Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](Br)=[CH:9][C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[O:27][B:28](OC)[O:29]C.Cl>CCCCCC.C(OCC)C>[Br:6][C:7]1[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][C:10]([B:28]([OH:29])[OH:27])=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1
Reactant: Brc1cc(-c2ccccc2)c(Br)cc1-c1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cc(-c2ccccc2)c(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromo-2,5-diphenylbenzeneboronic acid is prepared as follows: A solution of n-butyllithium (1.6 M, 15 ml) in hexane is added slowly to a cooled (-40° C.) solution of 1,4-di-bromo-2,5-diphenylbenzene (25 mmol) in diethylether (100 ml). This mixture is allowed to warm to room temperature and is stirred for 2 hours. This solution is transferred into a dropping funnel and added to a cooled (-60° C.) solution of trimethylborate (74 mmol) in ether (200 ml). It is then stirred for 8 hours at room temperature. After hydrolysis with aqueous HCl (2M, 150 ml), the layers are separated and the aqueous layer is extracted with ether (100 ml). The solvent is then removed from the combined organic layers and water (5 ml) and petroleum ether (100) are added. The precipitate is recovered by filtration, and recrystallized from toluene.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])=[O:15])=[CH:12][C:11]([C:26]([F:29])([F:28])[F:27])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:30][N:31]([CH2:39][CH:40]=O)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:14]([C:13]1[N:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][CH2:40][CH2:39][N:31]([CH3:30])[C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[N:10]=[C:11]([C:26]([F:28])([F:29])[F:27])[CH:12]=1)=[O:15]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CN)c1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNCCN(C)C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
To a stirred solution of 58 (200 mg, 0.386 mmol) in MeOH (2.0 mL) was added tert-butyl methyl(2-oxoethyl)carbamate (100 mg, 0.579 mmol) followed by acetic acid (44.2 μl, 0.772 mmol). After stirring for 30 min, sodium cyanoborohydride (61 mg, 0.964 mmol) was added and the resulting solution was allowed to stir at 21° C. for 16 h. The solvent was removed by evaporation and the residue taken in saturated NaHCO3. It was then extracted three times with CH2Cl2, dried over Na2SO4 and evaporated. The residue was purified via silica gel flash chromatography (40% to 100% EtOAc/hexanes). The title product 59 (81 mg, 37% yield) was isolated as a yellow solid. LRMS (ESI): calc. 561.6; found 562.7 (MH)+.
Reaction SMILES: [P:1]([F:5])([O-:4])([O-:3])=[O:2].[Na+:6].[Na+].[F-:8].[Na+]>>[F:8][F:5].[P:1]([F:5])([O-:4])([O-:3])=[O:2].[Na+:6].[Na+:6]
Reactant: [F-]
Agent: O=P([O-])([O-])F
Agent: [Na+]
Product: FF

Procedure:
Sodium monofluorophosphate is used in amount to provide about 700-1090 ppm fluorine to the dental cream in which the total amount of fluorine is about 1000-1670, with about 30-35% by weight to the total fluorine being provided by sodium fluoride (about 300-580 ppm). This corresponds to about 0.5-1.2% by weight of sodium monofluorophosphate and about 0.06-0.11% by weight of sodium fluoride. Preferably, the dental cream contains about 1000-1500 ppm, most preferably, about 950-1000 ppm fluorine provided by sodium monofluorophosphate and about 450-500 ppm provided by sodium fluoride.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[C:9]3[N:44]=[C:42]([NH:41][C:31]4[CH:32]=[CH:33][C:34]([N:35]5[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]5)=[C:29]([O:28][CH3:27])[CH:30]=4)[N:43]=[CH:3][C:4]=3[CH2:5][CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(c2ccc(Cl)cc2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2ccc(Cl)cc2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-(4-chloro-phenyl)-cyclohexanone (134 mg, 0.50 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (186 mg, 0.50 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (69 mg, 31%). MS ISP (m/e): 446.1 [(M+H)+]. mp 210-212° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.N1C=CC=CC=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+]([O-])=O)=[CH:29][CH:28]=1)=[O:25]>ClCCl>[C:27]1([O:26][C:24](=[O:25])[NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2)OC1(C)C
Reaction time: 13 h

