Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:13])[CH:6]([CH3:12])[C:7]([O:9][CH2:10]C)=[O:8])C.C[O-].[Na+].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CO>[CH3:2][O:4][C:5](=[O:13])[C:6]([CH3:12])([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Reaction time: 0.5 h

Procedure:
11.5 g (0.5 mol) of sodium in a stream of nitrogen was placed in a dry 1000 ml three-necked flask with a reflux condenser, a drying tube and a dropping funnel with pressure compensation. Next, 350 ml of methanol was carefully added dropwise and agitated until the sodium had completely dissolved. A methanolic solution of 87 g (0.5 mol) methylmalonic acid diethyl ester was added very slowly dropwise to the sodium methanolate solution, which was still warm. At the end of the addition, the mixture was stirred for a further 30 minutes, after which 4-nitrobenzyl bromide was added in portions, using a powder funnel. After everything had dissolved, the mixture was first reflux-heated for two hours and then agitated at room temperature overnight. The solvent was removed in a rotary evaporator and water was added to the residue, which was repeatedly extracted with ethyl acetate (250 ml portions). The combined organic extracts were washed with saturated common salt solution and dried over sodium sulphate. After removing the solvent, faintly yellow crystals were left. Recrystallisation was from dimethyl formamide (DMF) and water.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][CH:29]1[CH2:31][O:30]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CC2CO2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Yield: 47 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 2-bromomethyl-oxirane gave the title compound in 47% yield. ES-MS m/e (%): 423.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
0.25 g (0.94 mmol) of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1M]), 0.15 g (1.03 mmol) of phthalimide and 0.32 g (1.20 mmol) of triphenylphosphine were dissolved in 10 ml of THF. The stirred reaction mixture was cooled down to 0° C. and a solution of 0.27 g (1.15 mmol) of di-tert.-butyl azodicarboxylate in 2 ml of THF was added drop by drop. Then, the reaction was warmed up to ambient temperature. After 1 hour, the solvent was evaporated and the residue purified by crystallization from MeCl2 and n-heptane to give 0.32 g of the title compound as a colorless solid.
Reaction SMILES: Br.C([O:9][C:10]1[CH:15]=[CH:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:12](=[O:28])[C:11]=1[Cl:29])C1C=CC=CC=1>C(O)(=O)C>[Cl:29][C:11]1[C:12](=[O:28])[N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:21][CH:22]=2)[CH:14]=[CH:15][C:10]=1[OH:9]
Reactant: O=c1c(Cl)c(OCc2ccccc2)ccn1Cc1ccc(OC(F)(F)F)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=c1c(Cl)c(O)ccn1Cc1ccc(OC(F)(F)F)cc1
Temperature: 130 °C

Procedure:
Hydrobromic acid (0.1 ml) was added to a mixture of intermediate D15 (4.5 g, 10.98 mmol) in acetic acid (20 ml). The solution was heated at 130° C. for 30 minutes under microwave irradiation. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was treated with an aqueous saturated solution of NaHCO3 until the solution reached a pH of approximately 8. The white solid that precipitated was collected by filtration and washed with cold DIPE to yield intermediate D16 (1.1 g, 31%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[CH2:11][C@@H:10]2[C@@H:12]([NH2:15])[CH2:13][CH2:14][C@@H:9]2[CH2:8]1.Br[CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:22]([NH:15][C@@H:12]1[C@@H:10]2[C@@H:9]([CH2:8][N:7]([CH2:6][C:5]3[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:1])[F:20])[CH:4]=3)[CH2:11]2)[CH2:14][CH2:13]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(CN2C[C@H]3CC[C@H](NC(c4ccccc4)c4ccccc4)[C@H]3C2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(3aR,4S,6aS)-2-(3-(Trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine (60 mg, 0.211 mmol), from Example 156 Step A was combined with (bromomethylene)dibenzene (62.6 mg, 0.253 mmol) and potassium carbonate (87 mg, 0.633 mmol) in N,N-dimethylformamide (1 mL). The reaction was stirred at room temperature for 72 hours. The reaction was quenched with water and extracted with diethyl ether. The ether extracts were washed with water (3×1 mL) and the solvent removed. The crude material was purified using a 12 g silica gel cartridge eluting with a gradient of 0-3% methanol (2 N ammonia)/dichloromethane to give (3aR,4S,6aS)-N-benzhydryl-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.71 (s, 1H), 7.64-7.59 (m, 4H), 7.52 (d, J=7.7, 1H), 7.44 (t, J=7.7, 1H), 7.33 (td, J=7.6, 4.7, 4H), 7.25-7.21 (m, 4H), 5.09 (s, 1H), 3.51 (q, J=13.5, 2H), 3.02 (dd, J=12.9, 5.5, 1H), 2.63-2.54 (m, 1H), 2.51 (dd, J=8.8, 2.8, 1H), 2.47-2.41 (m, 1H), 2.37 (t, J=8.0, 1H), 2.32-2.25 (m, 2H), 1.98 (td, J=11.4, 5.6, 1H), 1.89 (ddd, J=12.7, 10.4, 5.8, 1H), 1.45 (ddd, J=14.7, 11.9, 8.1, 1H), 1.32-1.23 (m, 1H); MS (ESI+) m/z 451 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH2:31]([NH2:33])[CH3:32]>>[Cl:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:33][CH2:31][CH3:32])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Product: CCNCC1Cc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1

Procedure:
The title compound was prepared (0.068 g, 56%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-fluoro-7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.32 mmol) and ethylamine (0.138 g, 3.2 mmol). mp 138.140° C.
