Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C>CO>[CH:23](=[C:19]1[C:20](=[O:21])[C:4]2([CH3:3])[CH:17]([CH:16]3[CH:7]([CH2:6][CH2:5]2)[C:8]2[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=2[CH2:14][CH2:15]3)[CH2:18]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccccc1)C2=O
Reaction time: 4 h

Procedure:
Potassium hydroxide (1.0 g) was added to a solution of estrone (1.350 g, 5.0 mmol) and benzaldehyde (1.0 g, 9.4 mmol) in methanol (50 ml) at room temperature. The resulting orange solution was stirred at this temperature for 4 h. Then glacial acetic acid (ca. 5 ml) was added with stirring. The colour changed to light yellow and a white solid precipitated. The solid was filtered off and washed with water (50 ml), methanol (20 ml), diethyl ether (50 ml) and hexane and dried under high vacuum. Yield 1.578 g (88%). H-NMR (CDCl3, 400 MHz), δ: 1.00 (s, 3H), 1.40-1.77 (m, 5H), 2.04-2.12 (m, 2H), 2.26-2.34 (m, 1H), 2.38-2.45 (m, 1H), 2.50-2.60 (m, 1H) 2.86-3.03 (m, 3H), 4.76 (s, 1H, —OH), 6.60 (d, J=2.3 Hz, 1H), 6.66 (dd, J=8.2, 2.3 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 7.34-7.45 (m, 3H), 7.48 (s, 1H), 7.54-7.59 (m, 2H). LRMS (FAB+): 359.2 (100, [M+H]+). LRMS (FAB−): 357.2 (100, [M−H]−). HRMS (FAB+) 359.202332 C25H27O2 requires 359.201105
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@H:29]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:30][S:31]([C:34]([CH3:45])([CH3:44])[CH2:35][NH:36]C(=O)OC(C)(C)C)(=[O:33])=[O:32])=[O:28])[CH2:20][C:21]2[N:22]=[CH:23][NH:24][CH:25]=2)=[O:18])[C@@H:9]([OH:15])[C@H:10]([CH:12]2[CH2:14][CH2:13]2)[OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:53]>O1CCOCC1>[ClH:53].[ClH:53].[NH2:36][CH2:35][C:34]([S:31]([CH2:30][CH:29]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:27]([NH:26][C@@H:19]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:17]([NH:16][C@@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C@@H:9]([OH:15])[C@H:10]([CH:12]1[CH2:13][CH2:14]1)[OH:11])=[O:18])=[O:28])(=[O:33])=[O:32])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(CN)S(=O)(=O)CC(Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 1 h

Procedure:
A solution of 32 mg (0.043 mmol) of tert-butyl [2-[[(S)-2-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulphonyl]-2-methylpropyl]carbamate in 2 ml of dioxan is treated with 2 ml (4 mmol) of 2N hydrochloric acid in dioxan while cooling with ice and stirred for 1 hour. Subsequently, the solution is lyophilized and there are obtained 30 mg of (S)-α-[(S)-α-[[[(2-amino-1,1-dimethylethyl)sulphonyl]methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide dihydrochloride as a colourless powder; MS: 646 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:10])=[N:4][CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ncc(Br)cn1
Product: Cc1cnc(N2CCN(C(=O)c3ncc(Br)cn3)CC2)c(C)c1
Yield: 71.9 %

Procedure:
Using 5-bromopyrimidine-2-carboxylic acid (0.81 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (0.77 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.08 g) was obtained.
Reaction SMILES: C(N(CC)C([C:6]1C=CC=C[C:7]=1[S:12]([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.C(S)C>>[Si:37]([O:36][C@@H:34]([C@H:33]1[C:32](=[O:44])[N:17]2[C:18]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[C:14]([S:12][CH2:7][CH3:6])[C@H:15]([CH3:45])[C@H:16]12)[CH3:35])([C:40]([CH3:42])([CH3:43])[CH3:41])([CH3:39])[CH3:38]
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Solvent: CCS
Product: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 18, but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and ethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a crystal in a yield of 83%. Recrystallization of this product from diisopropyl ether afforded the title compound in the form of crystals melting at 121°-121.5° C.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][CH:21]([C:23](N(OC)C)=[O:24])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Mg]I.N#N>CCOCC>[Si:1]([O:18][CH:19]1[CH2:20][CH:21]([C:23](=[O:24])[CH3:29])[CH2:22]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]I
Reactant: CON(C)C(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: N#N
Solvent: CCOCC
Product: CC(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1