Procedure:
4-(4,4,5,5-tetramethyl 1,3,2 dioxaborolan-2-yl) aniline (3 g, 0.013 mol) was dissolved in dichloromethane (350 mL) to which pyridine (1.02 g, 0.013 mol) and 4-nitrophenyl chloroformate was added. The reaction was stirred for 13 hr where TLC analysis showed consumption of all starting materials. The solution was washed with saturated NaHCO3 (3×50 mL), water (3×50 mL) and brine (3×50 mL). The organic layer was dried over Na2SO4 and solvent removed to yield a white crystalline solid [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid phenyl ester, 4.45 g, 91%. 1H NMR (CDCl3 300 MHz) δ 1.4 (s, 12H), 7.1 (brs, 1H), 7.3 (d, 2H), 7.5 (d, 2H), 7.8 (d, 2H), 8.3 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:18]#[N:19])=[CH:5][S:6][C:7]=1[C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12]C[C:10]=2[CH:9]=1.C1C2C(=CC(B(O)O)=CC=2)CC1>>[CH2:14]1[C:15]2[C:16](=[CH:17][C:8]([C:7]3[S:6][CH:5]=[C:4]([C:18]#[N:19])[C:3]=3[O:2][CH3:1])=[CH:9][CH:10]=2)[CH2:12][CH2:13]1
Reactant: COc1c(C#N)csc1-c1ccc2c(c1)CCCC2
Agent: OB(O)c1ccc2c(c1)CCC2
Product: COc1c(C#N)csc1-c1ccc2c(c1)CCC2
Yield: 85.6 %

Procedure:
Synthesis was carried out in the same manner as in Synthesis Method 2 (4) in Reference Synthetic Example 3 by using 4.08 g (0.0252 mol) of (2,3-dihydro-1H-inden-5-yl)boronic acid described in Reference Synthetic Example 5(1) to obtain 5.0 g of the desired product (yield: 85.6%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C:21]([OH:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>CO>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@H:10]([C:21]([OH:23])=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 48.8 g (146 mmol) (3R,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidine-3-carboxylic acid and 15.6 mL sulfuric acid in 400 mL methanol was heated to reflux for 21 h and evaporated. the residue was diluted with ice-water and extracted with ethyl acetate. the combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with ethyl acetate and heptane. The intermediate was dissolved in 500 mL methanol and 4.06 mL sodium methoxide (5.4N in methanol) was added and stirred at room temperature overnight. Another 31.3 mL sodium methoxide (5.4N in methanol) was added and stirred for 1 h at room temperature. Water was added and the mixture was stirred for 2 h at room temperature. After evaporation of methanol, water was added and the pH was adjusted to 6-7 with acetic acid. The product precipitated and the mixture was decanted. The organic layer from the extraction with THF and ethyl acetate was washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was washed with hexane and diethyl ether and filtered to yield after drying 44 g (49%) of the title compound as colorless solid. MS m/e: 334.3 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:28])[C:13]4[CH:14]=[N:15][N:16]([S:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[Cl:38][CH2:39][C:40]1[S:41][CH:42]=[C:43]([C:45](Cl)=[O:46])[N:44]=1.O>C(Cl)(Cl)Cl>[Cl:38][CH2:39][C:40]1[S:41][CH:42]=[C:43]([C:45]([NH:28][C:12]2[CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH:3]=[CH:2][NH:1]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][N:16]3[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[O:46])[N:44]=1
Reactant: O=C(Cl)c1csc(CCl)n1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To solution of 6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazol-4-amine (1.5 g) in chloroform (20 ml) at 0° C. was added DIPEA (1.35 ml). 2-(Chloromethyl)-1,3-thiazole-4-carbonyl chloride (1.8 g) in chloroform (20 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h 15 min. The mixture was allowed to warm to RT and stirring continued for 18 h. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (0.2 g) was added to the mixture which was stirred at RT for 30 min. Water (50 ml) was added and the mixture was extracted with DCM (2×100 ml), separating the layers using a hydrophobic frit. The organics were collected and solvent removed in vacuo to give a brown solid which was triturated with ether (10 ml). The solid was filtered and dried in a vacuum oven overnight to afford the title compound, 1.6 g.
Reaction SMILES: [BrH:1].[CH3:2][O:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][NH:6][C@H:5]1[CH2:10][C:11](=[O:13])[CH3:12].Br>C(O)(=O)C>[BrH:1].[Br:1][CH2:12][C:11](=[O:13])[CH2:10][C@H:5]1[C@H:4]([O:3][CH3:2])[CH2:9][CH2:8][CH2:7][NH:6]1
Reactant: CO[C@@H]1CCCN[C@H]1CC(C)=O
Agent: Br
Solvent: CC(=O)O
Product: CO[C@@H]1CCCN[C@H]1CC(=O)CBr

