Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:16])[CH2:14][CH3:15].[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[C:25](=[O:32])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1.P([O-])([O-])([O-])=O>C1COCC1.CCCCCC>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[C:25]([OH:32])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[CH:14]([CH3:15])[C:13]#[N:16]
Reactant: CCC#N
Reactant: O=C(Cn1cncn1)c1cc(F)ccc1F
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C#N)C(O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (11 g) in dry THF (100 ml) 1.6 M solution of butyllithium in hexane (63 ml) was slowly added at −78° C. under nitrogen atmosphere. The mixture was allowed to warm up to −30° C., then re-cooled to −78° C. before propionitrile (5.4 g) was slowly added (exothermic reaction, cooling). The mixture was stirred at this temperature for ca. 15 min, 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (10 g) was added, the reaction mixture warmed up to −20° C. within ca. 1 hr and finally poured on aqueous solution of phosphate buffer (pH 7). The aqueous phase was extracted 3 times with ethylacetate (300 ml) and the combined organic phase was twice with water, dried with sodium carbonate, filtered and evaporated under reduced pressure providing the title compound: 9 g. The analytical data were identical with published in U.S. Pat. No. 6,300,353 and WO99/45008 for (2S,3R)-enantiomer.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](Cl)=[O:6].FF.Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C>ClCCl.O>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: O=C(Cl)C1CC1(F)F
Reactant: CNOC
Agent: Cl
Agent: FF
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.00 g (49.8 mmol) of 2,2-difluorocyclopropanecarbonyl chloride (described in the Journal of Fluorine Chemistry 1990, 49, 127-139) in 100 ml of dichloromethane were mixed with 6.32 g (64.8 mmol) of N,O-dimethylhydroxylamine hydrochloride and 18.1 ml (130 mmol) of triethylamine and stirred at RT overnight. Water was added to the reaction mixture, the phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. 5.73 g (70% of theory) of the title compound were obtained and were reacted without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]#N)=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH2:35].[OH-:36].[Li+].Cl>O>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]([OH:36])=[O:35])=[C:8]([C:10]([OH:14])([CH3:13])[CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCCc1nc(C(C)(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Product: CCCCc1nc(C(C)(O)CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of 360 mg of 2-butyl-5-cyano-4-(1-hydroxy-1-methylpropyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole [prepared as described in step (b) above], 266 mg of lithium hydroxide monohydrate and 3.6 ml of water was stirred in an oil bath kept at 115° C. for 16 hours. At the end of this time, the reaction mixture was cooled and 6.4 ml of 1N aqueous hydrochloric acid were added to the mixture, whilst ice-cooling. The crystals which precipitated were collected by filtration, to give 302 mg of the title compound, melting at 152°-154° C.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5](C#N)=[CH:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.C(OCC)(=O)[CH2:15][C:16]([O:18]CC)=[O:17]>>[CH2:7]([CH:6]([CH2:5][C:4]([OH:3])=[O:13])[CH2:15][C:16]([OH:18])=[O:17])[CH:8]([CH3:9])[CH3:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)C(C#N)=CCC(C)C
Product: CC(C)CC(CC(=O)O)CC(=O)O

Procedure:
Reacting the 2-cyano-5-methylhex-2-enoic acid ethyl ester with diethyl malonate to form 3-isobutylglutaric acid;
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:32]1([C:22]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:30]3[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:14])[F:13])[CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3C(F)(F)F)CC12
Reaction time: 0.75 h
Yield: 50.6 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(2-(trifluoromethyl)phenyl)acetic acid (1.42 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 1 hour 45 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred at 20° C. for 18 hours, then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (10 cc). The crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-(trifluoromethyl)phenyl)acetyl]-4-perhydroisoindolone (1.68 g) melting at 207° C. is obtained.
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[O:12]=[CH:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])[OH:15].[CH:24]([Cl:27])([Cl:26])[Cl:25]>>[CH2:22]([OH:23])[C@@H:20]([OH:21])[C@H:18]1[O:19][C@@H:13]2[O:12][C@@H:1]([C:24]([Cl:27])([Cl:26])[Cl:25])[O:15][C@@H:14]2[C@H:16]1[OH:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: ClC(Cl)Cl
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@H]1O[C@@H]2O[C@@H](C(Cl)(Cl)Cl)O[C@@H]2[C@H]1O
Reaction time: 0.33 h