Procedure:
A solution of 3-[tert-butyl(diphenyl)silyl]oxy-N-methoxy-N-methylcyclobutanecarboxamide (0.7 g, 0.002 mol) in ether (10 mL) was added into 3.0 M of methylmagnesium iodide in ether (3 mL) slowly under N2. The reaction was stirred and heated to reflux for 2 h. The mixture was quenched with ice and the ether layer separated. The aq. layer was acidified with 1N HCl and extracted several times with ether. The organic layers were combined, dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-30% EtOAc/Hex) to give the desired product (0.6 g) as colorless oil. LCMS calculated for C22H29O2Si(M+H)+: 353.2; Found: 353.3.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O.C([O-])(=O)C.[Cu+2:26].C([O-])(=O)C>C(O)C>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cu+2:26].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Reaction time: 3 h

Procedure:
14.2 g of stearic acid was added to 200 ml of an ethanol solution and sufficiently stirred at 60° C. until the stearic acid was completely dissolved. 5.0 g of copper acetate-monohydrate was dissolved in 200 ml of ethanol solution. Then, the two solutions were mixed and stirred for 3 hours. White powder on the surface of the result was collected and washed three times each with distilled water and with methanol to obtain copper stearate. An anode active material was prepared as in Example 1, except that copper stearate was used, the molar ratio of copper to silicon was 0.2:1, the weight ratio of silicon to graphite was 0.5:1, and the carbon layer was 6.3 wt % of the anode active material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:17]([CH3:19])[CH3:18]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([O:8][CH:17]([CH3:19])[CH3:18])[CH:7]=1
Reactant: Oc1cc(Br)ccc1Cl
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-chlorophenol (2.08 g, 10 mmol, 1.0 eq.) and potassium carbonate (4.15 g, 30 mmol, 3.0 eq.) in MeCN (19 mL), 2-iodopropane (1.53 mL, 15 mmol, 1.5 eq.) was added. The mixture was stirred at r.t. for 18 hours. The mixture was heated up to 50° C. and stirred at that temperature for 2.5 hours. The reaction mixture was partitioned between AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The comb. org. extracts were washed with water and sat. aq. NaCl soln., dried over MgSO4, filtered, and concentrated in vacuo to give 4-bromo-1-chloro-2-isopropoxy-benzene as a yellow oil. The product was used without further purification. LC-MS 3: tR=0.98 min; [M+H]+=no ionization
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].BrC[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][O:7][CH2:6][C:5]#[C:4][CH2:3][OH:8]
Reactant: OCC#CCO
Reactant: COC(=O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCC#CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.32 g, 58 mmol) was added to a solution of 2-butyne-1,4-diol (5.0 g, 58 mmol) in THF (60 mL) at 0° C. under nitrogen. After 1 h at 0° C., methyl bromomethylacetate (5.5 mL, 58 mmol) was added and the reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with 1 N HCl (60 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (1×100 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→5% MeOH/CH2Cl2, gradient) afforded 3.2 g (35%) of (4-hydroxy-but-2-ynyloxy)-acetic acid methyl ester.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH2:26][SH:27])[CH:23]=[CH:24][CH:25]=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:27][CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1cccc(CS)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and (3-trifluoromethyl-phenyl)-methanethiol.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[S:19][CH2:18][C:17]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Reactant: COC(=O)CS
Product: COC(=O)CSC(c1ccc(C)cc1)c1ccc(C)cc1
Yield: 73 %

Procedure:
Following the procedure of Example 4, 4,4'-dimethylbenzhydrol, synthesized in accordance with M. R. Pavia, et. al. in J. Med. Chem. 35, 4238 (1992), is reacted with methyl thioglycolate for 18 hours at room temperature. Chromatography on silica gel, eluting with 10% ethyl acetate in hexane, gives methyl [[bis-(4-methylphenyl)methyl]thio]acetate as a colorless oil in 73% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](N)[CH:7]=[CH:6][C:5]=1[Br:11].S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:14])[CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: COC(=O)c1cc(N)ccc1Br
Reactant: O=S(=O)(O)O
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: COC(=O)c1cc(O)ccc1Br
Temperature: 2.5 °C