Procedure:
Using the procedure of U.S. Pat. No. 2,775,597, the product of Step A4 was reacted with a solution of 15% hydrogen bromide in acetic acid for 2 hours at room temperature and the mixture was evaporated to dryness under reduced pressure to obtain dextrorotary trans 3-bromo-1-(3-methoxy-2-piperidyl)-2-propanone hydrobromide melting at 143° C. and having a specific rotation [α]D20 =+25° (c=1% in methanol).
Reaction SMILES: [ClH:1].[CH2:2]([NH:8][C:9]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)=[CH:14][CH:15]=1)=[NH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>[Pd].C(O)C>[ClH:1].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[O:12][C:11]([C:9](=[NH:10])[NH:8][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:15][CH:14]=1
Reactant: CCCCCCNC(=N)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCCCNC(=N)c1ccc(-c2ccccc2N)o1
Reaction time: 4 h

Procedure:
A mixture of the compound of Example III (17 g, 0.048 mole), ethanol (250 ml), and 5% Pd/C-50% H2O (1.0 g) was subjected to hydrogenation at room temperature for 4 hours, using 6.0 psia H2 (theory: 5.9 psia H2). The catalyst was removed by filtration, the filtrate was diluted with anhydrous ether (1000 ml), and cooled. The product was collected by filtration and air dried; m.p. 148°-150°, yield: 15 g (97%).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.[N:51]1([CH2:57][CH2:58]O)[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:58][CH2:57][N:51]5[CH2:56][CH2:55][O:54][CH2:53][CH2:52]5)=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Reactant: OCCN1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)OCCN4CCOCC4)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 3c from 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 17 μL (0.14 mmol) 2-morpholin-4-yl-ethanol. After purification by HPLC the product obtained was dissolved in 10 mL DCM and stirred with 5 mL of 5% NaHCO3 solution. The organic phase was separated off and dried on Na2SO4. After the elimination of the desiccant and solvent the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][C@H:12]2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=O)=[CH:6][CH:5]=1.[ClH:31]>C(#N)C.O=P(Cl)(Cl)Cl>[ClH:31].[CH3:25][O:24][C:21]1[C:20]([O:26][CH3:27])=[CH:19][C:18]2[C@H:12]3[C@H:11]([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]3)[N:10]=[C:8]([C:7]3[CH:28]=[CH:29][C:4]([C:3]([O:2][CH3:1])=[O:30])=[CH:5][CH:6]=3)[C:23]=2[CH:22]=1
Reactant: COC(=O)c1ccc(C(=O)N[C@H]2CCN(C)C[C@H]2c2ccc(OC)c(OC)c2)cc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C2=N[C@H]3CCN(C)C[C@H]3c3cc(OC)c(OC)cc32)cc1