Procedure:
Under stirring 0.05 g of 4-methyl-benzene sulphonic acid and 20 ml of chloroform are added to a mixture of 4.5 g of glucose and 19 g of choral. The mixture is heated to reflux temperature and the formed water is separated by means of a Dean-Stark apparatus. The solvent is distilled off, then the mixture is kept at a temperature of 60° C. for 20 minutes. The separated material is filtered off.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27](O)=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:74][CH2:75][CH2:76][CH2:77][N:78]1[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:74][CH2:75][CH2:76][CH2:77][N:78]4[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]4)=[O:28])[S:26][C:19]=23)=[CH:30][CH:31]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Reactant: NCCCN1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN5CCCCC5)sc34)cc2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred, cooled (0° C.) solution of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.27 mmol) in anhydrous DMF (10 ml) were added PyBOP (156 mg, 0.30 mmol) and N,N-diisopropylethylamine (70 mg, 0.54 mmol). The mixture was stirred at 0° C. for 5 minutes, followed by addition of N-(3-aminopropyl)piperidine (58 mg, 0.41 mmol). Stirring was continued at 0° C. for another 30 minutes. The mixture was poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried to give 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-piperidin-1-ylpropyl)thieno[3,2-b]pyridine-2-carboxamide as beige solid. Yield: 151 mg, 98%. 1H NMR (600 MHz, DMSO-d6) δ ppm 9.21 (s, 1H) 8.94 (t, J=5.58 Hz, 1H) 8.56 (d, J=5.28 Hz, 1H) 8.50 (d, J=2.64 Hz, 1H) 8.22 (s, 1H) 7.98 (dd, J=7.63, 2.05 Hz, 1H) 7.57-7.60 (m, 2H) 7.23-7.27 (m, 2H) 7.11 (dd, J=11.30, 8.36 Hz, 1H) 6.80-6.83 (m, 1H) 6.71 (d, J=5.28 Hz, 1H) 3.30-3.35 (m, 2H) 2.31 (br. s., 6H) 2.28 (s, 3H) 1.69-1.75 (m, 2H) 1.47-1.52 (m, 4H) 1.38 (br. s., 2H)
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([S:13][CH3:14])[C:10]2[C:5](=[CH:6][C:7]([C:15]#[N:16])=[CH:8][CH:9]=2)[N:4]=1.S(=O)(=O)(O)[OH:26].C(=O)(O)[O-].[Na+]>O>[F:24][C:2]([F:1])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([S:13][CH3:14])[C:10]2[C:5](=[CH:6][C:7]([C:15]([NH2:16])=[O:26])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C#N)ccc12
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C(N)=O)ccc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-7-carbonitrile from Example 8 step A (174 mg, 0.5 mmol) were added concentrated sulfuric acid (2.88 mL) and water (0.32 mL). The mixture was stirred at 65° C. for 1 h and then allowed to cool to rt. The mixture was neutralized by slow addition of saturated aq sodium bicarbonate and then extracted with EtOAc. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-7-carboxamide (178 mg, 98%), which was used without further purification. LC-MS (ESI) m/z 365 (M+H)+.
Reaction SMILES: [Li][CH2:2]CCC.CCCCCC.[CH:12]([C:14]1[S:15][CH:16]=[C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:18]=1[CH3:19])=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:12]([C:14]1[S:15][CH:16]=[C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:18]=1[CH3:19])=[CH2:2]
Reactant: Cc1c(C2CCCCC2)csc1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCCCCC
Product: C=Cc1scc(C2CCCCC2)c1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (4.983 g, 13.96 mmol) in ether at 0° C. was added dropwise 1.6 M n-BuLi solution in hexane (8.7 ml, 13.96 mmol). The solution was stirred at 0° C. for 40 min and then was warmed to room temperature. A solution of 2-formyl-3-methyl-4-cyclohexylthiophene dimer (2.7 g, 6.98 mmol) in a minimum of ether was added. The solution was stirred overnight. The reaction mixture was then diluted with ether and washed with water and brine, and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by column chromatography using hexane as the eluant to afford 2-vinyl-3-methyl-4-cyclohexylthiophene dimer 1.32 g (50% yield) as a white solid. 1H NMR (CDCl3) δ 6.98 (s, 1H), 6.90 (dd, 1H), 5.52 (d, 1H), 1.15 (d, 1H), 2.22 (s, 1H), 2.19 (s, 1H), 2.11 (s, 1H), 2.10 (s, 1H), 2.09 (s, 1H), 2.08 (s, 1H). 13C NMR (CDCl3) δ 147.93, 146.37, 137.41, 136.09, 134.78, 129.97, 128.44, 127.57, 118.61, 112.7, 40.07, 38.86, 33.74, 31.37, 27.19, 26.91, 26.30, 26.12, 13.61, 13.33.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[C:9]([SH:11])#[N:10].N>CC(CC)=O>[S:11]([CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4])[C:9]#[N:10]
Reactant: N#CS
Reactant: CC(=O)C(Cl)CCCl
Agent: N
Solvent: CCC(C)=O
Product: CC(=O)C(CCCl)SC#N
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A suspension of 7.8 g (0.05 moles) of 3,5-dichloro-2-pentanone with 3.9 g (0.051 moles) of ammonium rhodanide in 50 cm3 of methyl-ethyl-ketone is boiled for 1 hour under stirring. Then the procedure described in Example 1 is followed. 8.5 g (95.5%) of 3-thiocyanato-5-chloro-2-pentanone are obtained, which after distillation is identical in all respect with the product of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C:5](Cl)=[O:6])[CH3:2].[C:9]([SiH2:13][O:14][C:15]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:16]1[N:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:21]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:8])[C:5]([C:22]1[N:20]2[CH:21]=[C:16]([C:15]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:14][SiH2:13][C:9]([CH3:12])([CH3:11])[CH3:10])[N:17]=[CH:18][C:19]2=[N:24][C:23]=1[CH3:25])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cn2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ncc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(C)nc2cnc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn12
Temperature: 120 °C
Yield: 64.3 %