Procedure:
Compound of example 151 (12 g, 52.1 mmol) was added to 10% aqueous sulfuric acid (110 mL) at 0° C. An aqueous solution (40 mL) of NaNO2 (4.3 g, 62.32 mmol) was added dropwise, with stirring at 0-5° C. The reaction mixture was stirred for 10 min. and was added to an ice cold aqueous solution of copper sulfate (156 g, 1 L, 625 mmol) containing Cu2O (6.8 g, 47.55 mmol). The resultant mixture was stirred at 0° C. for 10 min. It was diluted with water and extracted using EtOAc (3×500 mL). The organic extract was washed with water, dried (anhydrous Na2SO4), concentrated and purified using a silica gel column and 2% EtOAc in petroleum ether (60-80° C.) as eluant to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:10]1([CH3:15])[O:14][CH2:13][CH2:12][O:11]1)[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5].[F:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2[C:20]([O:22][C:23](=O)[C:18]=12)=[O:21]>C(Cl)(Cl)Cl>[F:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2[C:18]=1[C:23](=[O:22])[N:1]([CH2:2][CH:3]([C:10]1([CH3:15])[O:11][CH2:12][CH2:13][O:14]1)[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[C:20]2=[O:21]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: C=CCOC(=O)C(CN)C1(C)OCCO1
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C1(C)OCCO1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
Allyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (400 mg, 1.86 mmol) was dissolved in 10 mL of chloroform, and 3-fluorophthalic anhydride (401 mg, 2.42 mol) was added to the obtained solution. The resulting mixture was then refluxed at 80° C. for 3 days after adding. After the reaction was completed, the solvent was evaporated by distilling under a reduced pressure. The residue was purified by performing column chromatography (eluent: n-hexane/ethyl acetate=3/1) to obtain the desired product as a white solid (351 mg, 52%). Rf=0.29 (eluent: n-hexane/ethyl acetate=2/1)
Reaction SMILES: CO.[OH-].[K+].C([O:8][C@@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:11]([CH2:12][C@@H:13]([O:36]C(=O)C)[C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH2:10]1)(=O)C>C(O)(C)C>[CH3:26][C@@H:19]([C@@H:18]1[C@@:27]2([CH3:35])[CH2:28][CH2:29][C@@H:30]3[C@@:31]4([CH3:34])[CH2:32][CH2:33][C@@H:9]([OH:8])[CH2:10][C@H:11]4[CH2:12][C@@H:13]([OH:36])[C@H:14]3[C@@H:15]2[CH2:16][CH2:17]1)[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(C)=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a solution of 3 ml of methanol, 5 ml of isopropanol and 0.8 g of potassium hydroxide was added 0.294 g (0.000599 mol) of methyl 3α,7α-diacetyloxy-5β-cholan-24-oate. The mixture was heated to reflux under an argon atmosphere for 4 hr. then stirred overnight at room temperature. The solvents were removed in vacuo. The mixture was acidified with 1 N HCl and extracted with 3×25 ml of ethyl acetate. The combined ethyl acetate extracts were washed with water then dried over anhydrous sodium sulfate. The mixture was filtered and solvents removed in vacuo. The residue were recrystallized from ethyl acetate to give 0.163 g (69.3%) of chenodeoxycholic acid, mp 117°-118° C., which did not depress when mixed with authentic material (mp 117°-118° C. from ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([F:14])[C:10]=2[O:12][CH3:13])[C:5](=[O:16])[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3]1.[N+:22]([O-])([O-:24])=[O:23].[K+]>OS(O)(=O)=O>[CH3:1][N:2]1[C:11]2[C:6](=[C:7]([N+:22]([O-:24])=[O:23])[C:8]([F:15])=[C:9]([F:14])[C:10]=2[O:12][CH3:13])[C:5](=[O:16])[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3]1
Reactant: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of ethyl 1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (800 mg, 2.69 mmol) in concentrated H2SO4 (7 mL) was treated portionwise at 0° C. with solid KNO3 (380 mg, 3.76 mmol). After stirring at 0° C. for 1 h, the reaction mixture was poured into ice-water and the resulting precipitate was removed by filtration. The resulting solid washed with EtOH, dried to yield ethyl 1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (765 mg, 83%) as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C:5]([CH3:13])([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:6].[CH:15](O)=O.C=O>[OH-].[Na+]>[CH3:2][O:3][C:4](=[O:14])[C:5]([CH3:6])([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH3:15])[CH2:8]1)[CH3:13]
Reactant: O=CO
Reactant: COC(=O)C(C)(C)C1CCCNC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)C(C)(C)C1CCCN(C)C1
Temperature: 60 °C