Procedure:
2.31 g of (-)-cis-terephthalic acid N-[3-(3,4-dimethoxyphenyl)-1-methylpiperidin-4-yl]amide mono-methyl ester are heated to boiling under reflux for 4 h in 25 ml of acetonitrile and 3 ml of phosphorus oxytrichloride. After distilling off the excess phosphorus oxytrichloride, the residue is partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. The solid residue is purified by silica gel chromatography, the main product fraction is separated and this is concentrated. The solid residue is dissolved in a little methanol, and the solution is treated with one equivalent of aqueous HCl and concentrated. The solid residue is recrystallized in methanol/diethyl ether. 1.76 g (70% of theory) of the title compound are obtained as a 1.25-hydrochloride 0.5-hydrate having the m.p. 188-192° C. (unsharp, slow deliquescence).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:37])[CH2:16][NH:17][C:18]([CH3:36])([CH3:35])[CH2:19][CH2:20][N:21]2[C:25]([CH3:26])=[N:24][C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[N:22]2)=[CH:11][C:10]=1[CH2:38][OH:39])C1C=CC=CC=1>CO.[Pd]>[OH:37][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:38][OH:39])[CH:11]=1)[CH2:16][NH:17][C:18]([CH3:36])([CH3:35])[CH2:19][CH2:20][N:21]1[C:25]([CH3:26])=[N:24][C:23]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[N:22]1
Reactant: COc1ccc(-c2nc(C)n(CCC(C)(C)NCC(O)c3ccc(OCc4ccccc4)c(CO)c3)n2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-c2nc(C)n(CCC(C)(C)NCC(O)c3ccc(O)c(CO)c3)n2)cc1

Procedure:
5 g of 1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-{3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethanol dissolved in 100 mL methanol are hydrogenated under normal pressure with 1 g of palladium on charcoal (5%) as catalyst. Then the catalyst is separated off and the filtrate is evaporated down. The residue is dissolved in 15 mL acetonitrile, acidified with 0.5 mL glacial acetic acid and seeded. The solid precipitated is filtered off and washed with acetonitrile and diethyl ether. Yield: 3.8 g (78%, acetate); m.p.=110-116° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)[CH:6]=1.[C:19]([C:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20].CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[C:19]([C:22]1[CH:26]=[C:25]([C:27]([NH:2][CH2:3][CH2:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)[CH:6]=2)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]
Reactant: N#Cc1ccc(-c2cc(CCN)on2)cc1Cl
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)c1cc(C(=O)NCCc2cc(-c3ccc(C#N)c(Cl)c3)no2)[nH]n1
Yield: 12 %

Procedure:
The title compound was prepared from 4-(5-(2-aminoethyl)isoxazol-3-yl)-2-chlorobenzonitrile hydrochloride (0.080 g, 0.282 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.043 g, 0.282 mmol), DIPEA (0.196 ml, 1.126 mmol 1), HOBt hydrate (0.065 g, 0.422 mmol) and EDCI (0.081 g, 0.422 mmol) using the method of Example 274 affording 0.013 g of the title compound after preparative HPLC purification. 1H-NMR (400 MHz; d6-DMSO): δ 2.53 (s, 3H), 3.20 (t, 2H), 3.83 (m, 2H), 6.54 (s, 1H), 7.33 (bs, 1H), 7.63 (bs, 1H), 7.79 (m, 1H), 7.97 (bs, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([CH3:25])[CH3:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([CH3:24])[CH3:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:34])=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCON=C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1CCCON=C(C)C
Yield: 65.6 %

