Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:16]1[CH2:21][CH2:20][O:19][C:18]2[CH:22]=[C:23]([C:26](=[O:32])[CH2:27][CH2:28]N(C)C)[CH:24]=[CH:25][C:17]1=2>O1CCOCC1.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[O:16]1[CH2:21][CH2:20][O:19][C:18]2[CH:22]=[C:23]([C:26](=[O:32])[CH2:27][CH2:28][C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:15])[CH:24]=[CH:25][C:17]1=2
Reactant: CN(C)CCC(=O)c1ccc2c(c1)OCCO2
Reactant: O=Cc1ccccc1
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(CCC(=O)c1ccc2c(c1)OCCO2)c1ccccc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
Triethylamine (3.61 mmol) and benzaldehyde (4.3 mmol) in dry dioxane (10 mL) was added to a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(dimethylamino)propan-1-one (XVI) (5.4 mmol) and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (0.43 mmol) in dioxane heated at 95° C. under nitrogen. The solution was further heated overnight at 95° C. The solution was cooled and excess solvent was evaporated under vacuum. The residue was partitioned between CH2Cl2 and water. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate in hexane gradient to yield 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-phenylbutane-1,4-dione 1 as a white solid (12% yield). 1H NMR (DMSO-d6, 400 MHz): δ ppm 3.33-3.37 (m, 4H), 4.29 (m, 2H), 4.34 (m, 2H), 6.98 (m, 1H), 7.48 (m, 1H), 7.55 (m, 3H), 7.64 (m, 1H), 8.00-8.02 (m, 2H); ESIMS found C18H16O4 m/z 297 (M+H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:4].Br[CH2:16][C:17](Br)=[O:18].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[C:17]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:13])([F:14])[F:1])=[C:7]([CH3:12])[CH:8]=1)(=[O:18])[CH3:16]
Reactant: O=C(Br)CBr
Reactant: Cc1ccccc1NC(=O)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc(NC(=O)C(F)(F)F)c(C)c1
Yield: 39.3 %

Procedure:
2,2,2-trifluoro-N-o-tolylacetamide (8.0 g; 39.4 mmol) was dissolved in 20 mL CS2. Bromoacetic bromide (8.4 g; 68.3 mmol) was added dropwise. AlCl3 (16.0 g; 120 mmol) was added in portions, with drying tube attached to the reaction flask. The reaction mixture was refluxed overnight. After reaction, the solvent was removed. Ice and water were added, and some yellow solid precipitated. The solid was isolated by filtration, and purified by silica gel column chromatography, to afford 3.8 g (yield 39%) of product as off-white solid. 1H NMR (300 MHz; CDCl3), δ 8.30 (s, 1H, Ar—H), 7.91 (brs, 1H, NH), 7.81 (d, 3JHH=8.2 Hz, 1H, Ar—H), 7.36 (d, 3JHH=7.9 Hz, 1H, Ar—H), 2.60 (s, 3H, COCH3), 2.36 (s, 3H, CH3).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]1[C:27]#[N:28].Cl.[NH2:30][OH:31].N1C=CC=CC=1>C(O)C>[OH:31][N:30]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]1[C:27]#[N:28]
Reactant: NO
Reactant: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=NO
Temperature: 25 °C
Yield: 75.6 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carbonitrile (293 mg, 0.80 mmol) obtained in Example 11 was dissolved in ethanol (20 mL), and hydroxylamine hydrochloride (167 mg, 2.41 mmol) and pyridine (254 mg, 3.21 mmol) were added thereto, refluxed for 3 hrs, and cooled to RT. The resulting mixture washed with saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 230 mg of 1-hydroxyimino-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carbonitrile (yield: 75%). Subsequently, 1-hydroxyimino-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carbonitrile (230 mg, 0.60 mmol) thus obtained was dissolved in methanol (20 mL), and 10%-palladium (230 mg) was added thereto. The mixture was stirred for 15 hrs at RT while providing H2 gas thereto using a balloon, filtered through celite, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 90 mg of the titled compound (yield: 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.O.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: NCC/C=C\c1cccc(Cl)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: NCCCCc1cccc(Cl)c1
Yield: 74.2 %