Reaction SMILES: BrC1C(Br)[C:9]2[C:4](=[CH:5][C:6]([F:12])=[CH:7][CH:8]=2)/[C:3]/1=[CH:13]/[C:14]([NH2:16])=[O:15].[CH2:17]([CH2:20][O:21]C)[O:18]C>O.C(=O)([O-])[O-].[Ag+2]>[OH:21][CH:20]1[CH:17]([OH:18])[C:9]2[C:4](=[CH:5][C:6]([F:12])=[CH:7][CH:8]=2)/[C:3]/1=[CH:13]/[C:14]([NH2:16])=[O:15]
Reactant: COCCOC
Reactant: NC(=O)/C=C1/c2cc(F)ccc2C(Br)C1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: NC(=O)/C=C1/c2cc(F)ccc2C(O)C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of (Z)-2-(2,3-dibromo-6-fluoro-1-indanylidene)acetamide (0.54 g, 1.55 mmoles) and silver carbonate (0.56 g, 2.03 mmoles, Aldrich) in dimethoxyethane (15 mL) and water (30 mL) was refluxed for 6 hours. The mixture was stirred overnight at ambient temperature and refluxed again for 6 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (6×30 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with hexane:ethyl acetate (2:1). The fractions containing the compound with Rf=0.15, eluting with ethyl acetate, were combined and evaporated in vacuo to give 0.12 g (35%) of crude (Z)-2-(2,3-dihydroxy-6-fluoro-1-indanylidene) acetamide as a beige solid. Recrystallization from ethyl acetate:hexane mixtures gave 0.037 g (11%) of (Z)-2-(2,3-dihydroxy-6-fluoro-1-indanylidene)acetamide as an off-white solid which was shown by 1H-NMR to be a mixture (85:15) of diastereomers, mp 212-220° C., 1H-NMR (DMSO-d6): d 7.82 (d, 2H, 7.28-7.76 (m, 3H), 6.96 (s, 1H), 6.80 (s, 0.15H), 6.54 (s, 0.85H), 6.51 and 6.12 (m, 0.3H), 5.92 (d, 1H), 4.81 (m, 1.7H); steady-state nOe: irradiation at 6.47d, observed 20% nOe at 7.38d.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)(=[O:6])=[O:5])[CH3:2].Cl>CO>[CH2:16]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)(=[O:6])=[O:5])[CH3:17]
Reactant: CCN(CC)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Product: CCN(CC)S(=O)(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The N,N-diethyl-3-(nitro)benzenesulfonamide (3.9 g) was dissolved in methanol (60 ml) and, after an addition of conc. hydrochloric acid (10 ml), reduced iron (4.2 g) was added and the mixture was stirred at room temperature for 2 hours. After filtration, methanol was evaporated under a reduced pressure and the residue was made basic with an addition of 4N sodium hydroxide. The iron oxide precipitated was separated by filtration, washed with methylene chloride (50 ml). Also the filtrate was extracted with methylene (50 ml×2) and combined with the methylene chloride washing, followed by drying over anhydrous sodium sulfate. Evaporation of the solvent gave N,N-diethyl-3-(amino)benzenesulfonamide (3.0 g) (m.p. 82°-84° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:28][C:29]([OH:31])=O)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[O:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=2)[CH2:16][CH2:15]1.C1C=CC2N(O)N=NC=2C=1.O.C[CH2:44][N:45]=[C:46]=NCCCN(C)C.Cl.Cl.CNC>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:28][C:29]([N:45]([CH3:46])[CH3:44])=[O:31])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[O:24][N:23]=[C:22]([CH:25]([CH3:26])[CH3:27])[N:21]=2)[CH2:18][CH2:19]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)O)cc3F)CC2)n1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)N(C)C)cc3F)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution of 2-(3-fluoro-4-((((1R,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)methoxy)methyl)phenyl)acetic acid (Step D product, 60 mg, 0.139 mmol), HOBT.H2O (32 mg, 0.209 mmol), and EDC.HCl (40 mg, 0.209 mmol) dissolved in DCM (1 mL) was stirred at rt for 30 min. Dimethylamine hydrochloride (35 mg, 0.431 mmol) was added to this solution and the reaction aged at rt for 3 hrs. The reaction mixture was then diluted with DCM (1 mL) and the residue loaded directly onto 2×2000 micron silica preparative TLC plates (uv 254 active) which were developed using 100% EtOAc as the solvent system. The desired silica (Rf=0.4 @ 100% EtOAc) was collected and extracted to give the title compound (37 mg, 58%). 