Procedure:
The general method described in Part C of Example 5 was used to oxidize acetone O-{3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}oxime (1.06 g, 3.12 mmol) with mCPBA (838 mg, 3.74 mmol) to provide 729 mg of acetone O-{3-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]propyl}oxime as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:27])[NH:25][OH:26])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.C(C(CCCC)[CH2:42][O:43]C(Cl)=O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[NH:27][C:42](=[O:43])[O:26][N:25]=3)=[CH:22][CH:23]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C(=N)NO)cc2)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(-c3noc(=O)[nH]3)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-N-[4-(N-hydroxycarbamimidoyl)-phenyl]-benzamide (145 mg, 0.30 mmol) in dimethylformamide (2.0 ml) was treated with pyridine (26 mg, 1.08 equiv.) and cooled to 0° C. Chloroformic acid 2-ethylhexyl ester (59 mg, 0.30 mmol, 1 equiv.) in DMF (0.1 ml) was added dropwise. The mixture was stirred at 0° C. for 30 min, then diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. The residue was suspended in xylene and the mixture was stirred at 100° C. for 1 h and then at 145° C. for 1 h. After cooling to room temperature, the precipitated solid was filtered, washing with xylene, and dried under high vacuum to yield the title compound (115 mg, 75%) as a white solid, MS (ISP): m/e=499.0 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1Cl.[CH2:10]([CH:15]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16]1)[CH2:11][CH:12]([CH3:14])[CH3:13]>>[Cl:1][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH:20][CH:17]1[CH2:18][CH2:19][CH:15]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:16]1
Reactant: CC(C)CCC1CCC(N)C1
Reactant: Cc1nccc(Cl)c1Cl
Product: Cc1nccc(NC2CCC(CCC(C)C)C2)c1Cl
Yield: 61 %

Procedure:
Preparation was carried out as in Example 59 from 3,4-dichloro-2-methylpyridine and 3-isoamylcyclopentylamine. Yield: 61%
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([O:21][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2ccccc2C=O)C1
Temperature: 120 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
A mixture of 2-fluoro-benzaldehyde (0.85 mL; 8.06 mmol; 1 eq.), 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.54 g mg; 8.86 mmol; 1.1 eq.) and K2CO3 (2.23 g; 16.11 mmol; 2 eq.) in DMF (20 mL) was stirred at 120° C. for 16 hours. 3-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester (279 mg; 1.61 mmol; 0.2 eq.) was added and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with DCM, washed with water then brine, dried over magnesium sulfate and concentrated in vacuo. Recrystallization from Et2O afforded the title compound (1.03 g, 46%) as a yellow solid. HPLC (max plot) 99.4%; Rt 4.07 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>CCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1
Reactant: OCCCCCCCCCCCCBr
Reactant: C1=COCCC1
Solvent: CCCCCC
Product: BrCCCCCCCCCCCCOC1CCCCO1
Reaction time: 15 h
Yield: 118.9 %

Procedure:
12-Bromo-dodecan-1-ol (5.12 g, 19.3 mmol) was added to a vigorously stirred solution of dihydropyran (2.1 mL, 23.2 mmol) and Amberlyst HI5 (0.25 g, Aldrich D10,620-8) in hexane (100 mL). After 3 hours dihydropyran (2.1 mL) was added and the solution stirred for a further 15 hours. The mixture was then filtered, and the filtrate concentrated in vacuo and chromatographed graphed on silica gel, eluting with 2% ethyl acetate in hexane to give the title compound, (a), 8.02 g (75%), as an oil.
Reaction SMILES: [C:1]([C@H:4]1[N:8](C(OC(C)(C)C)=O)[C:7]([CH3:17])([CH3:16])[CH2:6][CH2:5]1)(=[O:3])[NH2:2].[ClH:18]>O1CCOCC1>[ClH:18].[CH3:16][C:7]1([CH3:17])[NH:8][C@H:4]([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1[C@H](C(N)=O)CCC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CC[C@@H](C(N)=O)N1

Procedure:
In analogy to the procedure described in Example 82 a), (S)-tert-butyl 5-carbamoyl-2,2-dimethylpyrrolidine-1-carboxylate (CAN 1292838-05-1) was treated with a 4 M solution of HCl in dioxane to give the title compound as colorless solid which was sufficiently pure to be used in the next step; MS (EI): m/e=143.2 [(M-Cl)H+].