Procedure:
A solution of cis-4-(3-chlorophenyl)-but-3-enylamine (1.2 g) in 20 mL methanol was added to platinum(IV) oxide monohydrate (0.12 g). The mixture was stirred under 1 atm of hydrogen for 16 h. The mixture was filtered through celite, and the methanol was removed in vacuo to yield 0.9 g of 4-(3-chlorophenyl)-butylamine.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:31]=[CH:30][CH:29]=[CH:28][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([CH:26]=[CH2:27])=[CH:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1>CO.[Pd]>[CH2:26]([C:23]1[N:22]=[CH:21][C:20]([CH2:19][C:14]2[CH:15]=[C:16]3[C:11](=[C:12]4[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=24)[N:10]=[CH:9][N:8]([C@H:7]2[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]2[OH:1])[C:17]3=[O:18])=[CH:25][CH:24]=1)[CH3:27]
Reactant: C=Cc1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1
Reaction time: 15 h

Procedure:
To a solution of 3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-vinylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one (0.040 g, 0.097 mmol) in 2 mL of methanol was added palladium on carbon (8.0 mg, 0.075 mmol). The mixture was placed under an atmosphere of hydrogen (1 atm) for 15 h and was then filtered through a pad of Celite, which was washed with MeOH. The filtrate was concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 416.1960 for [M+H]+ [Calc'd for C25H26N3O3, [M+H]+=416.1969]: 1H NMR (400 MHz, CDCl3 δ 8.82 (d, J=7.9 Hz, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.60-7.52 (m, 3H), 737 (d, J=7.7 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 4.78-4.71 (m, 1H), 4.29-4.25 (m, 3H), 4.23 (s, 2H), 4.06-3.99 (m, 1H), 3.55 (t, J=11.2 Hz, 1H), 3.38-3.31 (m, 1H), 2.83 (q, J=7.4 Hz, 2H), 2.26-2.19 (m, 1H), 1.97-1.94 (m, 1H), 1.24 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([F:11])([F:10])[C:7]([F:13])([F:12])[C:6]=2[CH:14]=1.[C:15](Cl)(Cl)=[O:16].[F:19][CH:20]([F:39])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[NH:29][NH:30][CH2:31][C:32]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C(OCC)C.C(N(CC)CC)C>[F:11][C:8]1([F:10])[C:7]([F:13])([F:12])[C:6]2[CH:14]=[C:2]([NH:1][C:15]([N:30]3[CH2:31][C:32]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[C:28]([C:25]4[CH:24]=[CH:23][C:22]([O:21][CH:20]([F:19])[F:39])=[CH:27][CH:26]=4)[NH:29]3)=[O:16])[CH:3]=[CH:4][C:5]=2[O:9]1
Reactant: O=C(Cl)Cl
Reactant: FC(F)Oc1ccc(C2=C(c3ccccc3)CNN2)cc1
Reactant: Nc1ccc2c(c1)C(F)(F)C(F)(F)O2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)C(F)(F)C(F)(F)O2)N1CC(c2ccccc2)=C(c2ccc(OC(F)F)cc2)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.75 g (0.0036 mole) of the 5-amino-2,2,3,3-tetrafluorobenzofuran of part A, dissolved in 109 ml of toluene, was added dropwise to a stirred solution of 8.0 ml 20% phosgene in toluene. After complete addition the mixture was heated at reflux for two hours. The mixture was cooled and the solvent removed by evaporation under reduced pressure leaving a residue. This residue was dissolved in 15 ml of diethyl ether and added to a stirred solution of 1.04 g (0.0036 mole) 3-(4-difluoromethoxyphenyl)-4-phenylpyrazoline and three drops of triethylamine in 100 ml of diethyl ether. After complete addition the mixture was heated at reflux for one hour, then cooled to room temperature and stirred for approximately 18 hours. The solvent was removed from the reaction mixture by evaporation under reduced pressure leaving a solid residue. Recrystallization from ethanol provided 0.99 g of N-(2,2,3,3-tetrafluorobenzofuran-5-yl)-3-(4-difluoromethoxyphenyl)-4-phenylpyrazoline-1-carboxamide (mp 155°-159° C.). The nmr spectrum and elemental analysis were consistent with the proposed structure.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH2:19])[N:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:19][C:5](=[O:7])[CH3:6])[N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(N)cc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc2ccccc2c(C)n1
Reaction time: 3.5 h