1H NMR (500 MHz, CD3CN) δ 7.37 (t, 1H), 7.06 (d, 1H), 6.99 (d, 1H), 4.52 (q, 2H), 3.99 (dd, 2H), 3.69 (s, 2H), 3.64 (q, 1H), 3.27 (t, 1H), 3.02 (s, 3H), 3.01-2.90 (m, 2H), 2.88 (s, 3H), 2.84 (t, 1H), 1.94 (d, 1H), 1.78 (d, 1H), 1.41-1.26 (m, 2H), 1.23 (s, 6H), 1.20-1.14 (m, 1H), 1.06-0.96 (m, 1H), 0.77 (p, 2H), 0.02 (q, 1H). LC/MS (m/z): 459 (M+H)+, GPR119 Human EC50: 1.6 nM.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[CH2:13]([O:15][CH2:16][C@H:17]([O:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][N:33]=3)[N:30]=[CH:31][C:24]=12)[C:18](OC)=[O:19])[CH3:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:18](=[O:19])[C@@H:17]([O:22][C:23]2[C:24]3[CH:31]=[N:30][N:29]([C:32]4[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][N:33]=4)[C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:16][O:15][CH2:13][CH3:14])=[N:10][CH:11]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1C(F)(F)F)C(=O)OC
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1C(F)(F)F)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
A solution of trimethylaluminium (2M in hexane) (0.322 mL, 0.64 mmol) was added dropwise to a stirred solution of 5-chloropyridin-2-amine (CAS no. 1072-98-6) (79 mg, 0.62 mmol) in toluene (5 mL) at 0° C., over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. A solution of (2S)-methyl 3-ethoxy-2-(1-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate Q1) (230 mg, 0.56 mmol) in toluene (5 mL) was added dropwise over a period of 2 minutes. The resulting solution was stirred at 0° C. for 10 minutes, allowed to warm to ambient temperature and then heated at 60° C. for 20 hours. The resulting mixture was allowed to cool and 1M citric acid (10 mL) added with vigorous stirring. Ethyl acetate (35 mL) and water (10 mL) were added and the organic phase was separated, washed with water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 50 to 100% ethyl acetate in isohexane and then chiral preparative HPLC to give the product (90 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 1.22 (3H, t), 3.60-3.68 (2H, m), 4.06-4.15 (2H, m), 6.05 (1H, t), 7.64-7.70 (2H, m), 8.22-8.25 (2H, m), 8.29 (1H, dd), 8.43 (1H, s), 8.62 (1H, s), 8.84 (1H, s)8.89 (1H, dd); m/z (ESI+) (M+H)+=508: HPLC tR=2.35 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:17]([CH3:19])([CH3:18])[C:16]([CH3:20])=[N:15][C:5]2=[N+:6]([CH2:8][CH2:9][CH2:10][S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=1.[CH3:21][C:22]1[C:30]([CH3:32])([CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([S:33]([O-:36])(=[O:35])=[O:34])[CH:28]=2)[N+:23]=1[CH2:37][CH2:38][CH2:39][S:40]([O-:43])(=[O:42])=[O:41].[Na+:44].[Br-].[Br:46]/[C:47](=[CH:56]\NC1C=CC=CC=1)/[CH:48]=[NH+]/C1C=CC=CC=1.C(OC(=O)C)(=O)C>C(OCC)C.N1C=CC=CC=1>[Br:46]/[C:47](/[CH:56]=[CH:20]/[C:16]1[C:17]([CH3:19])([CH3:18])[C:4]2[C:5]([N:15]=1)=[N+:6]([CH2:8][CH2:9][CH2:10][S:11]([O-:14])(=[O:13])=[O:12])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:48]\[CH:21]=[C:22]1\[N:23]([CH2:37][CH2:38][CH2:39][S:40]([O-:43])(=[O:42])=[O:41])[C:24]2[C:29]([C:30]\1([CH3:31])[CH3:32])=[CH:28][C:27]([S:33]([O-:36])(=[O:35])=[O:34])=[CH:26][CH:25]=2.[Na+:44].[Na+:44]
Reactant: CC1=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C