Procedure:
In a reaction tube, chloro-oxo-acetic acid ethyl ester (0.51 ml, 4.5 mmol, 7.2 equiv) is added to a solution of 6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyrazine (250 mg, 0.62 mmol) in anhydrous THF (5 ml) under an atmosphere of argon. The tube is sealed under argon, and the reaction mixture is heated under microwave irradiation for 30 minutes at 120° C. After cooling, the reaction mixture is carefully poured into an aqueous solution of sodium carbonate. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/EtOAc 4:1) affords the title compound (200 mg, 64%). 1H NMR (400 MHz, d6-DMSO): δ=9.49 (d, J=1.4 Hz, 1H), 9.25 (d, J=1.4 Hz, 1H), 7.70-7.67 (m, 4H), 7.48-7.42 (m, 6H), 4.95(s, 2H), 4.47 (q, J=7.4Hz, 2H), 2.57 (s, 3H), 1.38 (t, J=7.4 Hz, 3H), 1.11 (s, 9H). MS (ES+): 502 (M+H)+.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH:15]=[O:16]>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([CH:15]([OH:16])[CH2:4][N+:1]([O-:3])=[O:2])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])CC(O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add nitromethane (200 mL) to a suspension of potassium carbonate (30 g) and 3,5-difluorobenzaldehyde (200 g) in tetrahydrofuran (600 mL) at room temperature. Stir at room temperature overnight, filter, wash with ethyl acetate and concentrate to give the desired compound as a crude oil (330 g) which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@H:7]([NH:8][C@@H](C2C=CC=CC=2)C)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>[Pd].C(O)C>[NH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:2]1([CH3:24])[CH3:1]
Reactant: [H][H]
Reactant: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)CC1(C)C)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)C(C)(C)C1
Reaction time: 5 h
Yield: 97.1 %