Procedure:
Acetic anhydride (1.4 mL, 15 mmol) was added to a suspension of Example 141A (0.79 g, 5.0 mmol) and triethylamine (0.76 ml, 5.5 mmol) in CH2Cl2 (20 mL) at ambient temperature. The mixture was stirred for 3.5 hours, then the volatiles were removed under reduced pressure. The residue was chased with toluene (3×25 mL) and then concentrated under reduced pressure to provide the title compound. MS (ESI) m/z 201 (M+H)+.
Reaction SMILES: C([O:3][P:4]([O:21]CC)([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:5])C.[OH-].[K+]>C(OCC)C.O>[P:4](/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([OH:18])=[O:17])([OH:21])([OH:5])=[O:3]
Reactant: CCOC(=O)CNc1ccccc1C=CP(=O)(OCC)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)CNc1ccccc1/C=C/P(=O)(O)O
Yield: 12.3 %

Procedure:
A solution of ethyl N-[2-[2-(diethoxyphosphinyl)ethenyl]phenyl]glycinate (Example 2b)(1.3 g, 3.8 mmol) in diethyl ether (15 ml) is treated with potassium trimethylsilanoate (0.54 g, 4.2 mmol) and stirred over the weekend. The diethyl ether is removed and the oily residue suspended in acetonitrile (50 ml) and stirred under a nitrogen atmosphere for 30 minutes and further treated with trimethylsilylbromide (3 ml) and stirred at room temperature for four hours. 1H-NMR indicates some ester remains so the acetonitrile is removed and the residue is treated with a solution of potassium hydroxide (0.56 g, 10 mmol) in water (3 ml) and stirred for 16 hours. The water is removed and the residue purified on Dowex 50×400 ion exchange resin (water and 2N ammonium hydroxide as eluants). The desired material (fluorescent on tlc under uv light, ninhydrin positive) is obtained from the water eluate as a light, green-white solid (0.12 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>ClCCCl.[Cl-].[Zn+2].[Cl-]>[Cl:13][C:11]1[CH:12]=[C:7]([O:6][CH3:5])[CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[C:25](=[O:26])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: COc1ccc(CC(=O)c2c(Cl)cc(OC)cc2OC)cc1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To 1,2-dichloroethane (500 mL) were added anhydrous aluminum chloride (50.5 g) and zinc chloride (5.72 g), followed by stirring for 15 min. Under ice-cooling, a solution of 1,3-dimethoxy-5-chlorobenzene (55 g) in 1,2-dichloroethane (140 mL) was added. The mixture was cooled to −25° C. and 4-methoxyphenylacetyl chloride (53.9 mL) in 1,2-dichloroethane (250 mL) was added drop-wise. The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was cooled to 0° C., quenched with 1.0 N HCl (300 mL), and the resulting suspension was filtered through Celite and silica gel using ethyl acetate. Chromatography on silica gel (eluant: 10–40% ethyl acetate/hexane) provided the title compound (39 g). 1H NMR (DMSO-d6): 7.07 (d, 2H, J=8.77 Hz), 6.85 (d, 2H, J=8.77 Hz), 6.62 (m, 2H), 3.94 (s, 2H), 3.80 (s, 6H), 3.72 (s, 3H); MS: 321 (MH+).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[CH2:12][O:11]CC1.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](=[O:46])[CH:23]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:24](=[O:39])[CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([O:34][C:35]([F:38])([F:37])[F:36])[CH:28]=2)=[CH:16][C:15]=1[O:47][C:48]([F:51])([F:50])[F:49].[C:52](OC(=O)C)(=[O:54])[CH3:53]>O>[C:52]([O:33][C:30]1[CH:31]=[CH:32][C:27]([CH:26]=[CH:25][C:24](=[O:39])[CH:23]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:22](=[O:46])[CH:21]=[CH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:12](=[O:11])[CH3:8])=[C:15]([O:47][C:48]([F:49])([F:50])[F:51])[CH:16]=2)=[CH:28][C:29]=1[O:34][C:35]([F:37])([F:38])[F:36])(=[O:54])[CH3:53]
Reactant: CC(=O)OC(C)=O
Reactant: C1CCOC1
Reactant: COC(=O)CCC(C(=O)C=Cc1ccc(O)c(OC(F)(F)F)c1)C(=O)C=Cc1ccc(O)c(OC(F)(F)F)c1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCC(C(=O)C=Cc1ccc(OC(C)=O)c(OC(F)(F)F)c1)C(=O)C=Cc1ccc(OC(C)=O)c(OC(F)(F)F)c1