Reactant: BrC(=C\Nc1ccccc1)/C=[NH+]/c1ccccc1
Reactant: CC1=Nc2c(cc(Cl)c[n+]2CCCS(=O)(=O)[O-])C1(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC1(C)C(/C=C/C(Br)=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Temperature: 115 °C
Yield: 130.1 %

Procedure:
A 100-mL round-bottom flask fitted with a reflux condenser was charged with 3-(5-chloro-2,3,3-trimethyl-3H-pyrrolo[2,3-b]pyridin-7-ium-7-yl)propane-1-sulfonate (55, 500 mg), sodium 2,3,3-trimethyl-1-(3-sulfonatopropyl)-3H-indolium-5-sulfonate (4, 500 mg), (E)-N—((Z)-2-bromo-3-(phenylamino)allylidene)benzenaminium bromide (8, 100 mg), pyridine (1 mL), and acetic anhydride (10 mL) were added to the flask. The mixture was heated at 115° C. for 2 h, allowed to cool to room temperature, and diluted with ethyl ether (25 mL). The resulting dark blue dye precipitate was collected by filtration, dissolved in water (20 mL), and purified by preparative reverse-phase HPLC to afford the 9 as a blue powder (285 mg, 50%, UV 668 nm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:38])=[CH:23][C:24]([CH3:37])([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1)[CH3:25])(=O)C>O1CCCC1>[F:38][C:22](=[CH:23][C:24]([CH3:37])([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=1)[CH3:25])[CH2:21][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Reactant: CC(=O)OCC(F)=CC(C)(C)c1ccc(OC(F)(F)F)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C=C(F)Cc1ccc(F)c(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Yield: 31.7 %

Procedure:
The method of Example 16 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.4 g), tetrahydrofuran (4 ml) and magnesium (26 mg), and 2-fluoro4-methyl-4-(4-trifluoromethoxyphenyl)pent-2-enyl acetate (Example 15) (90 mg). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) to give the title compound (40 mg, 33%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:14][NH:13][C:12](=[O:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25](I)[CH3:26]>>[CH2:25]([N:13]1[C:12](=[O:24])[CH:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:14]1)[CH3:26]
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Reactant: CCI
Product: CCn1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)c(F)c2)cc1=O
Yield: 97.8 %

Procedure:
Using 5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one and ethyl iodide as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained in a yield of 97.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([NH:8][C:9]2[S:10][C:11]([CH3:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=3)[N:13]=2)[CH:7]=1.O.O.Cl[Sn]Cl>CO>[NH2:20][C:16]1[CH:15]=[C:14]([C:12]2[N:13]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:24][CH3:25])[S:10][C:11]=2[CH3:23])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(Cl)cc1Nc1nc(-c2cccc([N+](=O)[O-])c2)c(C)s1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1ccc(Cl)cc1Nc1nc(-c2cccc(N)c2)c(C)s1

Procedure:
A mixture of 12z (0.25 g, 0.66 mmol) and SnCl2.2H2O (1.35 g, 6.0 mmol) in methanol was refluxed for 48 h. Evaporation of the solvent under reduced pressure afforded 4-(3aminophenyl)-N-(5-chloro-2-methoxyphenyl)-5-methylthiazol-2-amine as a solid which was dissolved in chloroform and cooled in an ice bath to 0° C. Triethylamine (93 μL, 0.66 mmol) was added and the mixture was stirred for 15 min at the same temperature. Pivaloyl chloride (0.08 g, 0.66 mmol) was then added dropwise at 0° C. and the mixture was stirred overnight at which point the mixture was poured onto ice-cold water and the aqueous layer was extracted with DCM. The collected organic extract was washed with sat. aq. NaHCO3 and brine, dried over anhydrous MgSO4, and filtered. Evaporation of the solvent under reduced pressure afforded 13z as a yellowish white solid (0.21 g, 75%). Mp decomposition at 195° C. 1H NMR (300 MHz, CDCl3): δ 7.83 (s, 1H), 7.76 (s, 1H), 7.45 (m, 1H), 7.38 (d, J=2.40 Hz, 1H), 7.33 (s, 1H), 7.27 (m, 1H), 6.93 (d, J=9.0 Hz, 1H), 3.89 (s, 3H), 2.42 (s, 3H), 1.33 (s, 9H). 