])[CH2:3][C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN
Reactant: CCCCC(=O)CC(=O)OC
Product: CCCCNC(=O)CC(=O)CCCC
Yield: 20.1 %

Procedure:
0.9 mol (150 ml) of methyl 3-oxoheptanoate and 2.7 mol (270 ml) butylamine, were stirred 5 h at 100° C. in the pressure vessel. Thereafter, excess butylamine was distilled off on a rotary evaporator, the crude product was taken up in water/ethanol, and adjusted with concentrated HCl to pH 3. The mixture was again evaporated to dryness, taken up again in ethyl acetate and filtered. The filtrate was washed with 1 M HCl and water. The organic phase was dried over Na2SO4 and after filtration evaporated in a rotary evaporator to dryness. The crude product was dissolved in 100 ml diethyl ether and crystallized at 5° C. The product was filtered off and dried. There were obtained 36.0 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2I)=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1>>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2[C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1cccnc1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2cccnc2)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 7, [4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-methanone (example 46) was reacted with pyridin-3-yl-boronic acid to give the title compound as off-white foam. MS: 530.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:29](Cl)(Cl)=[S:30]>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:29]=[S:30])[C:14]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2 g of 6-amino-2-tert-butyl-5-[4-acetylpiperazin-1-yl]benzothiazole and 1.5 g of sodium bicarbonate in 150 ml of chloroform is cooled to 0° and 4 ml of thiophosgene is added dropwise and stirred at ambient temperature overnight. The solid is filtered off and the filtrate is evaporated under reduced pressure. The oil so obtained is applied on a silica gel column and eluted with 1% methanol in chloroform to yield 2-tert-butyl-6-isothiocyanato-5-[4-acetylpiperazin-1-yl]benzothiazole, melting at 100°-102°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:14][C@H:13](CS([O-])(=O)=O)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1[C:28]([NH2:29])=[C:27]2[C:23]([N:24]=[CH:25][NH:26]2)=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:12][C@H:13]([N:24]2[CH:25]=[N:26][C:27]3[C:23]2=[N:22][CH:21]=[N:20][C:28]=3[NH2:29])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])C[C@H]1C[C@H](CCOCc2ccccc2)C1
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@H]1C[C@@H](CCOCc2ccccc2)C1
Temperature: 120 °C
Yield: 42.2 %

Procedure:
In a 25 mL three-neck flask with trans-3-(benzyloxyethyl)cyclobutyl-mesylate (0.50 g, 1.76 mmol), adenine (0.35 g, 2.59 mmol) and Cs2CO3 (0.86 g, 2.64 mmol) inside, dry DMF 8 mL was added under argon. Then began to heat to 120° C. and after 24 hr, the solvent was removed and directly applied to silica gel flash chromatography to give 0.24 g (43%) the desired product. 1H NMR (CDCl3, 300 MHz): δ 1.84-1.92 (m, 2H), 2.16-2.46 (m, 3H), 2.68-2.80 (m, 2H), 3.48-3.52 (t, J=6.3, 2H), 4.51 (s, 2H), 4.80-4.92 (m, 1H), 7.88 (s, 1H), 8.35 (s, 1H). MS (FAB): expected for C18H21N5O (M+H)+ 324.39. Found 324.18195. IR (neat) νmax 3398, 2927, 2862, 1718, 1453, 1315, 1276, 1113, 1071, 1027, 738, 714, 698.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C([O:15][CH2:16][CH3:17])(=O)C>>[CH2:4]([N:5]([CH2:17][CH:16]=[O:15])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11])[C:1]#[CH:2]
Reactant: O=C=Nc1nnc(C2CC2)s1
Reactant: CCOC(C)=O
Product: C#CCN(CC=O)C(=O)Nc1nnc(C2CC2)s1

Procedure:
A mixture of 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (7 grams), the dimethyl acetal of 2-propargylaminocetaldehyde (5 grams) and ethyl acetate (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the mixture is stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-[1-propargyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde as an oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][NH:7][NH2:8].[CH3:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14]>C(O)C>[C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[N:7]([CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[N:8]=1)([CH3:17])([CH3:16])[CH3:9]
Reactant: NNC[C@@H]1CCCO1
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C[C@@H]2CCCO2)n1