Procedure:
Triethylamine 270 mg was added under room temperature to a THF 10 mL solution containing 1,7-bis(4′-hydroxy-3′-trifluoromethoxyphenyl)-4-methoxycarbonylethyl 1,6-heptadiene 3,5-dione 500 mg and acetic anhydride 272 mg, and the resultant solution was agitated for 2 hours at room temperature. After the reaction was ended, water was poured, and the resultant solution was subjected to extraction with ethyl acetate. The extract was dried with sodium sulfate, and the solvent was removed. The crystal residue was washed with a small quantity of ethanol, filtered, and dried, whereby 430 mg of 1,7-bis(4′-acetoxy-3′-trifluoromethoxyphenyl)-4-methoxycarbonylethyl-1,6-heptadiene-3,5-dione having a melting point of 149 to 150° C. was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:10](Br)[CH2:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH2:3]1.[CH:12]([NH:15][CH2:16][CH:17]([OH:20])[CH2:18]O)([CH3:14])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[CH:12]([NH:15][CH2:16][CH:17]([OH:20])[CH2:18][O:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1)([CH3:14])[CH3:13]
Reactant: O=C1Cc2scnc2CC1Br
Reactant: CC(C)NCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)NCC(O)COc1ccc2ncsc2c1
Reaction time: 49 h
Yield: 57 %

Procedure:
A mixture of 6-oxo-5-bromo-4,5,6,7-tetrahydrobenzothiazole (100 parts), 3-isopropylamino-1,2-propanediol (67 parts), p-toluenesulfonic acid monohydrate (99 parts) and toluene (1550 parts) is heated under reflux for 21 hours while drying the refluxing azeotropic mixture according to the method described in Example I. After cooling, the reaction mixture is adjusted to pH 9 by adding aqueous 2.5N-sodium hydroxide and formed organic layer is separated. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The remaining 4'-isopropylaminomethyl-5-bromo-4,5,6,7-tetrahydrobenzothiazole-6-spiro-2'-[1,3]-dioxolane (156 parts) is dissolved in piperidine (1560 parts), and stirred for 49 hours on an oil bath heated at 95° to 100° C. The reaction mixture is concentrated under reduced pressure to leave residue which is mixed with ethyl acetate and water, shaken and fractionated to separate formed organic layer. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residue (172 parts) is recrystallized from ethanol-hydrochloric acid giving 6-(3-isopropylamino-2-hydroxypropoxy)benzothiazole) (65 parts) in 57% yield. mp. 132°-134° C. (hydrochloride trihydrate).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:33])[CH:14]([C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:20][CH:21]=2)[CH3:15])=[CH:9][C:8]=1[CH2:34][CH2:35][CH2:36][O:37][CH3:38])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:38][O:37][CH2:36][CH2:35][CH2:34][C:8]1[CH:9]=[C:10]([N:13]([CH3:33])[CH:14]([C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)=[CH:20][CH:21]=2)[CH3:15])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)COc1ccc(N(C)C(C)c2ccc(-c3cccc(C(F)(F)F)c3)nc2C)cc1CCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCc1cc(N(C)C(C)c2ccc(-c3cccc(C(F)(F)F)c3)nc2C)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
0.015 g (0.03 mmol) of the above prepared [rac]-[2-(3-methoxy-propyl)-4-(methyl-{1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-ethyl}-amino)-phenoxy]-acetic acid ethyl ester was dissolved in 0.2 ml of THF/EtOH=1/1, treated with 0.09 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 0.5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer washed with water and brine, dried over sodium sulfate, and evaporated to dryness to leave 0.012 g of the title compound as light brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O:11][C:12](=O)[CH:13]([CH3:15])[OH:14])(=O)C.N=C=N>O>[C:12]([C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=1)(=[O:11])[CH:13]([CH3:15])[OH:14]
Reactant: CC(=O)OC(=O)C(C)O
Reactant: Nc1ccncc1
Agent: N=C=N
Solvent: O
Product: CC(O)C(=O)c1cc(N)ccn1
Reaction time: 24 h