13C NMR (150 MHz, CDCl3): δ 177.4, 168.4, 151.5, 139.1, 129.9, 127.8, 125.9, 124.3, 123.6, 121.3, 120.3, 118.5, 114.5, 113.3, 111.4, 111.0, 56.4, 39.9, 27.7, 12.5. HRMS m/z (ESI) calcd. for C22H24ClN3O2S (M+H)+ 430.1351. Found 430.1345.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]([CH2:20]C3CC3)[C:10](=[O:11])[CH2:9][N:8]=2)=[CH:5][CH:6]=1.[OH-].[NH4+]>>[CH3:20][N:12]1[C:10](=[O:11])[CH2:9][N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]1=2.[CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[NH:12][C:10](=[O:11])[CH2:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1CC1CC1
Agent: [NH4+]
Agent: [OH-]
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reaction time: 0.08 h

Procedure:
50 μl of internal standard (15 mg/L prazepam) were added to 1.0 ml of serum sample. Concentrated ammonium hydroxide (0.2 ml) was added prior to extraction with 4.5 ml of n-butyl chloride. The samples were shaken for 5 minutes and then centrifuged. The organic layer was removed and evaporated. The sample was reconstituted in 25 μl ethanol; 2 μl were then injected into the gas chromatograph. Quantitation was done by comparison to standard curves obtained for diazepam and nordiazepam.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[CH2:17][O:16][C:7]2([CH2:14][CH:13]3[CH:9]([CH2:10][C:11](=O)[CH2:12]3)[CH2:8]2)[O:6][CH2:5]1>C1COCC1>[CH2:5]([O:6][C:7](=[O:16])[CH:8]=[C:11]1[CH2:12][CH:13]2[CH:9]([CH2:8][C:7]3([O:16][CH2:17][C:4]([CH3:18])([CH3:3])[CH2:5][O:6]3)[CH2:14]2)[CH2:10]1)[CH3:4]
Reactant: CC1(C)COC2(CC3CC(=O)CC3C2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CC2CC3(CC2C1)OCC(C)(C)CO3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 140.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 134 mg, 3.34 mmol) was suspended in THF (2 mL) and cooled to 0° C. Triethylphopsphonoacetate (0.55 g, 2.45 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min. The product of Step 1 (500 mg, 2.229 mmol) was added dropwise as a solution in THF (0.5 mL) and the reaction mixture was stirred 16 hrs while warming from 0° C. to room temperature. The mixture was partitioned between EtOAc and water, the organic layer dried over Na2SO4, concentrated under reduced pressure and the residue was purified by flash chromatography (7 to 60% EtOAc in hexanes) to give ethyl[5,5-dimethyltetrahydro-1′H-spiro[1,3-dioxane-2,2′-pentalen]-5′(3′H)-ylidene]ethanoate (460 mg, 1.563 mmol, 70.1% yield) as a colorless oil. MS ESI: [M+Na]+ m/z 295.7.
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12]C>>[C:7]1([C@@H:5]([OH:4])[CH3:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCCC
Reactant: C=C(C)OC(C)=O
Product: C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
(R, S)-1-Phenylethanol (0.244 gram, 2 mmol) and isopropenyl acetate (0.2 gram, 2 mmol) were dissolved in 10 ml of n-hexane dried in advance on Molecular Sieve 4A for one day. To the resulting solution was added 1 gram of an enzyme (Amano P: Product of Amano Seiyaku K. K.), and the mixture was stirred at 25° C. and 150 r.p.m. for 4 hours. The reaction mixture was filtered, and the filtrate was subjected to HPLC using an optically active column. (S)-1-phenylethanol was obtained in an optical purity of 100% with a theoretical yield of 100%.