Procedure:
To a stirred solution of the product from Example 12B (232 mg, 2.0 mmol) in ethanol (4 mL) was added 4,4-dimethyl-3-oxopentanenitrile (250 mg, 2.0 mmol). The mixture was refluxed for 2 hours. The ethanol was removed by evaporation under reduced pressure and the crude product was dissolved in CH2Cl2 (10 mL), which was used directly for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][C:37](=[O:38])[CH2:36][CH2:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-phenyl-propionyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[CH:5]=[O:6].B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cc(Br)cc(C=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cc(O)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.7 %

Procedure:
3-Bromo-5-methoxybenzaldehyde (1 g, 4.65 mmol) was dissolved in 20 mL dichloromethane. A solution of boron tribromide (1M in dichloromethane, 23 ml, 23 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. A mixture of ethyl ether and diisopropyl ether was added and the precipitate was filtered to give 1.1 g (68% yield) of the title compound as an orange solid. Purity 99%.
Reaction SMILES: C([BH3-])#[N:2].[Na+].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=O.C([O-])(=O)C.[NH4+].Cl>CO.C(OCC)C>[F:14][C:10]1[CH:9]=[C:8]([CH:6]([NH2:2])[CH3:5])[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: CC(N)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Add sodium cyanoborohydride (452 mg, 7.2 mmol) to a solution of 3-fluoroacetophenone (500 mg, 3.6 mmol) and ammonium acetate (2.8 g, 36 mmol) in methanol (11 mL). Stir the mixture for 96 h at ambient temperature under a nitrogen atmosphere. Adjust to pH 2 with 2M hydrogen chloride in diethyl ether. Concentrate the slurry in vacuo, dilute the residue with DCM and wash with 5N aqueous NaOH followed by saturated aqueous NaHCO3. Dry the organic layer, concentrate in vacuo to half of the volume, and load the solution onto a SCX column (pre-wash column with methanol followed by DCM, then elute with 2M ammonia in methanol). Concentrate the fractions to half of the volume to remove ammonia, add excess of 2M hydrogen chloride in diethyl ether and concentrate to obtain the hydrochloride salt (70:30 mixture of title compound and dimer). Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (20:1) to obtain the title compound (323 mg, 51%). MS (ES+) m/z: 140 (M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37]O>>[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][O:22][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:23]
Reactant: OCc1ccco1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Product: O=C(OCc1ccco1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) and furan-2-ylmethanol. A colorless powder (190 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[S:26][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:9]=2[CH:8]=1>>[N:1]1([C:12]2[N:13]=[C:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:9]3[CH:8]=[CH:7][S:26][C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2ncnc3sc(Cl)cc23)c1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3ccnc3)nc3sccc23)c1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 6-chloro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]1[CH2:17][CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:13]=2[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])O.[Na+]>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][O:22][C:20]1[CH:19]=[CH:18][C:14]2[CH2:15][CH2:16][CH2:17][CH:11]([N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][C:13]=2[CH:21]=1)[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(O)cc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)CC(N(Cc1ccccc1)C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, to a suspension of sodium hydride (60% in oil, 300 mg) in N,N-dimethylformamide (20 ml) was added N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (2.5 g) in N,N-dimethylformamide (25 ml) at 5° C. After being stirred at room temperature for 30 minutes, to this one were added ethyl bromoacetate (0.75 ml) and tetra-n-butylammonium bromide (1.1 g) at 5° C., and the mixture was stirred at room temperature for 32 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 2-[8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (1.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([CH3:14])=[N:9]2)=[CH:4][C:3]=1[O:15][CH3:16].[OH-].[Na+].[F:19][CH:20]([F:22])Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1CCCCC1>[F:19][CH:20]([F:22])[N:11]1[C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:15][CH3:16])[CH:4]=2)[N:9]=[C:10]1[CH3:14]
Reactant: COc1cc(-n2nc(C)[nH]c2=O)ccc1C
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: COc1cc(-n2nc(C)n(C(F)F)c2=O)ccc1C
Temperature: 70 °C
Yield: 24.5 %