Procedure:
A mixture of 4-aminopyridine (5 mmol) and lactyl acetate (5 mmol) is added to 0.1M carbodiimide [N-cyclohexyl-N′-2-(4-methyl-morpholinium) ethyl carbodiimide-p-toluene sulphonate or CMC] in distilled water adjusted to pH 4.5, such that the final volume is 200 ml. The reaction is performed for 24 hours at 4° C. The resulting lactyl-4-aminopyridine is collected as an oil and purified to pharmaceutical purity.
Reaction SMILES: Cl[C:2]1[C:3]([F:20])=[CH:4][N:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][CH3:13])[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:19].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[F:20][C:3]1[C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[CH:11][C:10]2[N:5]([C:6](=[O:19])[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][C:9]=2[NH:12][CH3:13])[CH:4]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cc(NC)c2cc(Cl)c(F)cn2c1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NC)c2cc(N3CCN(C)CC3)c(F)cn2c1=O
Temperature: 70 °C

Procedure:
Ethyl 8-chloro-7-fluoro-1-methylamino-4H-quinolizin-4-one-3-carboxylate (899 mg, 3.0 mmol), the product of Step 6, is suspended in 12 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution is added 6.0 mL (6.0 mmol) of N-methylpiperazine and the reaction mixture is heated at 70° C. for 8 hours. The reaction mixture is then concentrated in vacuo in order to remove all of the pyridine. The dry residue is dissolved in 125 mL of methylene chloride and the methylene chloride solution is washed with 125 mL of brine. The aqueous layer is extracted with 125 mL of methylene chloride and the combined methylene chloride solutions are dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford the title compound.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[C:16]([CH2:20][C:21](Cl)=[O:22])([CH3:19])([CH3:18])[CH3:17].[F:24][C:25]([F:36])([F:35])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:20][C:21]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:34]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH2:26][C:25]([F:24])([F:35])[F:36])=[CH:29][CH:30]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)=[O:22]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Product: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(OCC(F)(F)F)cc1)C2=O

Procedure:
Off-white crystalline solid. MS (ESI): 427.3 (MH+). This example was prepared in analogy to example 7 step A) to B) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), tert-butyl acetyl chloride and 4-(2,2,2-trifluoro-ethoxy)-phenylamine.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[CH:20]=1)=[O:13]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[N:23]1[CH:22]=[CH:21][N:19]2[CH:20]=[C:15]([CH:14]3[CH2:8][CH2:9][CH2:10][CH2:11][S:12]3=[O:13])[CH:16]=[CH:17][C:18]=12
Reactant: O=S(CCCCCl)Cc1ccc2nccn2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=S1CCCCC1c1ccc2nccn2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
8.68 g of potassium t-butoxide was added to 80 ml of a tetrahydrofuran/hexamethylphosphoric triamide [4:1 (v/v)] mixture, followed by the cooling with ice. A solution of 9.51 g of the 6-((4-chlorobutyl)sulfinylmethyl)imidazo [1,2-a]pyridine prepared in the Preparative Example 8 in 80 ml of a tetrahydrofuran/hexamethylphosphoric triamide [4:1 (v/v)] mixture was dropped into the obtained mixture. The obtained mixture was stirred for one hour, followed by the addition of ice-water. The obtained mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The obtained oil was solidified by allowing to stand, followed by the addition of ether. The obtained mixture was filtered to give 5.84 g of the title compound as a dark-creamy powder (yield: 71%). The NMR spectroscopic analysis of this powder revealed that the powder was a mixture comprising two diastereomers at a ratio of about 2:1.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[C:19]3=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]3[CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>C1COCC1>[C:33]([N:15]1[CH2:16][CH2:17][N:18]2[C:19](=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23]2)[C@@H:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=S1(=O)CCN2CCN[C@@H](c3ccc(Oc4ccccc4)cc3)C2=N1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCN2CCS(=O)(=O)N=C2[C@@H]1c1ccc(Oc2ccccc2)cc1
Reaction time: 20 h

Procedure:
A mixture of (9S)-9-(4-phenoxyphenyl)-3,4,6,7,8,9-hexahydropyrazino[2,1-c][1,2,4]thiadiazine 2,2-dioxide (129 mg), triethylamine (0.100 mL) and acetyl chloride (0.026 mL) in THF (4 mL) was stirred at 0° C. to room temperature for 20 hr. The reaction mixture was added with water, and the precipitate was filtered. The collected solid was purified by recrystallization from MeOH-EtOAc then preparative HPLC (C18, MeCN in H2O with 10 mM NH4HCO3). The combined collected fractions were concentrated in vacuo. The resulting solid was recrystallized from EtOAc-IPE to give the title compound (60 mg) as a white solid.