Procedure:
0.370 g of 2-methyl-2-piperidin-3(R,S)-yl-propionic acid methyl ester hydrochloride (Example 102) are dissolved in 0.5 ml of 3M NaOH. 2 ml of formic acid and 0.19 ml of formaldehyde (35% aqueous solution) are added and the reaction solution is warmed to 60° C. for 20 hours. The solution is cooled to room temperature, neutralised with 3M NaOH to pH 8-9 and extracted with dichloromethane (3×10 ml). The combined organic phases are washed with water (10 ml), dried over sodium sulphate and concentrated by evaporation. The residue is purified by means of flash chromatography (SiO2 60F) to provide the title compound as a colourless oil. Rf 0.19 (200:20:1 dichlormethane-methanol-25% conc. ammonia).
Reaction SMILES: [BH4-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:15]3[C:16](=[O:20])[CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=[C:12]2[CH:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][CH:9]=1>ClCCl.CO>[I:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:15]3[CH:16]([OH:20])[CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=[C:12]2[CH:21]([CH3:23])[CH3:22])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)c1nc2c(n1Cc1cccc(I)c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1cccc(I)c1)C(O)CCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.8 %

Procedure:
NaBH4 (1.670 g) was added to a stirred solution of Intermediate 90 (5.8 g) in Dichloromethane (DCM) (30 mL) and Methanol (30 mL). The reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated in vacuo before being partitioned between EtOAc (60 ml) and water (60 ml). The two phases were separated and the aqueous phase was extracted with further EtOAc (2×60 ml). The organic phases were combined, filtered through a hydrophobic frit and concentrated in vacuo to give the desired product (5.7 g) as an off white solid. LC/MS MH+ 397, Rt 2.54 min (5 min run).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:30][CH3:31])[CH:12]=2)[C:8]2[CH:32]=[CH:33][C:34]([NH:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])=[CH:35][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:13]([O:30][CH3:31])[CH:12]=2)[C:8]2[CH:32]=[CH:33][C:34]([NH:36][C:37]([N:39]([CH3:40])[CH3:41])=[O:38])=[CH:35][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(NC(=O)N(C)C)ccc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2cc(NC(=O)N(C)C)ccc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)c(OC)c1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]-3-methoxybenzyl]-5-dimethylaminocarbonylamino-benzimidazole and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([CH3:28])([CH3:27])[C:22](OCC)=[O:23])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([CH3:28])([CH3:27])[CH2:22][OH:23])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)(C)CC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
Into a solution of 2.7 g of lithium aluminum hydride in tetrahydrofuran (200 ml) was slowly dropped at 0° C. a solution of 21.5 g of ethyl 3-(1-benzylpiperidin-4-yl)-2,2-dimethylpropanoate in tetrahydrofuran (20 ml) and the resulting mixture was stirred at room temperature for 30 minutes. After adding water and a 10% aqueous solution of sodium hydroxide to the reaction mixture, the insoluble matters were filtered off. After distilling off the solvent under reduced pressure, 19 g of crude 3-(1-benzylpiperidin-4-yl)-2,2-dimethylpropanol was obtained as a yellow oily substance. This oily substance was dissolved in 300 ml of ethanol. After adding 20 ml of acetic acid, the mixture was subjected to hydrogenation at ordinary temperature under atmospheric pressure for 12 hours. After filtering off palladium-carbon, the solvent was concentrated under reduced pressure to thereby give 23 g of crude 3-(piperidin-4-yl)-2,2-dimethylpropanol as a yellow oily substance. This crude product was further dissolved in 200 ml of dichloromethane and 23 ml of pyridine was added thereto. Then 15.5 g of di-tert-butyl dicarbonate was dropped thereinto at 0° C. and the resulting mixture was reacted at room temperature for 2 hours. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 14.9 g of the title compound as colorless crystals.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11](O[C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.[NH3:16]>>[CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([NH:16][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1
Reactant: N
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Product: O=C1NC(=O)c2cccc3cccc1c23

Procedure:
U.S. Pat. No. 3,812,130 describes reacting solid 1,8-naphthalic anhydride with gaseous ammonia to produce 1,8 naphthalimide. The product is isolated directly by evaporating off the water. Although this procedure minimizes waste water, it still requires a pressure vessel and has the disadvantage of not allowing for any water soluble impurities or unreacted starting material to be removed after the reaction. Thus, a potentially impure product is produced.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.N[C:48]1[CH:53]=CC=[CH:50][CH:49]=1>>[NH:22]([C:20]([C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[CH:8]([CH2:7][C:6]2[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]1)=[O:17])[CH2:31][CH3:32])=[O:21])[C:23]1[CH:50]=[CH:49][CH:48]=[CH:53][CH:24]=1
Reactant: Nc1ccccc1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccccc1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, aniline was used for the similar procedure as in Example 220 to obtain the title compound.