Procedure:
A stirred mixture of 60.0 g (0.28 mole) of 4,5-dihydro-1-(4-methyl-3-methoxyphenyl)-3-methyl-1,2,4-triazol-5(1H)-one, 60.0 g (0.19 mole) of tetrabutylammonium bromide and 60.0 g (1.5 mole) of powdered sodium hydroxide in 2 liters of cyclohexane was heated at reflux. During a two hour period 60.0 g (0.67 mole) of gaseous difluorochloromethane was bubbled into the mixture. After complete addition the mixture was stirred at reflux for one hour, then allowed to cool to 70° C. The supernatant liquid was decanted and washed with aqueous 10% hydrochloric acid followed by an aqueous 10% sodium hydroxide solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave a solid. This solid was triturated with petroleum ether and filtered. The filter cake was air dried to yield 18.5 g of 4-difluoromethyl-4,5-dihydro-1-(4-methyl-3-methoxyphenyl)-3-methyl-1,2,4-triazol-5-(1H)-one.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][CH:32]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH:33]([F:35])[F:34])=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][CH:32]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH:33]([F:35])[F:34])=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2)C(F)F)cc1
Yield: 83.5 %

Procedure:
TFA (5.3 mL) was added to a stirred solution of N-(5-chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-1-tert-butoxycarbonyl-L-prolinamide (0.626 g, 1.20 mmol) in CH2Cl2 (5.3 mL). After 1 h the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The EtOAc layer was dried (Na2SO4) and evaporated in vacuo to give N-(5-chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-L-prolinamide (0.439 g) as a foam; MS m/z=438.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14](=[O:16])[CH3:15])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
A solution of 3-nitrobenzenesulfonamide (615 mg) in 10 ml of dry tetrahydrofuran was cooled to 0° C. and mixed with 0.34 ml of acetic anhydride and 166 mg of 4-N,N-dimethylaminopyridine. The reaction mixture was stirred for 30 minutes, quenched with 10% citric acid solution, and diluted with ethyl acetate. The reaction mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried, concentrated in vacuo to yield 946 mg of the title compound in pure form.
Reaction SMILES: [O:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=2)[CH2:7][CH2:6]1)[N+:2]([O-:4])=[O:3].[OH:20]O>C(O)(=O)C>[O:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH+:11]([O-:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=2)[CH2:7][CH2:6]1)[N+:2]([O-:4])=[O:3]
Reactant: O=C(N[C@H]1CC[C@H](O[N+](=O)[O-])CC1)c1cccnc1
Reactant: OO
Solvent: CC(=O)O
Product: O=C(c1cccnc1)[NH+]([O-])[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
1.5 g (0.005 mol) N-(trans-4-nitroxycyclohexyl)nicotinic acid amide (Example 6/5) are dissolved in 4 ml acetic acid, 4 ml 30% hydrogen peroxide added thereto and stirred for 2 d at 40° C. After concentration and trituration with ethyl acetate, the crystals awe filtered off with suction. There remain 0.9 g of the title compound of the melting point 170°-171° C., i.e. 53% of theory.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH:11]1(OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:11]1([O:10][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CS(=O)(=O)OC1CCCC1
Reactant: O=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(F)ccc1OC1CCCC1

Procedure:
In a manner similar to the method described in Example 4a, 5-fluoro salicylaldehyde (Aldrich) reacted with methanesulfonic acid cyclopentyl ester prepared in Example 133a and potassium carbonate in dimethylformamide to give a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[C:12]([N+:16]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[CH:5]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:16])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccnc(-c2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccnc(-c2cccc(N)c2)c1
Yield: 100.3 %

Procedure:
A suspension of 3-(4-ethoxypyridin-2-yl)nitrobenzene (0.3 g) in ethanol (6 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 0.2 g) under a hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(4-ethoxypyridin-2-yl)aniline (0.264 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:5]=1
Reactant: Clc1ncccn1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ncccn2)cn1
Yield: 68 %

Procedure:
As described for Example 12, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (92 mg, 68%) which was obtained as an off-white solid. MS: m/e=304.0 [M+H]+.