Procedure:
A pressure bottle was charged with palladium on carbon (0.192 g, 0.180 mmol) and (R)-tert-butyl 3,3-dimethyl-4-((R)-1-phenylethylamino)piperidine-1-carboxylate (3.00 g, 9.02 mmol) in ethanol (60 mL) and the resulting mixture was shaken under 50 psi of hydrogen on a Parr apparatus. After 5 h, the catalyst was removed by filtration, rinsed with methanol, and the filtrate was concentrated in vacuo to afford the title compound as a clear oil (2.0 g, 8.76 mmol, 97%). Material was not further purified and was used directly in next transformation. 1H NMR (500 MHz, methanol-d4) δ 4.07 (d, J=13.0 Hz, 1H), 3.78-3.62 (m, 1H), 3.01-2.62 (m, 2H), 2.56 (dd, J=11.1, 4.2 Hz, 1H), 1.74-1.63 (m, 1H), 1.51 (s, 9H), 1.49-1.43 (m, 1H), 1.00 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BrH:24].[NH+]1C=CC=CC=1.S([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:14]([Br:24])[NH:15]2)=[CH:11][CH:10]=1)(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Reactant: Br
Agent: O=S([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Yield: 78.3 %

Procedure:
To a solution of N-tert-butyl-3-cyclohexyl-1H-indole-6-sulfonamide (2.29 g, 6.86 mmol) in chloroform (30 ml) was added pyridinium hydrobromide perbromide (2.40 g, 7.50 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 30 min. 1M aqueous sodium hydrogen sulfite solution was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. A mixed solvent of hexane:ethyl acetate (5:1) was added to the residue. The precipitated solid was collected by filtration and dried in vacuo to give N-tert-butyl-2-bromo-3-cyclohexyl-1H-indole-6-sulfonamide (2.19 g, yield 78.3%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].[Na].[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:21][CH:20]=1.[OH-].[Na+]>C(O)C.O>[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][N:4]2[C:5](=[O:14])[C:6]3[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:15])=[CH:21][CH:20]=1
Reactant: COc1ccc(OCCCCBr)cc1
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCn1cnc2c1c(=O)n(CCCCOc1ccc(OC)cc1)c(=O)n2C
Yield: 64.8 %

Procedure:
3-Methyl-7-propylxanthine (10.4 g) was dissolved in 200 ml of an ethanol/water (3:2 (v/v)) mixed solution containing 2.2 g of sodium hyddroxide and 15.5 g of 4-(4-methoxyphenoxy)butylbromide was added to the solution. The mixture was then refluxed at elevated temperatures for 12 hours. The reaction mixture was concentrated under reduced pressure to give the residual liquid which in turn was alkalized with 1N-sodium hydroxide solution and then extracted with chloroform. The extract was dried and concentrated under reduced pressure to dryness. The residue was then subjected to silica gel column chromatography using a chloroform/ethanol (40:1 (v/v)) eluent to yield 12.5 g (65%) of 1-[4-(4-methoxyphenoxy)butyl]-3-methyl-7-propylxanthine.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].NC1C=CC2=NC(=O)N=C2C=1.O[C:19]1[C:20](C(Cl)=O)=[CH:21][C:22]2[C:27]([CH:28]=1)=C[CH:25]=[CH:24][CH:23]=2.OC1C(C(O)=O)=CC2C(C=1)=CC=CC=2>C1(C)C(C)=CC=CC=1.CN1CCCC1=O>[C:1]1(=[O:4])[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:28]=2)[CH:23]=[CH:24][CH2:25]1
Reactant: O=C(Cl)c1cc2ccccc2cc1O
Reactant: O=C([O-])[O-]
Agent: Nc1ccc2c(c1)=NC(=O)N=2
Agent: O=C(O)c1cc2ccccc2cc1O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN1CCCC1=O
Product: O=C1CC=Cc2ccccc21
Temperature: 100 °C
Reaction time: 6.5 h
Yield: 414.4 %

Procedure:
1750 ml of N-methylpyrrolidone are initially introduced into a 10 1 four-necked flask having a dropping funnel, reflux condenser, internal thermometer and stirrer. 291.5 g (2.75 mol) of sodium carbonate are added to this. 372.5 g (2.5 mol) of 5-aminobenzimidazolone are then added at about 25° C. 3181.8 g of 3-hydroxy-2-naphthoyl chloride (from 494.0 g (2.63 mol) of 3-hydroxy-2naphthoic acid) in xylene are metered into the suspension thus obtained with stirring in the course of 6.5 h at 25°-28° C. After addition is complete, the mixture is subsequently stirred at room temperature for 30 min. The precipitated product is filtered off with suction (suction time: 50 min) and the filter cake is washed in 10 portions with a total of 2150.0 g=2500 ml of xylene. 2500 ml of water are initially introduced into a 6 l four-necked flask having a stirrer, internal thermometer and distillation bridge having a 1 l one-necked flask as a receiver. The filter cake is then introduced. 200.0 g of sodium carbonate are then added and the mixture is heated to 100° C. Xylene and water distill off. The product is filtered off with suction at 100° C. and the suction filter cake is washed several times with a total of 6250 ml of water until neutral. 1571.4 g of naphthalone are obtained in water-moist form. After drying the filter cake at 100° C./100 mmHg, 681.7 g (2.135 mol) of 3-hydroxy-N-benzimidazolon-5-yl-2naphthamide are obtained; this corresponds to a yield of 85.4% of theory based on 5-aminobenzimidazolone.
Reaction SMILES: [NH2:1][CH:2]([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4].[C:9](OCC)(=O)[CH:10]=[O:11].[OH-].[Na+].Cl>O>[OH:4][C:3]1[C:2]([C:6]([NH2:8])=[O:7])=[N:1][CH:9]=[C:10]([OH:11])[N:5]=1
Reactant: CCOC(=O)C=O
Reactant: NC(=O)C(N)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ncc(O)nc1O
Reaction time: 0.67 h
Yield: 23 %

Procedure:
In 2.1 mL of water is suspended 0.5 g of 2-aminomalonamide. Under ice-cooling, 0.43 g of ethyl glyoxalate is added to the suspension, which is then stirred for 40 minutes. Then, 0.85 mL of 5 mol/mL sodium hydroxide is added to the resulting suspension, which is then stirred at the same temperature as above for 40 minutes. The reaction mixture is adjusted to pH 12 by adding 1 mol/L sodium hydroxide, and once made into a solution. The solution is then adjusted to pH 2 by adding 6 mol/mL hydrochloric acid. The deposited crystals are collected by filtration and washed successively with water and 50% (w/w) ethanol to obtain 0.15 g of 3,5-dihydroxy-2-pyrazinecarboxamide.
Reaction SMILES: [Cl:1]C1C=C(C=C(Cl)C=1)OCCCCl.[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:18][CH2:19][CH2:20][CH2:21]Br.[CH:27]([NH2:30])([CH3:29])[CH3:28]>C(Cl)(Cl)Cl>[ClH:1].[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:18][CH2:19][CH2:20][CH2:21][NH:30][CH:27]([CH3:29])[CH3:28]
Reactant: Clc1cc(Cl)cc(OCCCBr)c1
Reactant: CC(C)N
Reactant: ClCCCOc1cc(Cl)cc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)NCCCOc1cc(Cl)cc(Cl)c1
Product: Cl

Procedure:
Following the procedure of Preparation 1, a mixture of 3-[3,5-dichlorophenoxy]-1-chloropropane and 3-[3,5-dichlorophenoxy]-1-bromopropane and isopropyl amine were reacted in refluxing chloroform overnight and the reaction mixture processed to yield an oil, the free base of the title compound. A portion of the oil was reacted with ethereal hydrogen chloride to form the hydrochloride salt; m.p. 157°-159° C.